Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
METHODS AND DEVICES FOR TREATING POSTERIOR OCULAR
DISORDERS WITH AFLIBERCEPT AND OTHER BIOLOGICS
CROSS REFERENCE TO RELATED APPLICATIONS
[1001] This
application claims priority to U. S. Provisional Application No. 62/276,543,
filed January 8, 2016; and U.S. Provisional Application No. 62/324,708, filed
on April 19,
2016, each of which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[1002]
Treatment of chronic retinal diseases, such as neovascular (wet) age related
macular degeneration (AMD), often require intravitreal injections of a
biological drug, such
as Lucentis, Eylea or Avastin to prevent vision loss. Additionally, wet AMD
patients often
show new blood vessel formation from the choroid. Wet AMD affects the choroid
and retina
and specific targeting of these tissues might is therefore needed in
modulating disease
progression.
[1003] RVO is a
condition that affects vision, resulting from a blockage in one of the
veins returning blood flow from the retina. RVO is the second most common
cause of vision
loss due to retinal vascular disease. RVO affects 16.4 million adults
worldwide, according to
a 2010 study published in the journal Ophthalmology (Rogers et al. (2010).
Ophthalmology
117, pp. 313-319)). Inadequately treated macular edema associated with RVO can
cause
significant loss in visual acuity and eventually lead to blindness.
[1004] The
present invention provides novel methodology and devices for the treatment
of macular edema associated with uveitis, macular edema following retinal vein
occlusion
(RVO) (also referred to herein as wet AMD associated with RVO), wet AMD,
diabetic
macular edema (DME), choroidal neovascularization (CNV), and/or wet AMD
associated
with CNV, thereby addressing key needs in the field of ocular therapeutics.
SUMMARY OF THE INVENTION
[1005] This
invention is generally related to ophthalmic therapies, and more particularly
to methods and devices that allow for infusion of a fluid drug formulation
into posterior
ocular tissues for targeted, localized treatment, for example, for the
treatment of wet AMD or
1
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
wet AMD associated with RVO or wet AMD associated with choroidal
neovascularization.
In some embodiments, the drug formulation includes aflibercept and is injected
into SCS to
provide localized drug in the choroid and retina. In some embodiments, the
methods
comprise administering an anti-inflammatory, an anti-VEGF, an anti-PDGF, or an
anti-
angiopoetin drug formulation to the SCS of a subject. In further embodiments,
the methods
comprise administering a biologic to a subject concomitantly or sequentially
with the
administration of the anti-inflammatory, anti-VEGF, anti-PDGF, or anti-
angiopietin to the
SCS. In some embodiments, the biologic is administered intravitreally. In some
embodiments, the biologic is a VEGF modulator (e.g., aflibercept). In some
embodiments,
the anti-inflammatory drug formulation comprises triamcinolone acetonide (TA).
Surprisingly, the SCS administration of an anti-inflammatory, anti-VEGF, anti-
PDGF, or
anti-angiopietin enhances or improves the effectiveness of a biologic in the
treatment of an
ocular disease.
[1006] In some
embodiments, the drug formulation administered SCS and the biologic
act synergistically to improve treatment of an ocular disease in a subject.
[1007] In one
embodiment of the method for treating wet AMD, choroidal
neovascularization (CNV) and/or the method for treating wet AMD associated
with CNV,
subsequent to at least one dosing session, e.g., from about 1 week to about 14
weeks after at
least one dosing dession, e.g., about 12 weeks after a dosing session, the
patient experiences
an improvement in visual acuity as measured by best corrected visual acuity
of? 10 letters,?
15 letters or? 25 letters, as compared to patient's visual acuity prior to the
at least one dosing
session. In one embodiment of the method for treating macular edema associated
with
uveitis, subsequent to at least one dosing session, e.g., from about 1 week to
about 14 weeks
after at least one dosing dession, e.g., about 4 weeks, about 8 weeks or about
12 weeks after
at least one dosing session, the patient experiences a decrease in retinal
thickness (e.g.,
central subfield thickness) as compared to the patient's retinal thickness
prior to the at least
one dosing session. In one embodiment, the decrease in retinal thickness is >
25 p.m, > 50
> 75 p.m or > 100 [tm.In some embodiments, the methods set forth herein are
carried out
by inserting a distal end portion of a needle of a medical injector into a
target tissue to define
a delivery passageway within the target tissue and such that a distal end
surface of a hub of
the medical injector is in contact with a target surface of the target tissue.
A force is exerted
(e.g., a manual force by a user) on an actuator of the medical injector when
the distal end
2
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
surface of the hub is in contact with the target surface. The medical injector
is configured
such that the force is sufficient to move a distal end portion of the actuator
within the
medicament container when the distal end portion of the needle is disposed
within a first
region of the target tissue. The medical injector is configured such that the
force is
insufficient to move the distal end portion of the actuator within the
medicament container
when the distal end portion of the needle is disposed within a second region
of the target
tissue. In some embodiments, the force has a magnitude of less than about 6 N.
A substance,
e.g., a drug formulation, in response to the exertion, is conveyed from the
medicament
container into the target tissue via the needle when the distal end portion of
the needle is
disposed within the first region of the target tissue. The first region can
be, for example, a
suprachoroidal space of the eye, a lower portion of the sclera and/or an upper
portion of the
choroid. In some embodiments, the first region can be a retina of the eye.
[1008] In some
embodiments of the methods provided herein, a distal end portion of a
needle of a medical injector is inserted into a target tissue to define a
delivery passageway
within the target tissue. The insertion is performed such that a centerline of
the needle and a
surface line tangent to a target surface of the target tissue define an angle
of entry of between
about 75 degrees and about 105 degrees. A distal end surface of a hub of the
medical injector
is placed into contact with a target surface of the target tissue to
fluidically isolate the
delivery passageway. After the distal end surface of the hub is placed into
contact with the
target surface, a substance, e.g., drug formulation, is conveyed into the
target tissue via the
needle.
[1009] In some
embodiments, a distal end portion of a needle of a medical injector is
inserted into an eye to define a delivery passageway within a sclera of the
eye. After the
distal end portion of the needle is inserted into the eye, a force (e.g., a
manual force by a user)
is applied to the medical injector when a distal tip of the needle is disposed
within at least one
of a suprachoroidal space or a lower portion of the sclera, the force being
insufficient to
convey the substance from the medicament container via the needle when the
distal tip of the
needle is disposed within an upper portion of the sclera of the eye. In some
embodiments, a
method of treating wet age-related macular degeneration (AMD) or choroidal
neovascularization (CNV) in a human subject in need thereof is provided
herein. The method
includes, in a dosing session, non-surgically administering an effective
amount of an
aflibercept drug formulation comprising a first drug to the suprachoroidal
space (SCS) of the
3
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
eye of the human subject in need of treatment of the wet AMD or the CNV. In
other
embodiments, the method includes non-surgically administering an effective
amount of an
anti-inflammatory, an anti-VEGF, an anti-PDGF, or an anti-angiopoetin to the
SCS of the eye
of the human subject in need of treatment of the wet AMD or the CNV. In
further
embodiments, the method further comprises intravitreal administration of a
biologic. In yet
further embodiments, the biologic is an anti-VEGF, an anti-PDGF, or an anti-
angiopoetin. In
still further embodiments, the biologic is aflibercept.
[1010] In some
embodiments, a method of treating wet age-related macular degeneration
(AMD) in a human subject in need thereof is provided herein. In some
embodiments, the
method includes, in a dosing session, non-surgically administering an
effective amount of an
aflibercept drug formulation comprising a first drug to the suprachoroidal
space (SCS) of the
eye of the human subject in need of treatment of the wet AMD. Upon
administration, the
aflibercept drug formulation flows away from the insertion site and is
substantially localized
to the posterior segment of the eye. In some embodiments, the wet AMD is
associated with
choroidal neovascularization (CNV) in the human subject. In a further
embodiment, a VEGF
inhibitor is administered to the patient intravitreally.
[1011] In one
aspect, a method of improving the effectiveness of a biologic in the
treatment of an ocular disease in a human subject is provided herein, wherein
the
administration of the biologic is coupled with SCS administration of an anti-
inflammatory,
anti-VEGF, anti-PDGF, or anti-angiopoetin agent. In some embodiments, the
biologic and
the agent administered SCS act synergistically to improve effectiveness of
treatment of the
ocular disease. In some embodiments, the biologic is a VEGF modulator such as
aflibercept.
In some embodiments, the administration of the anti-inflammatory drug reduces
the number
of VEGF modulator drug treatments necessary to treat the ocular disease. In
another aspect,
a method of treating macular edema associated with retinal vein occlusion
(RVO) in a human
subject in need thereof is provided herein. In some embodiments, the methods
comprise
administering to the human subject an effective amount of a VEGF modulator,
and non-
surgically administering an effective amount of an anti-inflammatory drug to
the
suprachoroidal space (SCS) of the eye of the human subject. In some
embodiments, the
combination therapy acts synergistically relative to administration of either
drug alone.
[1012] In some
embodiments, the anti-inflammatory drug is selected from the group
consisting of a steroid and a non-steroid inflammatory drug (NSAID). In
further
4
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
embodiments, the steroid is triamcinolone acetonide (TA). In some embodiments,
the TA is
administered to the SCS of the human subject at a dose level of about 2 mg,
about 3 mg,
about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or
about 10 mg. In
some embodiments, the TA is administered to the SCS of the human subject at a
dose level of
about 4 mg.
[1013] In some
embodiments, the VEGF modulator is administered to the subject
intravitreally. In some embodiments, the VEGF modulator is a VEGF antagonist
selected
from a VEGF-receptor kinase antagonist, an anti-VEGF antibody or fragment
thereof, an
anti-VEGF receptor antibody, an anti-VEGF aptamer, a small molecule VEGF
antagonist, a
thiazolidinedione, a quinoline or a designed ankyrin repeat protein (DARPin).
In some
embodiments, the VEGF antagonist is aflibercept, ziv-aflibercept, bevacizumab,
sonepcizumab, VEGF sticky trap, cabozantinib, foretinib, vandetanib,
nintedanib,
regorafenib, cediranib, ranibizumab, lapatinib, sunitinib, sorafenib,
plitidepsin, regorafenib,
verteporfin, bucillamine, axitinib, pazopanib, fluocinolone acetonide,
nintedanib, AL8326,
2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3
antibody, AT001/r84 antibody, HyBEV, ANG3070, APX003 antibody, APX004
antibody,
ponatinib, BDM-E, VGX100 antibody, VGX200, VGX300, COSMIX, DLX903/1008
antibody, ENMD2076, INDUS815C, R84 antibody, KDO19, NM3, MGCD265, MG516,
MP0260, NT503, anti-DLL4NEGF bispecific antibody, PAN90806, Palomid 529,
BD0801
antibody, XV615, lucitanib, motesanib diphosphate, AAV2-sFLT01, soluble FM
receptor,
AV-951, Volasertib, CEP11981, KH903, lenvatinib, lenvatinib mesylate,
terameprocol,
PF00337210, PRS050, SP01, carboxyamidotriazole orotate, hydroxychloroquine,
linifanib,
ALG1001, AGN150998, MP0112, AMG386, ponatinib, PD173074, AVA101, BMS690514,
KH902, golvatinib (E7050), dovitinib, dovitinib lactate (TKI258, CHIR258),
ORA101,
ORA102, Axitinib (Inlyta, AG013736), PTC299, pegaptanib sodium, troponin,
EG3306,
vatalanib, Bmab100, GSK2136773, Anti-VEGFR Alterase, Avila, CEP7055, CLT009,
ESBA903, GW654652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593,
Nova21012, Nova21013, CP564959, smart Anti-VEGF antibody, AG028262, AG13958,
CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647,
enzastaurin hydrochloride, BC194, COT601M06.1, C0T604M06.2, MabionVEGF,
Apatinib,
RAF265 (CHIR-265), Motesanib Diphosphate (AMG-706), Lenvatinib (E7080), TSU-68
(SU6668, Orantinib), Brivanib (BMS-540215), MGCD-265, AEE788 (NVP-AEE788),
ENMD-2076, OSI-930, CYC116, Ki8751, Telatinib, KRN 633, SAR131675, Dovitinib
(TM-
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
258) Dilactic Acid, Apatinib, BMS-794833, Brivanib Alaninate (BMS-582664),
Golvatinib
(E7050), Semaxanib (SU5416), ZM 323881 HC1, Cabozantinib malate (XL184), ZM
306416,
AL3818, AL8326, 2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin0),
ANG3070, APX003 antibody, APX004 antibody, ponatinib (AP24534), BDM-E, VGX100
antibody (VGX100 CIRCADIAN), VGX200 (c-fos induced growth factor monoclonal
antibody), VGX300, COSMIX, DLX903/1008 antibody, ENMD2076, sunitinib malate
(Sutent0), INDUS815C, R84 antibody, KDO19, NM3, allogenic mesenchymal
precursor
cells combined with an anti-VEGF antagonist (e.g., anti-VEGF antibody),
MGCD265,
MG516, VEGF-Receptor kinase inhibitor, MP0260, NT503, anti-DLL4NEGF bispecific
antibody, PAN90806, Palomid 529, BD0801 antibody, XV615, lucitanib (AL3810,
E3810),
AMG706 (motesanib diphosphate), AAV2-sFLT01, soluble Fitt receptor, cediranib
(RecentinTm), AV-951, tivozanib (KRN-951), regorafenib (Stivarga0), volasertib
(BI6727),
CEP11981, KH903, lenvatinib (E7080), lenvatinib mesylate, terameprocol
(EM1421),
ranibizumab (Lucentis0), pazopanib hydrochloride (VotrientTm), PF00337210,
PRS050,
SPO1 (curcumin), carboxyamidotriazole orotate, hydroxychloroquine, linifanib
(ABT869,
RG3635), fluocinolone acetonide (Iluvien0), ALG1001, AGN150998, DARPin MP0112,
AMG386, ponatinib (AP24534), AVA101, nintedanib (Vargateffm), BMS690514,
KH902,
golvatinib (E7050), everolimus (Afinitor0), dovitinib lactate (TKI258,
CHIR258), ORA101,
ORA102, axitinib (Inlyta0, AG013736), plitidepsin (Aplidin0), PTC299,
aflibercept
(Zaltrap0, Eylea0), pegaptanib sodium (MacugenTm, LI900015), verteporfin
(Visudyne0),
bucillamine (Rimatil, Lamin, Brimani, Lamit, Boomiq), R3 antibody, AT001/r84
antibody,
troponin (BLS0597), EG3306, vatalanib (PTK787), Bmab100, GSK2136773, Anti-
VEGFR
Alterase, Avila, CEP7055, CLT009, ESBA903, HuMax-VEGF antibody, GW654652,
HMPL010, GEM220, HYB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012,
Nova21013, CP564959, Smart Anti-VEGF antibody, AG028262, AG13958, CVX241,
SU14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastaurin
hydrochloride (LY317615), BC194, quinolines, COT601M06.1, C0T604M06.2,
MabionVEGF, SIR-Spheres coupled to anti-VEGF or VEGF-R antibody, Apatinib
(YN968D1), or AL3818.
[1014] In some
embodiments, the VEGF modulator is aflibercept, and the aflibercept is
administered intravitreally to the human subject at a dose level of about 0.5
mg, about 1 mg,
about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg,
about 6 mg,
6
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments, the
aflibercept is
administered intravitreally to the human subject at a dose level of about 2
mg.
[1015] In some
embodiments, the VEGF modulator is administered intravitreally to the
subject concomitantly with the SCS administration of the anti-inflammatory
drug. In other
embodiments, the VEGF modulator and anti-inflammatory drug are administered
sequentially.
[1016] In some
embodiments, the methods provided herein decrease retina thickness
and/or macula thickness relative to a baseline measurement prior to treatment
of the subject
with the VEGF modulator or anti-inflammatory drug. In other embodiments, the
methods
provided herein decrease retina thickness and/or macula thickness relative to
a subject that
received the VEGF modulator but did not receive the anti-inflammatory drug
administered to
the SCS. In some embodiments, the retinal thickness is central subfield
thickness (CST). In
further embodiments, the CST is measured by spectral domain optical coherence
tomography
(SD-OCT). In some embodiments, the CST is decreased by at least about 20 p.m,
at least
about 40 p.m, at least about 50 p.m, at least about 100 p.m, at least about
150 p.m, or at least
about 200 p.m.
[1017] In some
embodiments, the methods provided herein increase a Best Corrected
Visual Acuity (BCVA) of the subject relative to a baseline measurement prior
to treatment of
the subject with the VEGF modulator or anti-inflammatory drug. In other
embodiments, the
methods provided herein increase the BCVA of the subject relative to a subject
that received
the VEGF modulator but did not receive the anti-inflammatory drug administered
to the SCS.
In some embodiments, the BCVA is assessed using an Early Treatment of Diabetic
Retinopathy Study (ETDRS) visual acuity charts protocol. In further
embodiments, the
increase in the BVCA is a gain of about 5, about 6, about 7, about 8, about 9,
about 10, about
15, about 20, about 25, about 30, or more letters.
[1018] In some
embodiments, the present disclosure provides methods for improving
anti-VEGF therapy (e.g., aflibercept therapy) in subjects suffering from RVO
by
administering a steroid formulation to the SCS of the eye of the subject. In
some
embodiments, the present disclosure provides methods for treating subjects
suffering from
RVO comprising administering an effective amount of a VEGF modulator and an
anti-
inflammatory drug to the eye of the subject. In some embodiments, the
administration is
7
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
surgical, and comprises, for example, insertion of a stent, shunt, or cannula.
In other
embodiments, the administration is non-surgical, for example, via injection.
In some
embodiments, the RVO is BRVO or CRVO. In other embodiments, the RVO is
ischemic or
non-ischemic RVO. In some embodiments the RVO is ischemic CRVO. In some
embodiments, the present disclosure provides surprisingly effective treatments
for ischemic
CRVO patients. In some embodiments, the present disclosure provides methods of
treatment
for ischemic CRVO patients that result in an increase in BVCA of 10, 12, 14,
16, 18, 20, 22,
24, 26, 28, 30, 32, 34, 36, 38, 40, or more letters. In some embodiments, the
steroid
formulation is administered to the SCS of the eye of the subject. In some
embodiments, the
steroid formulation is non-surgically administered to the SCS of the eye of
the subject. In
some embodiments, the steroid formuation is administered non-surgically to the
SCS of the
eye of the subject and the VEGF modulator is administered by intravitreal
injection.
[1019] In some embodiments, the present disclosure provides methods for
treating a
subject suffering from ischemic CRVO, the method comprising administering
aflibercept and
TA. In some embodiments, the aflibercept and/or TA is administered surgically.
In other
embodiments, the aflibercept and/or TA is administered non-surgically. In some
embodiments, the aflibercept is administered intravitreally in one or more
doses; and the TA
is nonsurgically administered to the SCS in one or more doses. In some
embodiments, the
method for treating RVO provided herein, comprising administration of a VEGF
modulator
(e.g., aflibercept) in combination with administration of the anti-
inflammatory drug, reduces
the need to retreat the subject with additional doses of the VEGF modulator.
In some
embodiments, the assessment for the need for retreatment with the VEGF
modulator is
assessed by the CST, BVCA, or a combination thereof In some embodiments, the
VEGF
modulator is aflibercept, and the aflibercept is administered intravitreally;
and the anti-
inflammatory drug is TA.
BRIEF DESCRIPTION OF THE DRAWINGS
[1020] FIG. 1 is a cross-sectional view of an illustration of the human
eye.
[1021] FIG. 2 is a cross-sectional view of a portion of the human eye of
FIG. 1 taken
along the line 2-2.
8
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1022] FIGS. 3 and 4 are cross-sectional views of a portion of the human
eye of FIG. 1
taken along the line 3-3, illustrating the suprachoroidal space without and
with, respectively,
the presence of a fluid.
[1023] FIG. 5 is a perspective view of a medical injector according to an
embodiment.
[1024] FIG. 6 is a partially exploded view of the medical injector of FIG.
5.
[1025] FIG. 7 is an exploded view of the medical injector of FIG. 5, shown
without a
needle cap.
[1026] FIG. 8 is a front view of a handle included in the medical injector
of FIG. 5.
[1027] FIG. 9 is a cross-sectional view of the handle of FIG. 8 taken along
the line 9-9.
[1028] FIG 10 is a perspective view of a barrel included in the medical
injector of FIG. 5.
[1029] FIG. 11 is an exploded view of a needle hub included in the medical
injector of
FIG. 5.
[1030] FIG. 12 is a front view of the needle hub of FIG. 9.
[1031] FIG. 13 is an enlarged view of a portion of the needle hub of FIG.
12, identified
by the region Zl.
[1032] FIG. 14 is a rear perspective view of a needle cap included in the
medical injector
of FIG. 5.
[1033] FIG. 15 is a front view of the medical injector of FIG. 5.
[1034] FIG. 16 is a cross-sectional view of the medical injector of FIG. 5,
taken along the
like 16-16 in FIG. 15.
[1035] FIG. 17 is a view of the medical injector of FIG. 5 in use during an
injection
procedure into the human eye.
[1036] FIG. 18 is an enlarged view of a portion of the medical injector of
FIG. 5 and the
human eye, identified in FIG. 17 by the region Z2.
9
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1037] FIG. 19 is an exploded view of a needle hub configured for use with
the medical
injector of FIG. 5, according to an embodiment.
[1038] FIG. 20 is a front view of the needle hub of FIG. 19.
[1039] FIG. 21 is a flowchart illustrating a method of using a medical
injector to inject a
medicament into an eye.
[1040] FIG. 22 is a graph of mean change in intraocular pressure vs. hours
or weeks post-
treatment.
[1041] FIG. 23 is a graph of improvement in best corrected visual acuity
(mean change in
visual acuity score (letters read) from baseline (base logMAR) vs. weeks post-
treatment. 0.1
logMAR = 1 line = 5 letters.
[1042] FIG. 24 is a plot of mean reduction in retinal thickness vs. weeks
post-treatment.
[1043] FIG. 25 are optical coherence tomography images of the eyes of a
bilateral
chronic uveitis patient with macular edema, prior to (top images) and
subsequent to (bottom
images) SCS TA injection (left 2 images) or sub-tenon TA injection (right 2
images).
[1044] FIG. 26 are optical coherence tomography images of the eyes of a
bilateral
chronic uveitis patient with macular edema, prior to (top images) and
subsequent to (bottom
images) SCS TA injection (right 2 images, right eye) or Ozurdex (dexamethasone
0.7 mg
intravitreal implant) (left 2 images, left eye).
[1045] FIG. 27 illustrates distribution in various parts of the eye
following intravitreal
and SCS injection of Triesence in rabbits.
[1046] FIGS 28A-F illustrate distribution of TA in various parts of the eye
(28A: sclera-
choroid-outer retina; FIG. 28B: inner retina; FIG. 28C: vitreous; FIG. 28D:
aqueous humour;
FIG. 28E: lens; FIG. 28F: iris-ciliary body) following intravitreal and SCS
injection of
Tri es ence.
[1047] FIGS. 29 and 30 illustrate TA concentration for Trisence and CLS-TA
over a 90-
day period in either the sclera-choroid-outer retina (FIG. 29) or the inner
retina (FIG. 30).
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1048] FIG. 31 is a bar graph showing the cumulative ophthalmoscopy
inflammation
scores (mean SD) for each treatment group. Group 1: Negative control (LPS /
BSS SCS);
Group 2: Oral high dose prednisone (LPS / Prednisonel mg/kg/day PO); c: Group
2 mean
cumulative inflammation score on Day 3 was significantly lower than Group 1 (p
< 0.034);
Group 3: CLS-TA (LPS / 2 mg CLS-TA) a: Group 3 mean cumulative inflammation
score
on Day 1 was significantly lower than Group 1 (p = 0.04); b: Group 3 mean
cumulative
inflammation score on Day 2 was significantly lower than Group 1 (p=0.023); d:
Group 3
mean cumulative inflammation score on Day 3 was significantly lower than Group
1 (p <
0.034); Group 4: Oral low dose prednisone (LPS / Prednisone 0.1 mg/kg/day PO).
[1049] FIG. 32 is a bar graph showing the intraocular pressure (mmHg; mean
SD) for
each treatment group over the study period. Group 1: Negative control (LPS /
BSS SCS);
Group 2: Oral high dose prednisone (LPS / Prednisonel mg/kg/day PO); Group 3:
CLS-TA
(LPS / 2 mg CLS-TA); Group 4: Oral low dose prednisone (LPS / Prednisone 0.1
mg/kg/day
PO); Group 4 mean IOP on Day 3 was significantly lower than Groups 1, 2, and 3
(P<0.0065).
[1050] FIG. 33 are graphs showing the mean histologic score for various
treatment
groups for the anterior segment (left) and posterior segment (right).
[1051] FIG. 34A is a bar graph showing mean lesion area 3 weeks post-laser
induced
choroidal neovascularization in a rat model, with rats treated, via the
suprachoroidal space,
either with saline or Eylea. FIG. 34B is a bar graph showing mean lesion area
22 days post-
laser induced choroidal neovascularization in a rat model, with rats treated,
via the
intravitreal space, either with saline. Anti-VEGF antibodies, or Eylea.
[1052] FIG. 35 is a chart showing an experimental protocol for laser
induced choroidal
neovascularization in a rat model.
[1053] FIG. 36 is a timeline for the experimental protocol of FIG. 35.
[1054] FIG. 37A is a bar graph showing mean lesion area 3 weeks post-laser
induced
choroidal neovascularization in a rat model, including the bar graphs of FIG.
34A as single-
injection treated animals, and further including additional plots to show data
for double-
injection treated animals. FIG. 37B illustrates the bar graph of FIG. 34B,
repeated herein for
direct comparison with FIG. 37A.
11
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1055] FIG. 38
is a bar graph showing mean lesion area 3 weeks post-laser induced
choroidal neovascularization in a rat model, for rats treated with saline or
Eylea, including
single-injection animals treated via the suprachoroidal space, double-
injection animals treated
via the suprachoroidal space, and single-injection animals treated via the
intravitreal space.
[1056] FIG. 39
is a bar graph showing some of the plots of FIG. 38 for direct comparsion,
including single-injection animals treated via the suprachoroidal space with
Eylea, and
single-injection animals treated via the intravitreal space with saline or
Eylea..
[1057] FIG. 40
is a bar graph showing some of the plots of FIG. 38 for direct comparison,
including single-injection animals treated via the suprachoroidal space and
double-injection
animals treated via the suprachoroidal space.
[1058] FIG. 41
is a bar graph showing the number of additional IVT injections of
aflibercept (EYLEAO) that were required in the Control Arm (IVT aflibercept
alone) versus
the Active Arm (aflibercept + SCS CLS-TA) of the study provided in Example 4.
[1059] FIG. 42
is a bar graph showing the improvement in BCVA at Month 3 in the
Active Arm (aflibercept + SCS CLS-TA) compared to the Control Arm (aflibercept
only) in
the study provided in Example 4.
[1060] FIG. 43
is a bar graph showing improvement in BCVA (the y axis represents the
BCVA letters read, change from baseline) at months 1, 2, and 3 in the Active
Arm
(aflibercept + SCS CLS-TA) compared to the Control Arm (aflibercept only) in
the study
provided in Example 4. At month 1, the Control group exhibited an 11.4
increase in BCVA
letters, and the Active group exhibited an increase in 16.1 letters; thus, at
month 1, the Active
arm provided a 4.7 letter increase relative to control. At month 2, the
Control group exhibited
an 11.9 increase in BCVA letters, and the Active group exhibited an increase
in 20.4 letters;
thus, at month 2, the Active arm provided an 8.5 letter increase relative to
control. At month
3, the Control group exhibited an 11.3 increase in BCVA letters, and the
Active group
exhibited an increase in 18.9 letters; thus, at month 3, the Active arm
provided a 7.6 letter
increase relative to control.
[1061] FIG. 44
is a bar graph showing that the Active arm (SCS-CLS-TA with IVT
aflibercept (EYLEAO)) exhibited an improvement in macular edema relative to
the control
arm (IVT aflibercept (EYLEAO) only) at month 3. Subjects in the Active group
exhibited
12
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
reduced central subfield thickness (CST) by 446 microns, while subjects in the
Control group
exhibited reduced CST by 343 microns, showing an increased reduction in
retinal thickness
of 103 microns for the Active group over the Control group.
[1062] FIG. 45
is a bar graph showing that the improvement in macular edema was also
present at months 1 and 2. At month 1, subjects in the Active group exhibited
a CST reduced
by 446 compared to a CST reduction of 405 in the Control group. At month 2,
subjects in the
Active group exhibited a CST reduced by 459 compared to a CST reduction of 344
in the
Control group.
[1063] FIG. 46
shows the patient number and percentage qualified for additional Eylea
treatment (aflibercept) for branch retinal vein occlusion (BRVO) and central
retinal vein
occlusion (CRVO) patients in both the Active and the Control groups. Both BRVO
and
CRVO patients in the Active group exhibited lower percentage qualified for
additional
aflibercept (21% and 22%, respectively) compared to the percentage qualified
for additional
aflibercept in the Control arm in BRVO and CRVO patients (67% and 71%,
respectively).
[1064] FIG. 47
shows the mean of central subfoveal thickness (CST) in subjects with
branch retinal vein occlusion (BRVO) treated either by aflibercept + Zuprata
(Active group)
or aflibercept + sham (control group). At month 1, subjects in both treatment
groups
exhibited reduced mean CST (approximately 300 p.m). At month 2, subjects in
Active group
maintained similar mean CST compared to an increased mean CST in subjects in
control
group (291 p.m vs. 455 p.m). At month 3, subjects in both treatment groups
exhibited similar
mean CST (approximately 300 p.m). IVT: Intravitreal.
[1065] FIG. 48
shows the mean changes in central subfoveal thickness (CST) in subjects
with branch retinal vein occlusion (BRVO) treated either by aflibercept +
Zuprata (Active
group) or aflibercept + sham (Control group). At month 1, subjects in Active
group exhibited
a CST reduced by 343 p.m compared to a CST reduction of 272 p.m in the control
group (71
p.m differences between the groups). At month 2, subjects in Active group
exhibited a CST
reduced by 347 p.m compared to a CST reduction of 130 p.m in the Control group
(217 p.m
differences between the groups). At month 3, subjects in Active group
exhibited a CST
reduced by 343 p.m compared to a CST reduction of 281 p.m in the Control group
(62 p.m
differences between the groups). IVT: Intravitreal.
13
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1066] FIG. 49
shows the mean best corrected visual acuity (BCVA) in subjects with
branch retinal vein occlusion (BRVO) treated either by aflibercept + Zuprata
(Active group)
or aflibercept + sham (Control group). Subjects in both treatment groups
exhibited increased
BCVA from baseline to month 3. At month 2, subjects in the Active group
exhibited higher
mean BCVA compared to the mean BCVA in control group (71 vs. 67,
respectively). IVT:
Intravitreal.
[1067] FIG. 50
shows the mean changes in best corrected visual acuity (BCVA) in
subjects with branch retinal vein occlusion (BRVO) treated either by
aflibercept + Zuprata
(Active group) or aflibercept + sham (Control group). At month 1, subjects in
Active group
exhibited an increased mean BCVA by score of 13 compared to an increased mean
BCVA by
score of 14 in the control group (1 score difference between the groups). At
month 2, subjects
in Active group exhibited an increased mean BCVA by score of 16 compared to an
increased
mean BCVA by score of 12 in the Control group (4 scores differences between
the groups).
At month 3, subjects in Active group exhibited an increased mean BCVA by score
of 17
compared to an increased mean BCVA by score of 18 in the Control group (1
score
difference between the groups)
[1068] FIG. 51
the mean of central subfoveal thickness (CST) in subjects with central
retinal vein occlusion (CRVO) treated either by aflibercept + Zuprata (Active
group) or
aflibercept + sham (Control group). At month 1, subjects in both treatment
groups exhibited
reduced mean CST (268 p.m vs. 326 p.m) compared to the mean CST at baseline
(876 p.m vs.
778 p.m). From month 1 to month 3, subjects in Active group consistently
exhibited lower
mean CST compared to the mean CST of the control group. IVT: Intravitreal.
[1069] FIG. 52
shows the mean changes in central subfoveal thickness (CST) in subjects
with central retinal vein occlusion (CRVO) treated either by aflibercept +
Zuprata (Active
group) or aflibercept + sham (Control group). At month 1, subjects in Active
group exhibited
a CST reduced by 607 p.m compared to a CST reduction of 452 p.m in the Control
group (156
p.m reduction between the groups). At month 2, subjects in Active group
exhibited a CST
reduced by 632 p.m compared to a CST reduction of 420 p.m in the Control group
(212 p.m
reduction between the groups). At month 3, subjects in Active group exhibited
a CST reduced
by 603 p.m compared to a CST reduction of 365 p.m in the Control group (238
p.m reduction
between the groups). IVT: Intravitreal.
14
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1070] FIG. 53
shows the mean best corrected visual acuity (BVCA) in subjects with
central retinal vein occlusion (CRVO) treated either by aflibercept + Zuprata
(Active group)
or aflibercept + sham (Control group). Subject in both treatment groups
exhibited increased
BCVA from baseline to month 1 (40 vs. 47 to 61 vs. 57). At month 2, subjects
in Active
group exhibited a further higher mean BCVA compared to decreased mean BCVA in
control
group (67 vs. 55, respectively). At month 3, subjects in Active group
exhibited the mean
BCVA of score of 62 compared to mean BCVA of score of 52 in control group.
IVT:
Intravitreal.
[1071] FIG. 54
shows the mean changes in best corrected visual acuity (BCVA) in
subjects with central retinal vein occlusion (CRVO) treated either by
aflibercept + Zuprata
(Active group) or aflibercept + sham (Control group). At month 1, subjects in
Active group
exhibited an increase of mean BCVA by score of 21 compared to an increase of
mean BCVA
by score of 10 in the control group (11 scores differences between the
groups). At month 2,
subjects in Active group exhibited an increase of mean BCVA by scrore of 27
compared to
an increase of mean BCVA by score of 9 (18 scores differences between the
groups) in
control group. At month 3, subjects in Active group exhibited an increase of
mean BCVA by
score of 22 compared to an increase of mean BCVA by score of 6 in the Control
group (16
scores differences between the groups). IVT: Intravitreal.
[1072] FIG. 55
shows the total number of patients that qualified for aflibercept
retreatment at any time in the study (independent of treatment), stratified by
non-ischemic
(left panel) and ischemic (right panel) perfusion type.
[1073] FIG. 56
shows the number of ischemic patients that qualified for aflibercept
retreatment during the study, in Control (left panel) vs. Active (right panel)
arm subjects.
[1074] FIG. 57
shows the number of nonischemic patients that qualified for aflibercept
retreatment during the study, in Control (left panel) vs. Active (right panel)
arm subjects.
[1075] FIG. 58A-
D shows the BVCA and CST data for ischemic versus non-ischemic
patients independent of treatment, at months 1, 2, and 3 of the study. FIG.
58A shows BVCA
in ischemic versus non-ischemic patients. FIG. 58B shows the change in BVCA in
ischemic
versus non-ischemic patients. FIG. 58C shows CST in ischemic versus non-
ischemic patients.
FIG. 58D shows the change in CST in ischemic versus non-ischemic patients.
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1076] FIG. 59A-D shows the BVCA and CST data for non-ischemic patients in
each
treatment group, at months 1, 2, and 3 of the study. FIG. 59A shows BVCA in
non-ischemic
patients in the control arm (aflibercept + sham) versus the active arm
(aflibercept + Zuprata).
FIG. 59B shows the change in BVCA in non-ischemic patients in the control arm
(aflibercept
+ sham) versus the active arm (aflibercept + Zuprata). FIG. 59C shows CST in
non-ischemic
patients in the control arm (aflibercept + sham) versus the active arm
(aflibercept + Zuprata).
FIG. 59D shows the change in CST in non-ischemic patients in the control arm
(aflibercept +
sham) versus the active arm (aflibercept + Zuprata).
[1077] FIG. 60A-D shows the BVCA and CST data for ischemic patients in each
treatment group, at months 1, 2, and 3 of the study. FIG. 60A shows BVCA in
ischemic
patients in the control arm (aflibercept + sham) versus the active arm
(aflibercept + Zuprata).
FIG. 60B shows the change in BVCA in ischemic patients in the control arm
(aflibercept +
sham) versus the active arm (aflibercept + Zuprata). FIG. 60C shows CST in
ischemic
patients in the control arm (aflibercept + sham) versus the active arm
(aflibercept + Zuprata).
FIG. 60D shows the change in CST in ischemic patients in the control arm
(aflibercept +
sham) versus the active arm (aflibercept + Zuprata).
[1078] FIG. 61A-D shows the BVCA data for each treatment group, stratified
into
ischemic or non-ischemic and BRVO or CRVO groups, at months 1, 2, and 3 of the
study.
FIG. 61A shows BVCA in ischemic BRVO patients in the control arm (aflibercept
+ sham)
versus the active arm (aflibercept + Zuprata). FIG. 61B shows BVCA in non-
ischemic BRVO
patients in the control arm (aflibercept + sham) versus the active arm
(aflibercept + Zuprata).
FIG. 61C shows BVCA in ischemic patients in the control arm (aflibercept +
sham) versus
the active arm (aflibercept + Zuprata). FIG. 61D shows BVCA in non-ischemic
patients in
the control arm (aflibercept + sham) versus the active arm (aflibercept +
Zuprata).
[1079] FIG. 62 provides a summary of the data shown graphically in FIG 61A-
D.
DETAILED DESCRIPTION OF THE INVENTION
[1080] Methods, devices and drug formulations are provided herein for
treating posterior
ocular disorders, for example wet AMD, CNV, wet AMD associated with CNV,
macular
edema associated with uveitis (e.g., infectious or non-infectious uveitis) and
macular edema
16
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
associated with retinal vein occlusion (RVO) in a human subject in need
thereof In one
embodiment, the RVO is branch retinal vein occlusion (BRVO), hemiretinal vein
occlusion
(HRVO) or central retinal vein occlusion (CRVO). In one embodiment, the
uveitis is
intermediate, posterior or pan uveitis, and can be infectious or non-
infectious uveitis. In
some embodiments, the drug formulation includes aflibercept.
[1081]
Intravitreal injections result in drugs diffusing throughout the eye,
including into
the lens, iris and ciliary body at the front of the eye, which for some drugs,
has been
associated with safety issues, such as cataracts and elevated intraocular
pressure (TOP) levels.
Specifically, intravitreal administration of triamcinolone (TA) has been
associated with
cataracts and increases in TOP levels in 20% to 60% of patients. Because SCS
injection of
drugs appears to result in drug remaining localized in the retina and choroid
without
substantial diffusion to the vitreous or the front portion of the eye, without
wishing to be
bound by theory, it is thought that SCS injection has the potential to reduce
the incidence of
these side effects.
[1082] Current
treatments for chronic retinal diseases often require intravitreal injections
of anti-VEGF drugs. However these diseases often affect the choroid and retina
and
therefore, specific targeting of these tissues might be more beneficial in
modulating disease
progression. The present invention addresses this need.
[1083] The
methods and devices provided herein, for example, for the treatment of
macular edema associated with uveitis, macular edema associated with RVO, wet
AMD
and/or diabetic macular edema (DME), choroidal neovascularization (CNV), wet
AMD
associated with CNV, in one embodiment, are used to restore or improve visual
function
primarily by reducing the macular edema affecting the retina, the tissue that
lines the inside
of the eye and is the part of the eye primarily responsible for vision, and
the choroid, the layer
adjacent to the retina that supplies the retina with blood, oxygen and
nourishment. Macular
edema is the build-up of fluid that can cause abnormal swelling of the macula,
the portion of
the retina responsible for central vision and color perception. This swelling
can rapidly result
in deterioration of vision and can eventually lead to blindness.
[1084] The two
main types of retinal vein occlusion (RVO) are Branch retinal vein
occlusion (BRVO) and central retinal vein occlusion (CRVO). BRVO is the most
common
form, and is characterized by venous occlusion at any smaller branch of the
central retinal
17
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
vein. CRVO is characterized by blockage of the main vein in the retina.
Occlusion occurring
at a main branch from the central retinal vein can be characterized as
hemispheric retinal or
hemi-retinal vein occlusion (HRVO). RVO can be further classified into
perfused (non-
ischemic) or nonperfused (ischemic). Non-ischemic RVO of any classification
(BRVO,
HRVO, or CRVO) is more common and less severe than ischemic RVO. Ischemic CRVO
is
characterized by a rapid onset of venous obstruction, resulting in reduced
retinal perfusion,
capillary closure, and retinal hypoxia; this type of CRVO can cause severe
vision loss. There
is a particular need in the art for effective treatments for the severe
condition of ischemic
CRVO.
[1085] As used
herein, "non-surgical" ocular drug delivery devices and methods refer to
methods and devices for drug delivery that do not require general anesthesia
and/or
retrobulbar anesthesia (also referred to as a retrobulbar block).
Alternatively or additionally,
a "non-surgical" ocular drug delivery method is performed with an instrument
having a
diameter of 28 gauge or smaller. Alternatively or additionally, "non-surgical"
ocular drug
delivery methods do not require a guidance mechanism that is typically
required for ocular
drug delivery via a shunt or cannula.
[1086] As used
herein, "surgical" ocular drug delivery includes insertion of devices or
administration of drugs by surgical means, for example, via incision to expose
and provide
access to regions of the eye including the posterior region, and/or via
insertion of a stent,
shunt, or cannula.
[1087] The
surgical and non-surgical posterior ocular disorder treatment methods and
devices described herein are particularly useful for the local delivery of
drugs to the posterior
region of the eye, for example the retinochoroidal tissue, macula, retinal
pigment epithelium
(RPE) and optic nerve in the posterior segment of the eye. In another
embodiment, the non-
surgical methods and microneedles provided herein can be used to target drug
delivery to
specific posterior ocular tissues or regions within the eye or in neighboring
tissue. In one
embodiment, the methods described herein deliver drug specifically to the
sclera, the choroid,
the Brach's membrane, the retinal pigment epithelium, the subretinal space,
the retina, the
macula, the optic disk, the optic nerve, the ciliary body, the trabecular
meshwork, the
aqueous humor, the vitreous humor, and/or other ocular tissue or neighboring
tissue in the
eye of a human subject in need of treatment. The methods and microneedles
provided herein,
18
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
in one embodiment, can be used to target drug delivery to specific posterior
ocular tissues or
regions within the eye or in neighboring tissue.
[1088] In one
embodiment of the methods described herein, a patient in need of treatment
is administered a drug, e.g., aflibercept or triamcinolone acetonide, to the
suprachoroidal
space of one or both eyes for at least one dosing session. Non-surgical
administration, in one
embodiment, is achieved by inserting a microneedle into one or both eyes of
the patient, for
example the sclera, and injecting or infusing a drug formulation through the
inserted
microneedle and into the suprachoroidal space of the eye. Surgical
administration, in another
embodiment, is achieved by making a conjunctival peritomy in the eye to expose
and provide
access to a posterior region of the eye; or by any other traditional surgical
means of accessing
the posterior region of the eye, known in the art. In some embodiments, the
treatment is
administered via a shunt, stent, or cannula that is surgically placed into the
eye of the subject.
[1089] In one
embodiment, the effective amount of the drug administered to the SCS
provides higher thereapeutic efficacy of the drug, compared to the therapeutic
efficacy of the
drug when the identical dosage is administered intravitreally, topically,
intracamerally,
parenterally or orally. In one embodiment, the microneedle drug delivery
methods described
herein precisely deliver the drug into the SCS for subsequent local delivery
to nearby
posterior ocular tissues (e.g., the retina and choroid) in need of treatment.
The drug may be
released into the ocular tissues from the infused volume (or, e.g., from
microparticles or
nanoparticles in the drug formulation) for an extended period, e.g., several
hours or days or
weeks or months, after the non-surgical drug administration has been
completed. This
beneficially can provide increased bioavailability of the drug relative, for
example, to
delivery by topical application of the drug formulation to ocular tissue
surfaces, or increased
bioavailability compared to oral, parenteral on intravitreal administration of
the same drug
dosage. In some embodiments, the drug formulation includes aflibercept. In
some
embodiments, the drug formulation includes triamcinolone acetonide.
[1090] With the
methods and microneedle devices described herein, the SCS drug
delivery methods advantageously include precise control of the depth of
insertion into the
ocular tissue, so that the microneedle tip can be placed into the eye so that
the drug
formulation flows into the suprachoroidal space and into one or more posterior
ocular tissues
surrounding the SCS, e.g., the choroid and retina. In one embodiment,
insertion of the
microneedle is in the sclera of the eye. In one embodiment, drug flow into the
SCS is
19
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
accomplished without contacting underlying tissues with the microneedle, such
as choroid
and retina tissues.
[1091] The
methods provided herein, in one embodiment, achieve delivery of drug to the
suprachoroidal space, thereby allowing drug access to posterior ocular tissues
(e.g., the
choroid and retina) not obtainable via topical, parenteral, intracameral or
intravitreal drug
delivery. Because the methods provided herein deliver drug to the posterior
ocular tissue for
the treatment of a posterior ocular disorder, the suprachoroidal drug dose
sufficient to achieve
a therapeutic response and/or the frequency of dosing in a human subject
treated with the
methods provided herein is less than the intravitreal, topical, parenteral or
oral drug dose or
dosing schedule sufficient to elicit the same or substantially the same
therapeutic response.
In one embodiment, the SCS delivery methods described herein allow for
decreased drug
dose of the posterior ocular disorder treating drug, compared to the
intravitreal, topical,
intracameral parenteral or oral drug dose sufficient to elicit the same or
substantially the same
therapeutic response. In a further embodiment, the suprachoroidal drug dose
sufficient to
elicit a therapeutic response is 75% or less, or 50% or less, or 25% or less
than the
intravitreal, topical parenteral or oral drug dose sufficient to elicit a
therapeutic response.
The therapeutic response, in one embodiment, is a reduction in severity of a
symptom/clinical
manifestation of the posterior ocular disorder (macular edema associated with
uveitis,
macular edema associated with RVO, wet AMD, choroidal neovascularization
(CNV), wet
AMD associated with CNV) for which the patient is undergoing treatment, or a
reduction in
number of symptom(s)/clinical manifestation(s) of the posterior ocular
disorder for which the
patient is undergoing treatment.
[1092] The term
"suprachoroidal space," is used interchangeably with suprachoroidal,
SCS, suprachoroid and suprachoroidia, and describes the potential space in the
region of the
eye disposed between the sclera and choroid. This region primarily is composed
of closely
packed layers of long pigmented processes derived from each of the two
adjacent tissues;
however, a space can develop in this region as a result of fluid or other
material buildup in
the suprachoroidal space and the adjacent tissues. Those skilled in the art
will appreciate that
the suprachoroidal space frequently is expanded by fluid buildup because of
some disease
state in the eye or as a result of some trauma or surgical intervention. In
the present
description, however, the fluid buildup is intentionally created by infusion
of a drug
formulation into the suprachoroid to create the suprachoroidal space (which is
filled with
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
drug formulation). Not wishing to be bound by theory, it is believed that the
SCS region
serves as a pathway for uveoscleral outflow (i.e., a natural process of the
eye moving fluid
from one region of the eye to the other through) and becomes a real space in
instances of
choroidal detachment from the sclera.
[1093] As used
herein, "ocular tissue" and "eye" include both the anterior segment of the
eye (i.e., the portion of the eye in front of the lens) and the posterior
segment of the eye (i.e.,
the portion of the eye behind the lens). For reference, FIGS. 1-4 are a
various views of a
human eye 10 (with FIGS. 2-4 being cross-sectional views). While specific
regions are
identified, those skilled in the art will recognize that the proceeding
identified regions do not
constitute the entirety of the eye 10, rather the identified regions are
presented as a simplified
example suitable for the discussion of the embodiments herein. The eye 10
includes both an
anterior segment 12 (the portion of the eye in front of and including the
lens) and a posterior
segment 14 (the portion of the eye behind the lens). The anterior segment 12
is bounded by
the cornea 16 and the lens 18, while the posterior segment 14 is bounded by
the sclera 20 and
the lens 18. The anterior segment 12 is further subdivided into the anterior
chamber 22,
between the iris 24 and the cornea 16, and the posterior chamber 26, between
the lens 18 and
the iris 24. The cornea 16 and the sclera 20 collectively form a limbus 38 at
the point at
which they meet. The exposed portion of the sclera 20 on the anterior segment
12 of the eye
is protected by a clear membrane referred to as the conjunctiva 45 (see e.g.,
FIGS. 2 and 3).
Underlying the sclera 20 is the choroid 28 and the retina 27, collectively
referred to as
retinachoroidal tissue. A vitreous humour 30 (also referred to as the
"vitreous") is disposed
between a ciliary body 32 (including a ciliary muscle and a ciliary process)
and the retina 27.
The anterior portion of the retina 27 forms an ora serrata 34. The loose
connective tissue, or
potential space, between the choroid 28 and the sclera 20 is referred to as
the suprachoroid.
FIG. 2 illustrates the cornea 16, which is composed of the epithelium 40, the
Bowman's layer
41, the stroma 42, the Descemet's membrane 43, and the endothelium 44. FIG. 3
illustrates
the sclera 20 with surrounding Tenon's Capsule 46 or conjunctiva 45,
suprachoroidal space
36, choroid 28, and retina 27, substantially without fluid and/or tissue
separation in the
suprachoroidal space 36 (i.e., the in this configuration, the space is
"potential" suprachoroidal
space). As shown in FIG. 3, the sclera 20 has a thickness between about 500 pm
and 700 pm.
FIG. 4 illustrates the sclera 20 with the surrounding Tenon's Capsule 46 or
the conjunctiva
45, suprachoroidal space 36, choroid 28, and retina 27, with fluid 50 in the
suprachoroidal
space 36.
21
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1094] The
dashed line in FIG. 1 represents the equator of the eye 10. In some
embodiments, the insertion site of any of the microneedles and/or methods
described herein is
between the equator and the limbus 38 (i.e., in the anterior portion 12 of the
eye 10) For
example, in some embodiments, the insertion site is between about two
millimeters and 10
millimeters (mm) posterior to the limbus 38. In other embodiments, the
insertion site of the
microneedle is at about the equator of the eye 10. In still other embodiments,
the insertion
site is posterior the equator of the eye 10. In this manner, a drug
formulation can be
introduced (e.g., via the microneedle) into the suprachoroidal space 36 at the
site of the
insertion and can flow through the suprachoroidal space 36 away from the site
of insertion
during an infusion event (e.g., during injection). In some embodiments, the
drug formulation
includes aflibercept or triamcinolone acetonide.
[1095] The
microneedle may extend from the base of the microneedle device at any angle
suitable for insertion into the eye 10. In a particular embodiment, the
microneedle extends
from the base at an angle of about 90 degrees to provide approximately
perpendicular
insertion of the microneedle into the surface of the eye. In another
embodiment, the
microneedle extends from the base at an angle from about 60 to about 110
degrees, from
about 70 degrees to about 100 degrees, from about 80 degrees to about 90
degrees, or from
about 85 degrees to about 95 degrees.
[1096] The
microneedle device may comprise a means for controllably inserting, and
optionally retracting, the microneedle into the ocular tissue. In addition,
the microneedle
device may include means of controlling the angle at which the at least one
microneedle is
inserted into the ocular tissue (e.g., by inserting the at least one
microneedle into the surface
of the ocular tissue at an angle of about 90 degrees).
[1097] In one
embodiment, the depth of microneedle insertion into the ocular tissue can
be controlled by the length of the microneedle, as well as other geometric
features of the
microneedle. For example, a flange or other a sudden change in microneedle
width can be
used to limit the depth of microneedle insertion. The microneedle insertion
can also be
controlled using a mechanical micropositioning system involving gears or other
mechanical
components that move the microneedle into the ocular tissue a controlled
distance and,
likewise, can be operated, for example, in reverse, to retract the microneedle
a controlled
distance. The depth of insertion can also be controlled by the velocity at
which the
microneedle is inserted into the ocular tissue. The retraction distance can be
controlled by
22
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
elastic recoil of the ocular tissue into which the microneedle is inserted or
by including an
elastic element within the microneedle device that pulls the microneedle back
a specified
distance after the force of insertion is released.
[1098] The
angle of insertion can be directed by positioning the microneedle at a first
angle relative to the microneedle base and positioning the base at a second
angle relative to
the ocular surface. In one embodiment, the first angle can be about 90 and
the second angle
can be about 0 . The angle of insertion can also be directed by having the
microneedle
protrude from a device housing through a channel in that housing that is
oriented at a
specified angle.
[1099] As
provided throughout, in one embodiment, the methods described herein are
carried out with a hollow or solid microneedle, for example, a rigid
microneedle. As used
herein, the term "microneedle" refers to a conduit body having a base, a
shaft, and a tip end
suitable for insertion into the sclera and other ocular tissue and has
dimensions suitable for
minimally invasive insertion and drug formulation infusion as described
herein. That is, the
microneedle has a length or effective length that does not exceed about 2000
microns and a
diameter that does not exceed about 600 microns. Both the "length" and
"effective length" of
the microneedle encompass the length of the shaft of the microneedle and the
bevel height of
the microneedle. In some embodiments, the microneedle used to carry out the
methods
described herein comprises one of the devices disclosed in International
Patent Application
Publication No. W02014/179698 (Application No. PCT/US2014/036590), filed May
2, 2014
and entitled "Apparatus and Method for Ocular Injection," incorporated by
reference herein
in its entirety for all purposes. In some embodiments, the microneedle used to
carry out the
methods described herein comprises one of the devices disclosed in
International Patent
Application Publication No. W02014/036009 (Application No. PCT/US2013/056863),
filed
August 27, 2013 and entitled "Apparatus and Method for Drug Delivery Using
Microneedles," incorporated by reference herein in its entirety for all
purposes.
[1100] In
another embodiment, the microneedle is designed to have a length longer than
the desired penetration depth, but the microneedle is controllably inserted
only part way into
the tissue. Partial insertion may be controlled by the mechanical properties
of the tissue,
which bends and dimples during the microneedle insertion process. In this way,
as a
microneedle is inserted into the tissue, its movement partially elastically
deforms the tissue
23
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
and partially penetrates into the tissue. By controlling the degree to which
the tissue deforms,
the depth of microneedle insertion into the tissue can be controlled.
111011 In one
embodiment, the device used to carry out one of the methods described
herein comprises the device described in U.S. Design Patent Application Serial
No.
29/506,275 entitled, "Medical Injector for Ocular Injection," filed October
14, 2014, the
disclosure of which is incorporated herein by reference in its entirety for
all purposes.
[1102] In one
embodiment, the microneedle is inserted into the eye of the human patient
using a rotational/drilling technique and/or a vibrating action. In this way,
the microneedle
can be inserted to a desired depth by, for example, drilling the microneedles
a desired number
of rotations, which corresponds to a desired depth into the tissue. See, e.g.,
U.S. Patent
Application Publication No. 2005/0137525, which is incorporated herein by
reference, for a
description of drilling microneedles. The rotational/drilling technique and/or
a vibrating
action may be applied during the insertion step, retraction step, or both.
[1103] As used
herein, the words "proximal" and "distal" refer to the direction closer to
and away from, respectively, an operator (e.g., surgeon, physician, nurse,
technician, etc.)
who would insert the medical device into the patient, with the tip-end (i.e.,
distal end) of the
device inserted inside a patient's body first. Thus, for example, the end of a
microneedle
described herein first inserted inside the patient's body would be the distal
end, while the
opposite end of the microneedle (e.g., the end of the medical device being
manipulated by the
operator) would be the proximal end of the microneedle.
[1104] As used
herein, the terms "about" and "approximately" generally mean plus or
minus 10% of the value stated. For example, about 0.5 would include 0.45 and
0.55, about
would include 9 to 11, about 1000 would include 900 to 1100.
[1105] The term
"fluid-tight" is understood to encompass both a hermetic seal (i.e., a seal
that is gas-impervious) as well as a seal that is only liquid-impervious. The
term
"substantially" when used in connection with "fluid-tight," "gas-impervious,"
and/or "liquid-
impervious" is intended to convey that, while total fluid imperviousness is
desirable, some
minimal leakage due to manufacturing tolerances, or other practical
considerations (such as,
for example, the pressure applied to the seal and/or within the fluid), can
occur even in a
"substantially fluid-tight" seal. Thus, a "substantially fluid-tight" seal
includes a seal that
prevents the passage of a fluid (including gases, liquids and/or slurries)
therethrough when
24
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
the seal is maintained at a constant position and at fluid pressures of less
than about 5 pounds
per square inch gage (psig), less than about 10 psig, less than about 20 psig,
less than about
30 psig, less than about 50 psig, less than about 75 psig, less than about 100
psig and all
values in between. Similarly, a "substantially liquid-tight" seal includes a
seal that prevents
the passage of a liquid (e.g., a liquid medicament) therethrough when the seal
is maintained at
a constant position and is exposed to liquid pressures of less than about 5
psig, less than about
psig, less than about 20 psig, less than about 30 psig, less than about 50
psig, less than
about 75 psig, less than about 100 psig and all values in between.
[1106] As used
herein, the term "hollow" includes a single, straight bore through the
center of the microneedle, as well as multiple bores, bores that follow
complex paths through
the microneedles, multiple entry and exit points from the bore(s), and
intersecting or
networks of bores. That is, a hollow microneedle has a structure that includes
one or more
continuous pathways from the base of the microneedle to an exit point
(opening) in the shaft
and/or tip portion of the microneedle distal to the base.
[1107] The
microneedle device in one embodiment, comprises a fluid reservoir for
containing the therapeutic formulation (e.g., drug or cell formulation), e.g.,
as a solution or
suspension, and the drug reservoir (which can include any therapeutic
formulation) being in
operable communication with the bore of the microneedle at a location distal
to the tip end of
the microneedle. The fluid reservoir may be integral with the microneedle,
integral with the
elongated body, or separate from both the microneedle and elongated body.
[1108] The
microneedle and/or any of the components included in the embodiments
described herein is/are formed and/or constructed of any suitbale
biocompatible material or
combination of materials, including metals, glasses, semi-conductor materials,
ceramics, or
polymers. Examples of suitable metals include pharmaceutical grade stainless
steel, gold,
titanium, nickel, iron, gold, tin, chromium, copper, and alloys thereof The
polymer can be
biodegradable or non-biodegradable. Examples of suitable biocompatible,
biodegradable
polymers include polylactides, polyglycolides, polylactide-co-glycolides
(PLGA),
poly anhy dri des, poly ortho esters , poly etheresters, poly caprol actones,
poly esterami des,
poly(butyric acid), poly(valeric acid), polyurethanes and copolymers and
blends thereof
Representative non-biodegradable polymers include various thermoplastics or
other
polymeric structural materials known in the fabrication of medical devices.
Examples
include nylons, polyesters, polycarbonates, polyacrylates, polymers of
ethylene-vinyl acetates
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
and other acyl substituted cellulose acetates, non-degradable polyurethanes,
polystyrenes,
polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole),
chlorosulphonate polyolefins,
polyethylene oxide, blends and copolymers thereof Biodegradable microneedles
can provide
an increased level of safety compared to non-biodegradable ones, such that
they are
essentially harmless even if inadvertently broken off into the ocular tissue.
[1109] In one
embodiment, the hollow microneedle provided herein is fabricated using a
laser or similar optical energy source. In one example, a microcannula may be
cut using a
laser to represent the desired microneedle length. The laser may also be use
to shape single
or multiple tip openings. Single or multiple cuts may be performed on a single
microncannula to shape the desired microneedle structure. In one example, the
microcannula
may be made of metal such as stainless steel and cut using a laser with a
wavelength in the
infrared region of the light spectrum (e.g., from about 0.7 to about 300 p.m).
Further
refinement may be performed using metal electropolishing techniques familiar
to those in the
field. In another embodiment, the microneedle length and optional bevel is
formed by a
physical grinding process, which for example may include grinding a metal
cannula against a
moving abrasive surface. The fabrication process may further include precision
grinding,
micro-bead jet blasting and ultrasonic cleaning to form the shape of the
desired precise tip of
the microneedle.
[1110] Further
details of possible manufacturing techniques are described, for example,
in U.S. Patent Application Publication No. 2006/0086689, U.S. Patent
Application
Publication No. 2006/0084942, U.S. Patent Application Publication No.
2005/0209565, U.S.
Patent Application Publication No. 2002/0082543, U.S. Patent No. 6,334,856,
U.S. Patent
No. 6,611,707, U.S. Patent No. 6,743,211 and PCT/U52014/36590, filed May
2,2014, all of
which are incorporated herein by reference in their entireties for all
purposes.
[1111] In some
embodiments, an apparatus includes a medicament container, a piston
assembly and a handle. The medicament container defines a lumen configured to
contain a
medicament. A distal end portion of the medicament container includes a
coupling portion
configured to be removably coupled to a needle assembly. A proximal end
portion of the
medicament container includes a flange and a longitudinal shoulder. A distal
end portion of
the piston assembly includes an elastomeric member movably disposed within the
lumen of
the medicament container. The handle is coupled to a proximal end portion of
the piston
assembly such movement of the handle produces movement of the elastomeric
member
26
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
within the medicament container. The proximal end portion of the medicament
container is
movably disposed within the handle. A portion of the handle is configured to
contact the
flange to limit proximal movement of the handle relative to the medicament
container. The
handle includes a protrusion configured to engage the longitudinal shoulder of
the
medicament container to limit rotation of the handle relative to the
medicament container.
[1112] Any of
the compositions described herein can be injected using any suitable
injector of the types shown and described herein. Any of the methods described
herein can
be performed use any suitable injector of the types shown and described
herein. In this
manner, the benefits of targeted drug delivery via a non-surgical approach can
be realized.
For example, in some embodiments, an apparatus includes a medicament
container, a needle
assembly, and a piston assembly. The medicament container contains a dose of a
medicament, such as, for example a drug or cellular therapeutic, e.g., a
steroid formulation or
a cell suspension (e.g., a stem cell suspension). The dose has a delivered
volume of at least
about 20 !IL, at least about 50 uL, at least about 100 !IL, at least about 200
[IL or at least
about 500 4. In one embodiment, the amount of therapeutic formulation
delivered into the
suprachoroidal space from the devices described herein is from about 10 [IL to
about 200 !IL,
e.g., from about 50 [IL to about 150 4. In another embodiment, from about 10
[IL to about
500 !IL, e.g., from about 50 pi to about 250 !IL, is non-surgically
administered to the
suprachoroidal space.
[1113] The
needle assembly is coupled to a distal end portion of the medicament
container, and includesss a contact surface and a needle. The contact surface
is configured to
contact a target surface of an eye, and can include a convex surface and/or a
sealing portion,
as described herein. The needle is coupled to the base. A distal end portion
of the piston
assembly includes an elastomeric member movably disposed within the medicament
container. A proximal end portion of the piston assembly is configured to
receive a force to
move the elastomeric within the medicament container to deliver the dose of
the medicament
via the needle assembly. The needle assembly and the piston assembly being
collectively
configured to deliver the dose of the medicament into the suprachoroidal space
of the eye
such that an intraocular pressure of the eye measured within 30 minutes after
delivery of the
dose is within five percent, ten percent, fifteen percent, twenty percent or
twenty-five percent
of an intraocular pressure of the eye measured before the delivery of the
dose.
27
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1114] In some
embodiments, an apparatus includes a medicament container, a needle
assembly, and a piston assembly. The medicament container contains a dose of a
medicament, such as, for example a steroidal composition such as a
triamcinolone
composition. The needle assembly is coupled to a distal end portion of the
medicament
container, and includesss a contact surface and a needle. The contact surface
is configured to
contact a target surface of an eye, and can include a convex surface and/or a
sealing portion,
as described herein. The needle is coupled to the base. A distal end portion
of the piston
assembly includes an elastomeric member movably disposed within the medicament
container. A proximal end portion of the piston assembly is configured to
receive a force to
move the elastomeric within the medicament container to deliver the dose of
the medicament
via the needle assembly. The needle assembly and the piston assembly being
collectively
configured to deliver the dose of the medicament into a suprachoroidal space
of the eye such
that a therapeutic response resulting from the dose is substantially
equivalent to a therapeutic
response resulting from the delivery of a corresponding dose of the medicament
via any one
of an intravitreal delivery method, a topical delivery method, a parenteral
delivery method or
an oral delivery method. An amount of the dose is less than about 75 percent
of an amount of
the corresponding dose.
[1115] In some
embodiments, an apparatus includes a medicament container, a needle
assembly, and a piston assembly. The medicament container contains a dose of a
medicament, such as, for example a steroidal composition such as a
triamcinolone
composition. The needle assembly is coupled to a distal end portion of the
medicament
container, and includesss a contact surface and a needle. The contact surface
is configured to
contact a target surface of an eye, and can include a convex surface and/or a
sealing portion,
as described herein. The needle is coupled to the base. A distal end portion
of the piston
assembly includes an elastomeric member movably disposed within the medicament
container. A proximal end portion of the piston assembly is configured to
receive a force to
move the elastomeric within the medicament container to deliver the dose of
the medicament
via the needle assembly. The needle assembly and the piston assembly being
collectively
configured to deliver the dose of the medicament into a suprachoroidal space
of the eye such
that an intraocular Cmax resulting from the dose is greater, for example at
least about 1.25x,
1.5x or 2x greater than an intraocular Cmax resulting from the delivery of a
corresponding
dose of the medicament via any one of an intravitreal delivery method, a
topical delivery
method, a parenteral delivery method or an oral delivery method.
28
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1116] The
needle assembly and the piston assembly being collectively configured to
deliver the dose of the medicament into a suprachoroidal space of the eye such
that an
intraocular AUC resulting from the dose is greater, for example at least about
1.25x, 1.5x or
2x greater than an intraocular AUC resulting from the delivery of a
corresponding dose of the
medicament via any one of an intravitreal delivery method, a topical delivery
method, a
parenteral delivery method or an oral delivery method.
[1117] FIGS. 5-
18 illustrate a medical injector 100 configured to deliver a medicament
to, for example, ocular tissue, according to an embodiment. The medical
injector 100 can be
used in conjunction with any of the methods and therapeutic formulations
described herein.
More specifically, the medical injector 100 (also referred to herein as
"injector") can have a
size, shape, and/or configuration that is based at least in part on
constraints and/or challenges
associated with delivering a drug formulation into ocular tissue. For example,
as described in
further detail herein, medicament delivery into ocular tissue using
conventional devices
and/or needles can lead to incomplete delivery of a dose, reduction in
efficacy of an injected
medicament, seeding of undersirable cells, trauma, etc. Thus, the medical
injector 100 can
have a size and/or configuration that effectively deliver a medicament to a
portion of the eye
such as a posterior region thereof
[1118] As
shown, the medical injector 100 includes a handle 110, a barrel 130, a piston
150, a needle hub 160, and a cap 170. The handle 110 can be any suitable
shape, size, and/or
configuration. For example, in some embodiments, the handle 110 can have an
ergonomic
shape and/or size, which can enable to manipulate the injector 100 with one
hand or with two
hands. The handle 110 has a proximal end portion 111 and a distal end portion
112, and
defines an inner volume 113 (see e.g., FIG. 9). The inner volume 113 of the
handle 110
receives and/or is configured to house at least a portion of the barrel 130
and the piston 150,
as described in further detail herein.
[1119] As shown
in FIG. 7-9, the handle 110 is formed by coupling a first handle
member 115A to a second handle member 115B. The handle member 115A and the
handle
member 115B can be relatively thin shelled or the like and can be formed from
any suitable
material such as the biocompatible materials described above. In other words,
the handle
members 115A and 1158B can be substantially hollow and/or can define an inner
volume
(e.g., the inner volume 113). The first handle member 115A has a proximal end
portion
116A and a distal end portion 117A. Moreover, the first handle member 115A has
an inner
29
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
surface 118A that can include any suitable feature, cutout, coupler, wall,
etc., any of which
can be used to facilitate the coupling of the first handle member 115A to the
second handle
member 115B and/or to engage a portion of the piston 150 and/or the barrel
130. For
example, as shown in FIG. 9, the inner surface 118A of the first handle member
115A can
form a rib 120A, a retention member 119A, and at least one coupler 121A, which
can be
used, iner alia, to engage the barrel 130, the piston 150, and/or the second
handle member
115B, respectively, as described in further detail herein.
[1120]
Similarly, the second handle member 115B has a proximal end portion 116B and a
distal end portion 117B. The second handle member 115B also has an inner
surface 118B
that forms a rib 120B, a retention member 119B, and at least one coupled 121B,
which can be
used to engage the barrel 130, the piston 150, and the first handle member
115A,
respectively, as described in further detail herein. As shown in FIG. 9, for
example, the first
handle member 115A and the second handle member 115B are coupled together to
collectively form the handle 100. The first handle member 115A and the second
handle
member 115B can be coupled in any suitable member. For example, in some
embodiments,
the retention member 119B of the second handle member 115B can define an
opening or the
like configured to matingly receive a portion of the retention member 119A of
the first handle
member 115A. Similarly, the at least one coupler 121B of the second handle
member 119B
can define an opening configured to matingly receive a portion of an
associated coupler 121A
of the first handle member 115A. In some embodiments, the retention member
119A and the
coupler(s) 121B of the first handle member 115A can be configured to form a
press or
friction fit with an inner surface of the retention member 119B and the
coupler(s) 121B of the
second handle member 115B, which can be operable in coupling the first handle
member
115A to the second handle member 115B. In other embodiments, the first handle
member
115A and the second handle member 115B can be coupled via any suitable method
such as,
for example, an adhesive, an ultrasonic weld, a mechanical fastener, and/or
the like.
Furthermore, when the first handle member 115A is coupled to the second handle
member
115B, the inner surfaces 118A and 118B of the handle members 115A and 115B,
respectively, collectively define the inner volume 113 of the handle 110, as
shown in FIG. 9.
[1121] The
barrel 130 of the injector 100 can be any suitable shape, size, or
configuration. As shown in FIG. 10, the barrel 130 has a proximal end portion
131 and a
distal end portion 132 and defines a lumen 133 therethrough. In addition, the
barrel 130 has
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
an outer surface that defines a set of slots 136 (only one is shown in FIG.
10) and a grip
portion 137. The grip portion 137 can be configured to facilitate the use of
the device by
providing a user with a predetermined location to engage the injector 100. The
grip portion
137 can have any suitable surface finish or the like, which can, in some
instances, increase a
friction between the grip portion 137 and a user's fingers and/or hand. In
other embodiments,
the barrel 130 does not include a grip portion.
[1122] The
lumen 133 of the barrel 130 movably receives at least a portion of the piston
150, as described in further detail herein. Moreover, at least a portion of
the lumen 133 can
define a medicament volume configured to receive, store, house, and/or
otherwise contain a
medicament (e.g., a corticosteroid such as triamcinolone acetonide, or any
other medicament
described herein). In some embodiments, at least a portion of the barrel 130
can be
substantially transparent and/or can include an indicator or the like
configured to allow a user
to visually inspect a volume of fluid (e.g., medicament/therapeutic
formulation) within the
lumen 133. In some instances, such an indicator can be, for example, any
number of lines
and/or markings associated with a volume of fluid disposed within the barrel
130. In other
embodiments, the barrel 130 can be substantially opaque and/or does not
include an indicator
or the like.
[1123] The
distal end portion 132 includes and/or forms a coupler 138 configured to be
physically and fluidically coupled to the needle hub 160, as described in
further detail herein.
The proximal end portion 131 of the barrel 130 includes a flanged end 135 and
defines a set
of slots 136 (only one slot is shown in FIG. 10). As described above, at least
a portion of the
barrel 130 is disposed within the inner volume 113 of the handle 110 (see,
e.g., FIG. 16).
Specifically, at least the proximal end portion 131 of the barrel 130 can be
inserted into the
handle 110 in such a manner that the handle 110 can be moved relative to the
barrel 130. In
other words, at least the proximal end portion 131 of the barrel 130 can be
movably disposed
within the inner volume 113 defined by the handle 110. Moreover, when the
proximal end
portion 131 of the barrel 130 is disposed in the handle 110, the ribs 120A and
120B of the
handle members 115A and 115B, respectively, are movably disposed in its
associated slot
136 defined by the barrel 130. Such an arrangement can, for example, define a
range of
motion of the handle 110 relative to the barrel 130. Such an arrangement can
also limit a
rotational motion of the handle 110 about the barrel 130 while allowing a
translational motion
of the handle 110 relative to the barrel 130 in a proximal or a distal
direction. In this manner,
31
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
during the injection operation, substantially all of the force applied by the
user will urge the
handle 110 (and therefore the piston 150) in the distal direction, and will
not cause rotation of
the piston 150 within the barrel 130. By limiting the rotational motion of the
piston 150 (and
particularly, the elastomeric member 155) within the barrel 130, the injection
operation can
be consistently performed. For example, by limiting the rotational motion of
the elastomeric
member 155 within the barrel 130, the force needed to overcome the static
coefficient of
friction between the elastomeric member 155 and the barrel 130 will be more
consistent
(between parts andor injection) than if an applied force includes both
translational (i.e., distal)
and rotational components. This arrangement facilitates a more consistent
"loss of
resistance" felt at the handle 110 during an injection operation, as described
below.
[1124]
Additionally, the arrangement of the flanged end 135 of the barrel 130 and the
inner surfaces 118A and 118B of the handle members 115A and 115B,
respectively, can
define a translational range of motion of the handle 110 relative to the
barrel 130 in the
proximal or the distal direction (see e.g., FIG. 16).
[1125] The
piston 150 of the injector 100 can be any suitable shape, size, and/or
configuration. For example, referring back to FIG. 7, the pison 150 can have a
size and shape
that are each associated with the handle 110 and/or the barrel 130, which in
turn, can allow at
least a portion of the piston 150 to be disposed within the handle 110 and/or
the barrel 130.
More specifically, the piston 150 has a proximal end portion 151 and a distal
end portion 152.
The proximal end portion 151 of the piston 150 is configured to be disposed
within the inner
volume 113 of the handle 110. As shown in FIG. 7, the proximal end portion 151
of the
piston 150 includes a tab 153 or the like that defines an opening 154, which
in turn, can
receive at least a portion of the retention members 119A and 119B of the
handle members
115A and 115B, respectively. For example, in some embodiments, during an
assembly
and/or manufacturing process and prior to coupling the handle members 115A and
115B, the
proximal end portion 151 of the piston 150 can be positioned relative to the
retention member
119B of the second handle member 115B such that at least a portion of the
retention member
119B is disposed within the opening 154 defined by the piston 150. In other
words, the tab
153 at or near the proximal end portion 151 of the piston 150 can be disposed
about a portion
of the retention member 119B prior to coupling the first handle member 115A to
the second
handle member 115B. As such, the piston 150 can be fixedly coupled to the
handle 110.
32
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1126] The
distal end portion 152 of the piston 150 is configured to be movably disposed
in the lumen 133 of the barrel 130. As shown in FIG. 7, the distal end portion
152 of the
piston 150 includes and/or is coupled to an elastomeric member 155. In some
embodiments,
the elastomeric member 155 can be monolithically formed with the piston 150
(e.g.,
overmolded or the like). In other embodiments, the elastomeric member 155 can
be formed
independently of the piston 150 and coupled thereto. The elastomeric member
155 can be
made of an inert and/or biocompatible material, which can have any suitable
hardness and/or
durometer. For example, in some embodiments, the elastomeric member 155 can be
formed
from and/or constructed out of a rubber, silicone, plastic, nylon, polymers,
any other suitable
material or combination thereof In some embodiments, at least a portion of the
elastomeric
member 155 can be configured to deform or the like while substantially
maintaining its
original shape. That is to say, the elastomeric member 155 can have a
durometer that is
sufficiently low to allow at least some deformation thereof, while preventing
the elastomeric
member 155 from being substantially reconfigured and/or the like.
[1127] The
elastomeric member 155 can be disposed in the lumen 113 such that an outer
surface of the elastomeric member 155 is in contact with an inner surface of
the barrel 130
defining the lumen 133. In some embodiments, the elastomeric member 155 and
the inner
surface of the barrel 130 collectively form a substantially fluid-tight seal
and/or a hermetic
seal, which can, for example, prevent leakage, out gassing, contamination,
and/or the like of a
substance (e.g., a medicament) disposed within the barrel 130. Moreover, the
elastomeric
member 155 can have a size, shape and/or can be constructed from a material
such that
movement of the piston 150 and/or elastomeric member 155 within the barrel 130
is limited
when a force applied is below a predetermined threshold. In this manner, the
piston 150 can
be maintained in a substantially fixed position relative to the barrel 130
until a force exerted,
for example, on the handle 110 is sufficient to inject a medicament into a
target tissue, as
described in further detail herein. In some
embodiments, the size, shape, and/or
configuration of the elastomeric member 155 can be changed to, for example,
increase or
decrease an amount of force used to move the piston 150 within the barrel 130,
which in
some instances, can be based on one or more characteristics associated with a
target tissue
and/or the like, as described in further detail herein.
[1128] The
needle hub 160 of the injector 100 can be any suitable shape, size, and/or
configuration. As shown in FIGS. 11-13, 15, and 16, the needle hub 160 has a
proximal end
33
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
portion 161, a distal end portion 162, an indicator portion 168, and a pair of
tabs 164, and
defines a lumen 167 (see e.g., FIG. 16). The proximal end portion 161 of the
needle hub 160
is configured to be coupled to the distal end portion 132 of the barrel 130.
For example, the
needle hub 160 can include a coupler 163 (see e.g., FIG. 16) that can matingly
engage the
coupler 138 of the barrel 130 to couple the needle hub 160 to the barrel 130
and to place the
lumen 167 of the needle hub 160 in fluid communication with the lumen 133 of
the barrel
130. In some embodiments, the coupler 163 of the needle hub 160 and the
coupler 138 of the
barrel 130 can form a threaded coupling or the like. In such embodiments, a
user can, for
example, engage the tabs 164 to rotate the needle hub 160 relative to the
barrel 130, thereby
threading the coupler 163 of the needle hub 160 onto the coupler 138 of the
barrel 130. In
some embodiments, the coupler 163 of the needle hub 160 can be a locking
mechanism
and/or the like such as, for example, a Luer-Lok0 (or other locking mechanism)
configured
to form a fluid tight seal with the distal end portion 132 of the barrel 130
when coupled
thereto. The distal end portion 162 of the needle hub 160 includes and/or is
coupled to a base
165, which in turn, is coupled to and/or forms a microneedle 166, as described
below. The
indicator portion 168 of the needle hub 160 is configured to provide a visual
indication
associated with one or more characteristics of the microneedle 166. For
example, in this
embodiment, the indicator portion 168 can be configured to provide a visual
indication
associated with an effective length of the microneedle 166 (e.g., "900"
micrometers, as
shown in FIG. 12).
[1129] The base
165 can be any suitable shape, size, and/or configuration and can be
configured to contact a portion of the ocular tissue during an injection
event. For example, as
shown, the base 165 has a convex distal end surface, which is configured to
contact a target
surface of a target tissue when a substance is conveyed through the needle
into the target
tissue (see, e.g., FIG. 18). In some embodiments, the distal end surface
includes a sealing
portion (not identified in the FIGS.) configured to define a substantially
fluid-tight seal with
the target surface when the distal end surface is in contact with the target
surface. For
example, the distal end surface of the base 165 can deform the target surface
such that the
sealing portion is contiguous with the target surface and forms the
substantially fluid-tight
seal. In some embodiments, the sealing portion can be symmetrical about the
microneedle
166.
34
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1130] In some
embodiments, the base 165 can be formed from a material or combination
of materials that is/are relatively flexible and/or that has/have a relatively
low durometer. In
some instances, the base 165 can be formed from a material with a durometer
that is
sufficiently low to limit and/or prevent damage to the ocular tissue when
placed in contact
therewith. In some instances, the base 165 can be configured to deform (e.g.,
elastically or
plastically) when placed in contact with the ocular tissue. In other
embodiments, the base
165 can be formed from a material of sufficient hardness such that the target
tissue (and not
the base) is deformed when the base 165 is placed in contact with and/or
pressed against the
target tissue. In some embodiments, for example, the base 165 is constructed
from a medical
grade stainless steel, and has a surface finish of less than about 1.6 p.m Ra.
In this manner,
the surface finish can facilitate the formation of a substantially fluid-tight
seal between the
base 165 and the target tissue.
[1131]
Furthermore, when the base 165 is coupled to the needle hub 160, a lumen 169
defined by the microneedle 166 is in fluid communication with the lumen 167 of
the needle
hub 160 (see, e.g., FIG. 16). Thus, a substance can flow through the lumen 167
of the needle
hub 160 and the lumen 169 of the microneedle 166 to be injected into a target
tissue, as
described in further detail herein.
[1132] The
microneedle 166 can be any suitable device or structure that is configured to
puncture a target tissue of a patient. For example, the microneedle 166 can be
any of the
microneedles described herein configured to puncture ocular tissue. In some
embodiments,
the microneedle 166 can be a 30 gauge microneedle, a 32 gauge microneedle or a
34 gauge
microneedle. As shown in FIG. 13, the microneedle 166 extends from a distal
surface of the
base 165 by a distance D1 (also referred to herein as an "effective length").
In some
embodiments, the shape and/or size of the microneedle 166 can correspond with
at least a
portion of a target tissue. For example, in some embodiments, the effective
length of the
microneedle 166 (e.g., the portion of the microneedle 166 that is outside or
distal to the base
165) can correspond with a portion of ocular tissue such that when the
microneedle 166 is
inserted into the ocular tissue, a portion of the microneedle 166 is disposed
within the sclera
or suprachoroidal space of the eye. Specifically, in this embodiment, the
effective length
and/or the distance D1 is about 900 micrometers (p.m). Moreover, the indicator
portion 168
of the needle hub 160 can be configured to provide a user with a visual
indication associated
the effective length and/or distance D1. Although not shown in FIGS. 11-13, in
some
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
embodiments, the microneedle 166 can have a bevel geometry (e.g., bevel angle,
bevel
height, bevel aspect ratio or the like), which can facilitate the piercing
and/or insertion of a tip
of the microneedle 166 into the target tissue and the opening (not shown) of
the microneedle
166 can be maintained within a desired region during an injection event. In
some
embodiments, the microneedle 166 or any of the microneedles described herein
can include a
bevel or other characteristics of the types shown and described in
International Patent
Application Publication No. W02014/036009 (Application No. PCT/US2013/056863),
filed
August 27, 2013 and entitled "Apparatus and Method for Drug Delivery Using
Microneedles" and/or International Patent Application Publication No.
W02014/179698
(International Application No. PCT/US2014/036590), filed May 2, 2014 and
entitled
"Apparatus and Method for Ocular Injection," each of which is incorporated by
reference
herein in its entirety for all purposes.
[1133] As
described above, the base 165 can be coupled to the needle hub 160, which in
turn, is coupled to the barrel 130 such that the lumen 133 of the barrel, the
lumen 167 of the
needle hub 160, and the lumen 169 of the microneedle 166 define a fluid flow
path through
which a medicament and/or substance contained within the barrel 130 can flow,
for example,
to be injected into a target tissue.
[1134] The cap
170 of the injector 100 is removably disposed adjacent to a distal end
portion 132 of the barrel 130 and is configured to substantially house, cover,
enclose, protect,
isolate, etc. at least a portion of the needle hub 160. More specifically, the
cap 170 can be
moved relative to the remaining portions of the medical injector 100 to
position at least a
portion of the needle hub 160 within an inner volume 174 (see, e.g., FIG. 14)
of the cap 170.
As such, the cap 170 can have a size and/or shape that is associated with
and/or at least
partially based on a size and/or shape of the needle hub 160. In some
embodiments, the cap
170 and a portion of the needle hub 160 can collectively define a friction fit
or the like, which
can be operable in maintaining the cap 170 in a substantially fixed position
relative to the
needle hub 160. In addition, in some embodiments, the cap 170 and the portion
of the needle
hub 160 can collectively form a substantially fluid tight and/or substantially
hermetic seal,
which in turn, can maintain the sterility of a microneedle 166 prior to use of
the medicament
delivery device 100. For example, although not shown, the cap 170 can include
a plug, a
seal, a sterilization member (e.g., wipe, pad, etc.), and/or the like
configured to maintain the
sterility of the microneedle 166 prior to use. Moreover, as shown in FIG. 14,
the cap 170
36
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
includes an indicator portion 173 that can provide a visual indication to a
user associated with
a size and/or effective length of the microneedle 166. In some embodiments,
the indicator
portion 173 can be substantially similar in form and function to the indicator
portion 168 of
the needle hub 160 and can be configured to provide substantially the same
visual indication.
[1135] As shown
in FIGS. 15-18, in some instances, a user (e.g., a doctor, technician,
nurse, physician, ophthalmologist, etc.) can manipulate the injector 100 to
deliver a drug
formulation to the suprachoroidal space of an eye according to an embodiment.
In some
embodiments, the drug formulation includes aflibercept and is used to treat a
patient for wet
AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO. In some
embodiments, the drug formulation includes triamcinolone acetonide and is used
in
conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD
associated with
CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in
ocular
disease. In some instance, prior to an injection event, the user can, for
example, couple the
distal end portion 132 of the barrel 130 to a fluid reservoir or the like
and/or any suitable
transfer device (not shown) to transfer a volume of a medicament and/or drug
formulation
into the lumen of the barrel 130. For example, in some embodiments, the distal
end portion
132 of the barrel 130 can be physically and fluidically coupled to a transfer
adapter and/or the
like having a puncture member configured to puncture a fluid reservoir
containing a drug
formulation such as those described herein. Such transfer adapters can be
similar to the
adapter 21280 shown and described in International Patent Application
Publication No.
W02014/179698 (Application No. PCT/U52014/036590), filed May 2, 2014 and
entitled
"Apparatus and Method for Ocular Injection," incorporated by reference herein
in its entirety
for all purposes. As such, the puncture member places the transfer adapter in
fluid
communication with the fluid reservoir. With the transfer adapter physically
and fluidically
coupled to the barrel 130, the transfer adapter similarly places the lumen 133
of the barrel
130 in fluid communication with the fluid reservoir.
[1136] With the
barrel 130 in fluid communication with the fluid reservoir (not shown),
the user can manipulate the injector 100 by moving the handle 110 relative to
the barrel 130
in the proximal direction, which in turn, moves the piston 150 disposed within
the lumen 133
of the barrel 130 in the proximal direction. As such, a volume associated with
a portion of
the lumen 133 defined by the barrel 130 distal to the elastomeric member 155
of the piston
150 increases and a volume associated with a portion of the lumen 133 proximal
to the
37
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
elastomeric member 155 decreases. In some embodiments, the friction fit and/or
fluidic seal
defined between the elastomeric member 155 and the inner surface of the barrel
130 can be
such that the proximal movement of the piston 150 (e.g., the increase in
volume of the
portion of the lumen 133 distal to the elastomeric member 155) produces a
negative pressure
differential within the portion of the lumen 133, which can be operable in
drawing a volume
of the medicament and/or the drug formulation from the fluid reservoir and
into the portion of
the lumen 133 distal to the elastomeric member 155 (e.g., a medicament
volume). In some
embodiments, a predetermined volume of the drug formulation can be drawn into
the lumen
133 of the barrel 130. In other embodiments, the volume of the drug
formulation drawn into
the lumen 133 is not predetermined. With the desired amount of drug
formulation contained
in the barrel 130, the user can, for example, decouple the barrel 130 from the
transfer adapter
(not shown). Moreover, in some embodiments, the coupler 138 and/or the distal
end portion
132 of the barrel 130 can include a self-sealing port and/or any other
suitable port configured
to fluidically isolate the lumen 133 of the barrel 130 from a volume outside
of the barrel 130.
Although described above as transferring a volume of the drug formation from
the fluid
reservoir and into the lumen 133 of the barrel 130, in other embodiments, the
injector 100 can
be prefilled during, for example, a manufacturing process and/or any other
time prior to use.
[1137] In some
instances, with the desired amount of the drug formulation contained in
the barrel 130, the user can manipulate the injector 100 to couple the needle
hub 160 (e.g.,
disposed within the cap 170 or not disposed within the cap 170) to the distal
end portion 132
of the barrel 130, thereby placing the lumen 169 of the microneedle 166 in
fluid
communication with the lumen 133 of the barrel 130. With the needle hub 160
coupled to the
barrel 130, the user can remove the cap 170 from the needle hub 160 if it is
disposed
thereabout. In other instances, the cap 170 can already be removed. As such,
the user can
position the injector 100 relative to the ocular tissue such that the
microneedle 166 disposed
at or near a desired injection site. In some instances, the injection site can
be a predetermined
distance from, for example, the limbus 32. For example, as shown in FIG. 17,
the injection
site can be a distance D2 from the limbus 32 that is about 1 mm, about 2 mm,
about 3 mm,
about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about
10 mm,
or more. In other instances, an injection site can be relative to any suitable
portion of the eye.
[1138] With the
microneedle 166 at or near the desired injection site, the base 165 of the
needle hub 160 can be pressed against a target surface of the eye 10 as the
microneedle 166 is
38
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
inserted into the target surface. As such, the base 165 of the needle hub 160
can deform,
define an indent, and/or otherwise form a "dimple" in the target surface
(e.g., the conjunctiva
45 of the eye 10, as shown in FIG. 18). The "dimple" can facilitate a desired
transfer of the
medicament from the barrel 130 to the target region via the microneedle 166.
The base 165
of the needle hub 160, and thus the dimple, can be maintained in such a
position throughout
the procedure (e.g., the injection of medicament into a SCS 36). In this
manner, the "dimple"
(e.g., the interface between the distal surface of the base 165 and the
surface of the target
location) can limit and/or prevent seepage of the medicament from the target
region during
injection and post-injection, thereby promoting desirable transfer of the
medicament to the
target region (e.g., the SCS 36). As described above, in some embodiments, the
distal (or
contact) surface of the base 165 can include a sealing portion, which can be a
convex surface,
a surface having a smooth finish (e.g., with a surface finish of less than Ra
= 1.6 p.m) or the
like.
[1139] In
addition, in some embodiments, the microneedle 166 is inserted substantially
perpendicular or at an angle from about 80 to about 100 , into the eye 10,
reaching the
suprachoroidal space in a short penetration distance (e.g., about 1.1 mm,
about 1 mm, about
0.9 mm, or less). This is in contrast to long conventional microneedles 166 or
a cannula,
which approach the suprachoroidal space at a steep angle, taking a longer
penetration path
through the sclera 20 and other ocular tissues, increasing the invasiveness of
the method, the
size of the microneedle track and consequently increasing the risk of
infection and/or
vascular rupture. With such long microneedles 166, the ability to precisely
control insertion
depth is diminished relative to the micromicroneedle 166 approach described
herein.
[1140] Once the
distal end portion of the microneedle 166 is disposed within at least one
of the SCS 36, a lower portion of the sclera 20, and/or an upper portion of
the choroid 28 of
the eye 10 (FIG. 18), the medicament can be conveyed from the barrel 130. More
specifically, while maintaining the dimple at the conjunctiva 45, a user can
exert a force on
the handle 110 to begin an infusion event. In some instances, such as during
insertion, the
force exerted by a user on the handle 110 can be insufficient to move the
piston 150 within
the barrel 130 when the distal tip of the microneedle 166 is not disposed
within the desired
position (e.g., when the microneedle 166 is in the sclera 20 and not the SCS
36 of the eye 10).
Said another way, the injector 100 can be configured to assist a user in
delivering at least a
39
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
portion of the drug formulation to the region, while be configured or
"calibrated" to limit
and/or prevent delivery to another, different region.
[1141] In some
embodiments, the injector 100 can be configured to inform the user when
the distal tip of the microneedle 166 is in the target region, for example,
such that the drug
formulation can be delivered to the target region with high confidence. For
example, the
injector 100 can be configured to limit movement of the piston 150 within the
lumen 133 of
the barrel 130 when the distal tip of the microneedle 166 is disposed within a
region of the
eye 10, which has a greater density, such as the sclera 20. In some instances,
the injector 100
can limit movement of the piston 150 within the lumen 133 when the applied
force is below a
predetermined threshold such as about 6 Newtons (N). Conyersly, the injector
100 can allow
movement of the piston 150 within the barrel 130 when the distal tip of the
microneedle 166
is disposed within the target location (e.g., a region having a lower density,
such as the SCS
36) and when the force having the magnitude of less than about 6 N is exerted
on the piston
150 and/or the handle 110. In this manner, the system can be configured or
"calibrated" to
provide feedback (e.g., tactile feedback) to a user to allow the user to
deliver the drug
formulation to a target region with high confidence. In some instances, the
user can observe
movement, or lack of movement, of the piston 150 within the barrel 130 to
determine
whether medicament has been conveyed to the eye. If the medicament has not
been
conveyed, the user can respond accordingly. For example, the user can re-align
the system,
relocate to a different injection site, and/or use a different sized
microneedle 166 (e.g., a
different microneedle 166 length).
[1142] By way
of example, a user can manipulate the injector 100 to insert the
microneedle 166 into the eye 10 at a desired injection site. In some
instances, if the distal tip
of the microneedle 166 is not disposed in the desired position and is,
instead, disposed in the
sclera 20, a force exerted by the user on the handle 110 can be insufficient
to move the piston
150 within the barrel 130. For example, the sclera 20 can produce a
backpressure that, in
conjunction with the friction between the elastomeric member 155 and the inner
surface of
the barrel 130 and resistance to flow caused by the characteristics of the
drug (e.g., viscosity,
density or the like), overcomes the force exerted by the user, thereby
preventing and/or
limiting delivery of the drug formulation to the sclera 20. In other words,
the injector 100 is
specifically configured or "calibrated" such that the force is insufficient to
convey the drug
formulation to the sclera 20. Conversely, when the distal tip of the
microneedle 166 is
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
disposed in, for example, the SCS 36 of the eye 10, the same force exerted by
the user can be
sufficient to move the piston 150 within the barrel, based at least in part on
anatomical
differences and/or the differences in material properties between the sclera
20 and the SCS 36
(e.g., densities or the like). In other words, the force can be sufficient to
overcome a
backpressure produced by the SCS 36. In this manner, the injector 100 can be
configured to
ensure that the injection is initiated only when the distal tip of the
microneedle 166 is in
and/or near the SCS 36 such that the drug formulation (e.g., a medicament such
as, for
example, a corticosteroid (e.g., triamcinolone) VEGF inhibitor, a combination
thereof, or any
other medicament described herein) can be delivered only to that region.
Moreover, the SCS
36 produces a first pressure that resists and/or opposes flow from the distal
tip of the
microneedle 166, and the sclera 20 produces a second pressure that resists
and/or opposes
flow from the distal tip of the microneedle 166, which is higher than the
first pressure. In this
manner, a user can be informed by a loss of resistance felt at the handle 110
when the distal
tip of the microneedle 166 is transitioned from the sclera 20 to or near the
SCS 36.
[1143] In some
embodiments, the force exerted can be about 2 N, about 3 N, about 4 N,
about 5 N, about 6 N or more and inclusive of all ranges therebetween. In some
embodiments, the piston 150 and the barrel 130 can be collectively configured
such that the
force produces an injection pressure within the barrel 130 of between about
100 kPa and
about 500 kPa. For example, in some embodiments, the injection pressure can be
about 100
kPa, 110 kPa, 120 kPa, 130 kPa, 140 kPa, 150 kPa, 160 kPa, 170 kPa, 180 kPa,
190 kPa, 200
kPa, 220 kPa, 240 kPa, 260 kPa, 280 kPa, 300 kPa, 320 kPa, 340 kPa, 360 kPa,
380 kPa, 400
kPa, 420 kPa, 440 kPa, 460 kPa, or about 480 kPa, inclusive of all ranges and
values
therebetween. The injection pressure can be sufficient to overcome the
backpressure
produced by SCS 36, but insufficient to overcome the backpressure produced by
the sclera
20. In some embodiments, the force can be varied depending on the diameter of
the barrel
130 and/or the piston 150, the viscosity of the drug formulation, and/or the
material of the
barrel 130 and/or the piston 150. In this manner, regardless of the variations
in the piston
150, the barrel 130, and/or the drug formulation, the injector 100 produces an
injection
pressure within the barrel 130 of between about 100 kPa and about 500 kPa. In
some
embodiments, the drug formulation includes aflibercept and is used to treat a
patient for wet
AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO. In some
embodiments, the drug formulation includes triamcinolone acetonide and is used
in
conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD
associated with
41
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in
ocular
disease.
[1144] In some
embodiments, the injector 100 can be configured such that injection
distance traversed by the piston 150 is sufficient to deliver substantially
the entire desired
dose of the drug formulation into the SCS 36. In other embodiments, the
injector 100 can be
configured such that the injection distance traversed by the piston 150 is
sufficient to deliver
only a portion of the desired dose of the drug formulation into the SCS 36. In
such
embodiments, the injector 100 can be configured to initiate delivery of the
drug formulation
into the SCS 36, for example, to inform the user that the distal tip of the
microneedle 166 is
disposed within the SCS 36 (e.g., the user would see or otherwise detect that
the piston 150
has moved, thus indicating the desired positioning of the microneedle 166).
Said another
way, the injector 100 can assist the user in determining whether the distal
tip of the
microneedle 166 is within the SCS 36 or not by initiating delivery of the drug
formulation. In
such embodiments, the injection distance can be a first injection distance.
The user can then
move the distal end portion of the piston 150 a second injection distance, for
example, by
applying a manual force on the piston 150 (e.g., by moving the handle 110
relative to the
barrel 130, as described herein).
[1145] After
desirable conveyance of the medicament from the medicament container,
the hub 160 can be maintained in contact with the target surface for a time to
allow for a
desired medicament absorption by the eye. In this manner, the medicament can
spread
through tissues of the back of the eye without the medicament seeping from the
injection site
(e.g., where the microneedle 166 pierced the conjunctiva). As described above,
in some
embodiments, the distal end surface of the base 165 can include a sealing
portion configured
to form a substantially fluid-tight seal with the conjunctiva to limit
movement of the
medicament out of the eye along the needle track. In this manner, the injector
100 and the
methods described herein can facilitate delivery of the desired dose to the
desired regions of
the eye.
[1146] Although
the microneedle 166 is described above as having an effective length
that is about 900 p.m, in other embodiments, the injector 100 can be coupled
to a needle hub
that includes a microneedle with any suitable effective length. For example,
FIGS. 19 and 20
illustrate a needle hub 260 according to another embodiment. The needle hub
260 has a
proximal end portion 261, a distal end portion 262, and an indicator portion
268. In some
42
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
embodiments, the needle hub 260 can be substantially similar in form and
function as the
needle hub 160 described in detail above with reference to FIGS. 11-13. Thus,
portions of
the needle hub 260 are not described in further detail herein. The needle hub
260 can differ,
however, by being coupled to a base 265 including a microneedle 266 with an
effective
length greater than the effective length of the microneedle 160. For example,
in this
embodiment, the microneedle 266 extends from the base 265 by a distance D3 of
about 1100
p.m. Moreover, the indicator portion 268 of the needle hub 260 is configured
to present a
visual indication associated with the effective length and/or distance D3
(e.g., represented in
FIGS. 19 and 20 with the text "1100").
[1147] In yet
other embodiments, an injector can include a microneedle having an
effective length of between about 200 p.m and about 1500 p.m. A short
effective length
microneedle (e.g., a length of between about 200 p.m and about 400 p.m) can be
used, for
example, in various subdermal injection procedures. Injectors with a longer
effective length
microneedle (e.g., a length of between about 1200 p.m and about 1500 p.m) can
be used, for
example, in various ocular procedures, such as, injection into the subretinal
space.
[1148]
Referring now to FIG. 21, a flowchart is shown illustrating a method 1000 of
using a medical injector to deliver a drug formulation to ocular tissue
according to an
embodiment. In some embodiments, the drug formulation includes aflibercept and
is used to
treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD
associated
with RVO. In some embodiments, the drug formulation includes triamcinolone
acetonide
and is used in conjunction with aflibercept to treat a patient for wet AMD,
CNV, wet AMD
associated with CNV or wet AMD associated with RVO; or is used to improve any
VEGF
therapy in ocular disease. The method 1000 includes placing a needle hub of an
injector in
contact with a surface of an eye at a target location, at 1001. The medical
injector (also
referred to herein as "injector") can be any suitable injector. For example,
in some
embodiments, the injector can be substantially similar to or the same as the
injector 100
described above. As such, the injector can include at least a handle, a
barrel, a piston, and the
needle hub. As described above, the piston can be at least partially disposed
in the handle
and fixedly coupled thereto. A portion of the barrel can be movably disposed
in the handle to
allow for relative movement, for example, in a proximal or distal direction.
The barrel can
define a lumen configured to movably receive a portion of the piston and that
can receive,
store, and/or contain a volume of a drug formulation. The needle hub can be
coupled to the
43
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
barrel to place a lumen of a microneedle coupled thereto, in fluid
communication with the
lumen of the microneedle.
[1149] A first
force is exerted on a portion of the injector to deform a portion of the
surface of the eye associated with the target location, at 1002. For example,
in some
instances, a user can align the injector with a target location along the
surface of the eye and
can move the injector to insert the microneedle into the eye and to place the
needle hub in
contact with a surface of the eye. The user can then exert the first force on
the handle, and in
response, at least a portion of the first force is transferred from the needle
hub to the surface
of the eye. For example, in some instances, the needle hub can exert on the
conjunctiva,
which can result in a dimple being formed in the conjunctiva. In some
instances, the needle
hub can remain in contact with the eye and can continue to deform the portion
of the eye until
after an injection event, which in turn, can prevent seepage and/or the like.
[1150] A second
force is exerted on the portion of the injector to move a needle (e.g., the
microneedle) of the injector through the sclera of the eye until a distal
surface of the needle is
disposed at a predetermined depth within the eye, at 1003. In some
embodiments, the
arrangement of the injector can be such that prior to the distal surface of
the needle being
disposed at the predetermined depth, the second force exerted on the portion
of the injector is
sufficient to move the needle through the ocular tissue, but insufficient to
move the piston
within the barrel. For example, in some embodiments, the piston can include an
elastomeric
member (e.g., a plunger or the like) that can form a friction fit with an
inner surface of the
barrel, which in turn, can define a reaction force that resists the movement
of the piston
within the barrel. Moreover, in some instances, the ocular tissue exerts a
backpressure or the
like in response to the insertion of the needle. As such, the amount of force
exerted to move
the needle through the ocular tissue (e.g., the sclera) can be less than an
amount of force to
move the piston within the barrel and/or otherwise inject the drug
formulation.
[1151] A volume
of a drug formulation is expelled through the needle and into a region
of the eye associated with a suprachoroidal space, at 1004. In some instances,
the region of
the eye can be disposed at the predetermined depth within the eye. More
specifically, while
the injector is described above as moving the needle through the eye
substantially without
expelling the drug formulation in response to the second force, the second
force exerted on
the portion of the injector (e.g., the handle) can be sufficient to expel the
drug formulation
through the needle and into the suprachoroidal space when the needle is
disposed at a
44
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
predetermined depth. For example, in some instances, the density of the sclera
and the
friction force between the piston and the inner surface of the barrel,
collectively, are
sufficient to resist a distal movement of the piston in response to the second
force.
Conversely, once the distal surface of the needle is disposed at a depth
within the eye (e.g., at
or near the suprachoroidal space), the density of that portion of the eye can
be less than the
density of the sclera. Thus, the collective force exerted by the friction
force and the anatomy
of the eye in response to the second force is reduced. In this manner, the
second force can
become sufficient to move the piston in the distal direction within the barrel
to expel the drug
formulation into the suprachoroidal space. In some instances, the user
exerting the second
force on the portion of the injector can feel a loss of resistance and/or the
like, which can be
an indication that the distal surface of the needle is disposed at a desired
depth.
[1152] While
the method 1000 is described above as including a set of steps, in some
instances, the method 1000 can include any number of optional steps and/or pre-
procedural or
post-procedural steps. For example, in some embodiments, a method of
delivering a drug
formulation to ocular tissue in a clinical study can be similar to the method
1000 and can
include at least some of the following steps:
1. Ensure a study participant's eye remains dilated.
2. Anesthetize study eye (e.g., with topical anesthesia).
3. Wait appropriate amount of time after the placement of anesthesia.
4. Sterilize and prep eye, insert lid speculum and ensure eyelids are fully
retracted per standard of care, and measure injection site with calipers.
5. Retrieve the study drug kit.
6. Remove vial of a drug formulation and shake vigorously for 10 seconds
before use to ensure a uniform suspension.
7. Remove plastic top from vial and prepare vial using standard aseptic
techniques.
8. Prepare an injector. The injector can be any of the injectors shown and
described herein, such as the injector 100.
a. Attach the provided drug transfer needle (sterile, disposable,
hypodermic needle) to the microinjector.
b. Insert the drug transfer needle into the vial by piercing the septum.
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
c. Invert the vial, inject the air and withdraw > 200 pL the drug
formulation by pulling back on the microinjector handle.
d. Withdraw drug transfer needle from the vial.
e. Remove the drug transfer needle from the microinjector handle and
attach the microneedle (900 pm). The microneedle can include the hub
160 shown and described above.
f Prime the injector and ensure enough drug is available to deliver 100 pt
of the drug formulation into the SCS.
9. After priming, the drug formulation should be injected without delay to
prevent settling of the drug in the syringe.
10. Holding the microinjector, insert the microneedle into the sclera
perpendicular to the ocular surface. Target location should be approximately
4-5 mm from the limbus and the superior temporal quadrant is the
recommended location for suprachoroidal injections. Ensure the approach is as
perpendicular to the sclera as possible. Do not bend or angle the microneedle
at any time during the procedure.
11. Once the microneedle is inserted into the sclera, ensure that the hub of
the
microneedle is in firm contact with the conjunctiva. Firm contact of the
microneedle injection system with the conjunctiva will be observed as a
slight,
localized dimple of the globe around the microneedle hub.
12. Stabilize the microneedle with one hand while applying this constant
downward force throughout the injection procedure.
13. Using the other hand (if necessary), advance the injector handle until up
to
100 pL of the drug formulation is injected over a 5-10 second period. During
this process, ensure that nominal pressure continues to be placed on the
needle
such that it is in tight contact with the conjunctiva.
14. If there is resistance to flow through the microneedle, remove the
microneedle from the eye and examine the eye for any issues. If subject safety
is not at risk, investigator may choose to verify potency of the microneedle
and
use best medical judgment to restart the injection procedure at a new site
adjacent to the original injection site or use a longer microneedle length
(1100
pm). Ensure there is enough the drug formulation remaining in the
46
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
microinjector to prime the replacement microneedle and deliver a 100 pl dose.
Repeat the microinjector process as stated above in step 9.
15. Maintain light pressure on the microneedle once injection is complete and
hold for 5-10 seconds.
16. Obtain cotton swab and remove the microneedle slowly from the eye.
Simultaneously cover the injection site with the cotton swab.
17. Hold the swab over the injection site with light pressure for a few
seconds
to ensure minimal reflux upon removal. Remove cotton swab.
18. Remove the lid speculum.
19. Following the SCS injection, assess eye via indirect ophthalmoscope.
111531 In some
embodiments, the drug formulation includes aflibercept and is used to
treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD
associated
with RVO. In some embodiments, the drug formulation includes triamcinolone
acetonide and
is used in conjunction with aflibercept to treat a patient for wet AMD, CNV,
wet AMD
associated with CNV or wet AMD associated with RVO; or is used to improve any
VEGF
therapy in ocular disease. In some embodiments, the triamcinolone acetonide is
administered
to the SCS using the methods provided herein, and aflibercept is administered
intravitreally.
111541
Alternatively, preparing an injector, which can be any of the injectors shown
and
described herein, suhb as the injector 100 (e.g., step 8 above) can include:
a. Attach the provided vial access device (sterile, disposable) to the vial of
study drug by inserting it into the vial while the vial is on a flat surface.
b. Detach the cap from the vial access device.
c. Fully pull back on the plunger handle to draw air into the injector.
d. Attach the microinjector handle (syringe) to the vial access device and
inject the air.
e. Invert the vial and withdraw > 200 pt of the drug formulation by
pulling back on the microinjector handle.
f Replace the vial access device with the 900 p.m needle.
g. Recap the vial access device.
h. Mark the injection site with the needle cap or calipers.
i. Prime the microinjector to remove the excess air.
47
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
j. Depress the handle until the plunger reaches the 100 1.1L marking on the
syringe.
[1155] Although
the medical injectors and methods described herein are shown as
including a device including a needle and a reservoir including a medicament,
in other
embodiments, a medical device or kit can include a simulated medicament
injector. In some
embodiments, the simulated medicament injector can correspond to an actual
medicament
injector (e.g., the medical injector 100 described above) and can be used, for
example, to train
a user in the operation of the corresponding actual medical injector, to
perform a "sham"
injection as part of a clinical trial protocol, or the like.
[1156] A
simulated medical injector can simulate the actual medical injector in any
number of ways. For example, in some embodiments, the simulated medical
injector can
have a shape corresponding to a shape of the actual medical injector (e.g.,
injector 100), a
size corresponding to a size of the actual medical injector (e.g., injector
100) and/or a weight
corresponding to a weight of the actual medical injector (e.g., injector 100).
Moreover, in
some embodiments, the simulated medical injector can include components that
correspond
to the components of the actual medical injector. In this manner, the
simulated medical
injector can simulate the look, feel and sounds of the actual medical
injector. For example, in
some embodiments, the simulated medical injector can include external
components (e.g., a
base, a handle, or the like) that correspond to external components of the
actual medical
injector. In some embodiments, the simulated medical injector can include
internal
components (e.g., a plunger) that correspond to internal components of the
actual medical
injector.
[1157] In some
embodiments, however, the simulated medical injector can be devoid of a
medicament and/or those components that cause the medicament to be delivered
(e.g., a
microneedle). In this manner, the simulated medical injector can be used to
train a user in the
use of the actual medical injector without exposing the user to a needle
and/or a medicament.
Moreover, the simulated medical injector can have features to identify it as a
training device
to prevent a user from mistakenly believing that the simulated medical
injector can be used to
deliver a medicament.
48
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1158] In some
embodiments, a method of delivering a drug formulation to ocular tissue
in a clinical study can be similar to the method 1000 and can include at least
some of the
following steps:
1. Ensure a study participant's eye remains dilated.
2. Anesthetize study eye (e.g., with topical anesthesia).
3. Wait appropriate amount of time after the placement of anesthesia.
4. Sterilize and prep eye, insert lid speculum and ensure eyelids are fully
retracted per standard of care, and measure injection site with calipers.
5. Retrieve the study drug kit.
6. Prepare microinjector. The microinjector can be any of the injectors shown
and described herein, such as the injector 100. Moreover, the microinjector
can be a simulated microinjector, including a needless hub. This preparation
includes:
a. Attach the needleless hub to the microinjector handle
7. Prepare for sham (or training) procedure:
a. Holding the microinjector, press the sham needleless hub into the sclera
at the target location.
b. Ensure the approach is as perpendicular to the sclera as possible. Do not
angle the microinjector at any time during the procedure.
c. Ensure that the needleless hub is in firm contact with the conjunctiva.
Firm contact of the microinjector with the conjunctiva will be observed as
a slight, localized dimple of the globe around the needleless hub.
8. Administer sham procedure:
a. Maintain the needle hub against the eye while gently depressing the
handle throughout the injection procedure. Perform a sham suprachoroidal
injection to the study eye over a 5-10 second period.
b. Maintain the needleless hub against the eye for 5-10 seconds following
the sham injection.
c. Obtain cotton swab and remove the needleless hub slowly from the eye.
Simultaneously cover the sham site with the cotton swab.
d. Hold the swab over the injection site for a few seconds and then remove
cotton swab.
9. Remove lid speculum.
10. Following the SCS injection, assess eye via indirect ophthalmoscope.
49
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1159] The
microneedle devices described herein also may be adapted to use the one or
more microneedles as a sensor to detect analytes, electrical activity, and
optical or other
signals. The sensor may include sensors of pressure, temperature, chemicals,
and/or
electromagnetic fields (e.g., light). Biosensors can be located on or within
the microneedle,
or inside a device in communication with the body tissue via the microneedle.
The
microneedle biosensor can be any of the four classes of principal transducers:
potentiometric,
amperometric, optical, and physiochemical. In one embodiment, a hollow
microneedle is
filled with a substance, such as a gel, that has a sensing functionality
associated with it. In an
application for sensing based on binding to a substrate or reaction mediated
by an enzyme,
the substrate or enzyme can be immobilized in the needle interior. In another
embodiment, a
wave guide can be incorporated into the microneedle device to direct light to
a specific
location, or for detection, for example, using means such as a pH dye for
color evaluation.
Similarly, heat, electricity, light, ultrasound or other energy forms may be
precisely
transmitted to directly stimulate, damage, or heal a specific tissue or for
diagnostic purposes.
[1160] The
microneedle device for non-surgically delivering drug to the suprachoroidal
space of the eye of a human subject, in one embodiment, comprises a hollow
microneedle.
The device may include an elongated housing for holding the proximal end of
the
microneedle. The device may further include a means for conducting a drug
formulation
through the microneedle. For example, the means may be a flexible or rigid
conduit in fluid
connection with the base or proximal end of the microneedle. The means may
also include a
pump or other devices for creating a pressure gradient for inducing fluid flow
through the
device. The conduit may in operable connection with a source of the drug
formulation. The
source may be any suitable container. In one embodiment, the source may be in
the form of a
conventional syringe. The source may be a disposable unit dose container. In
some
embodiments, the drug formulation includes aflibercept and is used to treat a
patient for wet
AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO. In some
embodiments, the drug formulation includes triamcinolone acetonide and is used
in
conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD
associated with
CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in
ocular
disease.
[1161] The
transport of drug formulation or biological fluid through a hollow
microneedle can be controlled or monitored using, for example, one or more
valves, pumps,
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
sensors, actuators, and microprocessors. For instance, in one embodiment the
microneedle
device may include a micropump, microvalve, and positioner, with a
microprocessor
programmed to control a pump or valve to control the rate of delivery of a
drug formulation
through the microneedle and into the ocular tissue. The flow through a
microneedle may be
driven by diffusion, capillary action, a mechanical pump, electroosmosis,
electrophoresis,
convection or other driving forces. Devices and microneedle designs can be
tailored using
known pumps and other devices to utilize these drivers. In one embodiment, the
microneedle
device may further include an iontophoretic apparatus, similar to that
described in U.S. Patent
6,319,240 to Beck, for enhancing the delivery of the drug formulation to the
ocular tissue. In
another embodiment the microneedle devices can further include a flowmeter or
other means
to monitor flow through the microneedles and to coordinate use of the pumps
and valves.
[1162] In some
embodiments, the flow of drug formulation or biological fluid can be
regulated using various valves or gates known in the art. The valve may be one
which can be
selectively and repeatedly opened and closed, or it may be a single-use type,
such as a
fracturable barrier. Other valves or gates used in the microneedle devices can
be activated
thermally, electrochemically, mechanically, or magnetically to selectively
initiate, modulate,
or stop the flow of material through the microneedles. In one embodiment, the
flow is
controlled with a rate-limiting membrane acting as the valve.
[1163] In other
embodiments, the flow of drug formulation or biological fluid can be
regulated by the internal friction of various components, the characteristics
of the
medicament to be injected (e.g., the viscosity) and/or the characteristics of
the desired
injection site. For example, as described above, in some embodiments, a drug
product can be
configured for delivery of a specific formulation to a specific location. In
such embodiments,
a drug product can include a microinjector (e.g., microinjector 100) and a
medicament (e.g.,
triamcinolone or any other formulations described herein) that is configured
to deliver the
medicament to a specific target region (e.g., the SCS). In this example, the
drug product can
be configured such that the flow of the medicament is limited when injection
is attempted
into a different target region having a higher density (e.g., the sclera).
Thus, the drug product
is configured to regulate the flow by allowing flow when the injection is
attempted into the
desired target region.
[1164] The
microneedle, in one embodiment, is part of an array of two or more
microneedles such that the method further includes inserting at least a second
microneedle
51
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
into the sclera without penetrating across the sclera. In one embodiment,
where an array of
two or more microneedles are inserted into the ocular tissue, the drug
formulation of each of
the two or more microneedles may be identical to or different from one
another, in drug,
formulation, volume/quantity of drug formulation, or a combination of these
parameters. In
one case, different types of drug formulations may be injected via the one or
more
microneedles. For example, inserting a second hollow microneedle comprising a
second drug
formulation into the ocular tissue will result in delivery of the second drug
formulation into
the ocular tissue.
[1165] In
another embodiment, the device includes an array of two or more microneedles.
For example, the device may include an array of from 2 to 1000 (e.g., from 2
to 100 or from 2
to 10) microneedles. In one embodiment, a device includes between 1 and 10
microneedles.
An array of microneedles may include a mixture of different microneedles. For
instance, an
array may include microneedles having various lengths, base portion diameters,
tip portion
shapes, spacings between microneedles, drug coatings, etc. In embodiments
wherein the
microneedle device comprises an array of two or more microneedles, the angle
at which a
single microneedle extends from the base may be independent from the angle at
which
another microneedle in the array extends from the base.
[1166] The SCS
drug delivery methods provided herein allow for the delivery of drug
formulation over a larger tissue area and to more difficult to target tissue
in a single
administration as compared to previously known needle devices. Not wishing to
be bound by
theory, it is believed that upon entering the SCS the drug formulation flows
circumferentially
from the insertion site toward the retinochoroidal tissue, macula, and optic
nerve in the
posterior segment of the eye as well as anteriorly toward the uvea and ciliary
body. In
addition, a portion of the infused drug formulation may remain in the SCS as a
depot, or
remain in tissue overlying the SCS, for example the sclera, near the
microneedle insertion
site, serving as additional depot of the drug formulation that subsequently
can diffuse into the
SCS and into other adjacent posterior tissues.
[1167] The
human subject treated with the methods and devices provided herein may be
an adult or a child. In one embodiment, the patient presents with a retinal
thickness of greater
than 300 p.m (e.g., central subfield thickness as measured by optical
coherence tomography).
In another embodiment, the patient in need of treatment has a BCVA score of?
20 letters
read in each eye (e.g., 20/400 Snellen approximate). In yet another
embodiment, the patient
52
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
in need of treatment has a BCVA score of? 20 letters read in each eye (e.g.,
20/400 Snellen
approximate) , but < 70 letters read in the eye in need of treatment.
[1168] The
patient in one embodiment has macular edema (ME) that involves the fovea.
In one embodiment, in a method for treating ME associated with uveitis, the ME
is due to the
uveits and not due to any other cause. In an embodiment for treating ME
following RVO, the
ME is due to RVO and not due to any other cause of ME. In a further
embodiment, the RVO
is branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO) or
central
retinal vein occlusion (CRVO). In one embodiment, the patient in need of
treatment
experiences a decrease in visual acuity due to the ME.
[1169] The
microneedle devices and non-surgical methods described herein may be used
to deliver drug formulations to the eye of a human subject, particularly for
the treatment,
diagnosis, or prevention of a posterior ocular disorder, such as uveitis
(e.g., non-infectious,
infectious, intermediate, posterior or pan uveitis), macular edema associated
with uveitis, e.g.,
non-infectious, intermediate, posterior or pan uveitis and macular edema
associated with
RVO. In one embodiment, the drug formulation comprises an effective amount of
an anti-
inflammatory drug. In one embodiment, the patient is in need of treatment of
macular edema
associated with uveitis or macular edema associated with RVO and the drug
formulation
comprises an anti-inflammatory drug selected from a steroid compound and a non-
steroidal
anti-inflammatory drug (NSAID). In even a further embodiment, the drug
formulation is a
triamcinolone formulation, e.g., a triamcinolone acetonide formulation.
[1170]
Posterior ocular disorders amenable for treatment by the methods, devices and
drug formulations described herein can include, but are not limited to,
uveitis (e.g.,
infectious uveitis, non-infectious uveitis, chronic uveitis, and/or acute
uveitis), macular
edema, diabetic macular edema (DME), macular edema associated with uveitis
(encompassing macular edema associated with infectious uveitis and macular
edema
associated with non-infectious uveitis), macular edema following retinal vein
occlusion
(RVO), macular edema associated with RVO,. In some embodiments, the posterior
ocular
disorder is macular edema associated with uveitis. In a further embodiment,
the uveitis is a
non-infectious uveitis.
[1171] The
uveitis can be either acute or chronic uveitis. Uveitis, and macular edema
associated with uveitis can be caused by infectious causes leading to
infectious uveitis, such
53
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
as infection with viruses, fungi, parasites, and/or the like. Uveitis can also
be caused by non-
infectious causes, such as the presence of noninfectious foreign substances in
the eye,
autoimmune diseases, surgical and/or traumatic injury, and/or the like.
Disorders caused by
pathogenic organisms that can lead to infectious uveitis, and to macular edema
associated
with infectious uveitis, include, but are not limited to, toxoplasmosis,
toxocariasis,
histoplasmosis, herpes simplex or herpes zoster infection, tuberculosis,
syphilis, sarcoidosis,
Vogt-Koyanagi-Harada syndrome, Behcet's disease, idiopathic retinal
vasculitis, Vogt-
Koyanagi-Harada Syndrome, acute posterior multifocal placoid pigment
epitheliopathy
(APMPPE), presumed ocular histoplasmosis syndrome (POHS), birdshot
chroidopathy,
Multiple Sclerosis, sympathetic opthalmia, punctate inner choroidopathy, pars
planitis, or
iridocyclitis. Acute uveitis and/or macular edema associated with acute
uveitis occurs
suddenly and may last for up to about six weeks. In chronic uveitis and/or
macular edema
associated with chronic uveitis, the onset of signs and/or symptoms is
gradual, and symptoms
last longer than about six weeks.
[1172] Signs of
uveitis include ciliary injection, aqueous flare, the accumulation of cells
visible on ophthalmic examination, such as aqueous cells, retrolental cells,
and vitreouscells,
keratic precipitates, and hypema. Symptoms of uveitis include pain (such as
ciliary spasm),
redness, photophobia, increased lacrimation, and decreased vision. Posterior
uveitis affects
the posterior or choroid part of the eye. Inflammation of the choroid part of
the eye is also
often referred to as choroiditis. Posterior uveitis is may also be associated
with inflammation
that occurs in the retina (retinitis) or in the blood vessels in the posterior
segment of the eye
(vasculitis). In one embodiment, the methods provided herein comprise non-
surgically
administering to a uveitis patient suffering from macular edema associated
with uveitis (e.g.,
non-infectious uveitis) in need thereof, an effective amount of an anti-
inflammatory drug
formulation to the SCS of the eye of the patient. In a further embodiment, the
patient
experiences a reduction in the severity of the symptoms of with macular edema
associated
with uveitis, after administration of the drug formulation. In one embodiment,
the drug is a
steroidal compound. In even a further embodiment, the drug is triamcinolone.
In some
embodiments, the drug formulation includes aflibercept and is used to treat a
patient for wet
AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO. In some
embodiments, the drug formulation includes triamcinolone acetonide and is used
in
conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD
associated with
54
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in
ocular
disease.
[1173] In one
embodiment, the patient undergoing one of the treatment methods provided
herein, for example, the treatment of macular edema associated with uveitis or
macular
edema associated with RVO, experiences a reduction in fluid accumulation,
inflammation,
neuroprotection, complement inhibition, drusen formation, scar formation,
and/or a reduction
in choriocapillaris or choroidal neocasvularization.
[1174] Without
wishing to be bound by theory, upon non-surgical SCS administration,
the drug remains localized in the posterior segment of the eye, specifically,
the choroid and
retina. Limiting drug exposure to other eye tissues, in one embodiment,
reduces the
incidences of side effects associated with the prior art methods.
[1175] In one
embodiment, from about 2 to about 24 dosing sessions are employed, for
example, from about 2 to about 24 intraocular dosing sessions (e.g.,
intravitreal or
suprachoroidal injection). In a further embodiment, from about 3 to about 30,
or from about
to about 30, or from about 7 to about 30, or from about 9 to about 30, or from
about 10 to
about 30, or from about 12 to about 30 or from about 12 to about 24 dosing
sessions are
employed.
[1176]
Treatment regimens will vary based on the therapeutic formulation being
delivered and/or the indication being treated. In one embodiment, a single
dosing session is
effective in treating one of the indications described herein. However, in
another
embodiment, multiple dosing sessions are employed. In one embodiment, where
multiple
dosing sessions are employed, the dosing sessions are spaced apart by from
about 10 days to
about 70 days, or from about 10 days to about 60 days, or from about 10 days
to about 50
days, or from about 10 days to about 40 days, or from about 10 days to about
30 days, or
from about 10 days to about 20 days. In another embodiment, where multiple
dosing
sessions are employed, the dosing sessions are spaced apart by from about 20
days to about
60 days, or from about 20 days to about 50 days, or from about 20 days to
about 40 days, or
from about 20 days to about 30 days. In even another embodiment, the multiple
dosing
sessions are weekly (about every 7 days), bi-weekly (e.g., about every 14
days), about every
21 days, monthly (e.g., about every 30 days), or bi-monthly (e.g., about every
60 days). In
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
yet another embodiment, the dosing sessions are monthly dosing sessions (e.g.,
from about 28
days to about 31 days) and at least three dosing sessions are employed.
[1177] In one
embodiment, the non-surgical SCS delivery methods, for example, with
one of the devices provided herein, are used to treat a patient in need of
treatment of macular
edema associated with uveitis (e.g., non-infectious uveitis). In one
embodiment, SCS
administration of a drug (e.g., an anti-inflammatory compound such as a
steroid or NSAID)
via the methods described herein reduces the vitreous haze experienced by the
patient.
[1178] In one
embodiment, vitreous haze will is assessed via indirect ophthalmoscopy
using a standardized photographic scale ranging from 0 to 4, with 0 - 4
defined below in
Table 1 (Nussenblatt 1985 as modified in Lowder 2011, incorporated by
reference herein in
their entireties). Vitreous haze in another embodiment, is graded from color
fundus
photographs according to a similar scale.
Table 1
Score Description
0 No inflammation
+ 0.5 Trace inflammation (slight blurring of the optic disc
margins
and/or loss of the nerve fiber layer reflex)
+ 1 Mild blurring of the retinal vessels and optic nerve
+ 1.5 Optic nerve head and posterior retina view obsuration
greater
than +1 but less than +2
+ 2 Moderate blurring of the optic nerve head
+ 3 Marked blurring of the optic nerve head
+ 4 Optic nerve head not visible
[1179] In yet
another embodiment, the non-surgical SCS delivery methods provided
herein reduce the macular edema experienced by a patient suffering from
macular edema
associated with RVO.
[1180] In one
embodiment, a method is provided for treating a human patient for wet
AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO. The
method comprises surgically or non-surgically administering aflibercept to the
SCS of one or
both of the patient's eyes, wherein upon administration, the drug is
substantially retained in
the SCS and/or another posterior region of the eye. In a further embodiment,
upon
administration, the drug is substantially localized to one or more of the SCS,
choroid and/or
56
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
retina. The efficacy of the method, in one embodiment, is measured by
measuring the
patient's mean change from baseline in macula thickness at one or more time
points after the
patient is treated. For example, at one week, two weeks, three weeks, one
month, two
months, three months, four months or more, including all durations in between,
after
treatment, e.g., with an anti-inflammatory drug delivered non-surgically to
the SCS, mean
change from baseline in retinal thickness and/or macula thickness is measured.
In a further
embodiment, a second drug formulation comprising a VEGF modulator (e.g., a
VEGF
antagonist) is administered to the eye of the patient via an intravitreal
injection. In a further
embodiment, the VEGF modulator is ranibizumab, aflibercept or bevacizumab.
[1181] A
decrease in retina thickness and/or macula thickness is one measurement of
treatment efficacy of the methods provided herein. For example, in one
embodiment, a
patient treated by one of the methods provided herein for example with one of
the devices
described herein experiences a decrease in retinal thickness from baseline
(e.g., retinal
thickness such as central subfield thickness (CST) prior to treatment), at any
given time point
after at least one dosing session (single session or multiple dosing sessions,
of at least about
20 p.m, or at least about 40 p.m, or at least about 50 p.m, or at least about
100 p.m, or at least
about 150 p.m or at least about 200 p.m, or from about 50-100 p.m, and all
values in between.
In another embodiment, the patient experiences a? 5%,> 10%,> 15%,> 20%,> 25%
decrease
in retinal thickness (e.g., CST) subsequent to at least one dosing session.
[1182] In one
embodiment, the decrease in retinal thickness is measured about 2 weeks,
about 1 month, about 2 months, about 3 months or about 6 months after the at
least one
dosing session. In another embodiment, the decrease in retinal thickness is
measured at least
about 2 weeks, at least about 1 month, at least about 2 months, at least about
3 months or at
least about 6 months after the at least one dosing session. In one embodiment,
where
multiple dosing sessions are employed, a decrease in retinal thickness is
sustained by the
patient for at least about 2 weeks, at least about 1 month, at least about 2
months, at least
about 3 months or at least about 6 months after each dosing session.
[1183] In one
embodiment, a macular edema associated with uveitis (e.g., non-infectious
uveitis) patient treated by the methods provided herein experiences a decrease
in retinal
thickness from baseline (i.e., retinal thickness prior to treatment), at any
given time point, of
from about 20 p.m to about 200 p.m, at from about 40 p.m to about 200 p.m, of
from about 50
p.m to about 200 p.m, of from about 100 p.m to about 200 p.m, or from about
150 p.m to about
57
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
200 p.m. In one embodiment, change in retinal thickness from baseline is
measured as a
change in CST, for example, by spectral domain optical coherence tomography
(SD-OCT).
[1184] In yet
another embodiment, the therapeutic response is a change from baseline in
macula thickness at one or more time points after the patient is treated. For
example, at one
week, two weeks, three weeks, one month, two months, three months, four months
or more,
including all durations in between, after a dosing session, e.g., with an anti-
inflammatory
drug such as triamcinolone delivered non-surgically to the SCS, change from
baseline in
macula thickness is measured. A decrease in macula thickness (as compared to
prior to
treatment) is one measurement of therapeutic response (e.g., by about 10%, or
about 20%, or
about 30%, or about 40%, or about 50%, or about 60% and more, including all
values in
between).
[1185]
Efficacy, in another embodiment, is assessed via a visual acuity measurement
at
one and/or two months post treatment (e.g., by measuring the mean change in
best corrected
visual acuity (BCVA) from baseline, i.e., prior to treatment). In one
embodiment, a patient
treated by one or more of the methods provided herein experiences an
improvement in BCVA
from baseline, at any given time point (e.g., 2 weeks after administration, 4
weeks after
administration, 2 months after at least one dosing session, 3 months after
administration), of
at least 2 letters, at least 3 letters, at least 5 letters, at least 8
letters, at least 12 letters, at least
13 letters, at least 15 letters, at least 20 letters, and all values in
between, as compared to the
patient's BVCA prior to the at least one dosing session.
[1186] In one
embodiment, the patient, for example a macular edema associated with
uveitis patient or a macular edema associated with RVO patient gains about 5
letters or more,
about 10 letters or more, 15 letters or more, about 20 letters or more, about
25 letters or more
in a BCVA measurement after a dosing regimen is complete, for example a
monthly dosing
regimen, compared to the patient's BCVA measurement prior to undergoing
treatment. In
even a further embodiment, the patient gains from about 5 to about 30 letters,
10 to about 30
letters, from about 15 letters to about 25 letters or from about 15 letters to
about 20 letters in a
BCVA measurement upon completion of at least one dosing session, compared to
the
patient's BCVA measurement prior to the at least one dosing session. In one
embodiment,
the BCVA gain is about 2 weeks, about 1 month, about 2 months, about 3 months
or about 6
months after the at least one dosing session. In another embodiment, the BCVA
is measured
58
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
at least about 2 weeks, at least about 1 month, at least about 2 months, at
least about 3 months
or at least about 6 months after the at least one dosing session.
[1187] In one
embodiment, the BCVA is based on the Early Treatment of Diabetic
Retinopathy Study (ETDRS) visual acuity charts and is assessed at a starting
distance of 4
meters.
[1188] In
another embodiment, the patient subjected to a treatment method, e.g., with
one
of the devices provided herein substantially maintains his or her vision
subsequent to the
treatment (e.g., a single dosing session or multiple dosing sessions), as
measured by losing
fewer than 15 letters in a best-corrected visual acuity (BCVA) measurement,
compared to the
patient's BCVA measurement prior to undergoing treatment. In a further
embodiment, the
patient loses fewer than 10 letters, fewer than 8 letters, fewer than 6
letters or fewer than 5
letters in a BCVA measurement, compared to the patient's BCVA measurement
prior to
undergoing treatment.
[1189] Decrease
in vitreous haze can also be used as a measure of the method's efficacy.
Decreases in vitreous haze can be qualitatively and/or quantitatively
determined by
techniques such as, but not limited to, photographic grading, a scoring
system, a multi-point
scale, a multi-step scale (e.g. a multi-step logarithmic scale, manual
screening by one or more
examiners, and/or the like).
[1190] In one
embodiment, the decrease in vitreous haze is present about 2 weeks, about
1 month, about 2 months, about 3 months or about 6 months after the at least
one dosing
session. In another embodiment, the decrease in retinal thickness is present
at least about 2
weeks, at least about 1 month, at least about 2 months, at least about 3
months or at least
about 6 months after the at least one dosing session. In one embodiment, where
multiple
dosing sessions are employed, a decrease in vitreous haze is experienced by
the patient and is
present at least about 2 weeks, at least about 1 month, at least about 2
months, at least about 3
months or at least about 6 months after each dosing session.
[1191] In one
embodiment, the methods provided herein provide for effective treatment
of a patient who had previously undergone treatment for wet AMD, CNV, wet AMD
associated with CNV or wet AMD associated with RVO but was unresponsive, or
not
properly responsive to the prior treatment for the respective posterior ocular
disorder. As one
of skill in the art will appreciate, a patient unresponsive or not properly
responsive to
59
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
treatment does not exhibit an improvement in a symptom or improvement in a
clinical
manifestation of macular edema associated with the disorder. In one
embodiment, the
symptom or clinical manifestation is lesion size, inflammation, edema, visual
acuity and/or
vitreous haze.
[1192] In
patients undergoing ocular treatment via shunts or cannulae, or other surgical
methods, a marked increase or decrease in intraocular pressure has been
reported after the
treatment method commences. In one embodiment, the intraocular pressure (TOP)
of the
patient's eye undergoing treatment for macular edema associated with uveitis
(e.g., non-
infectious uveitis), macular edema associated with RVO, 2 minutes, 10 minutes,
15 minutes,
30 minutes or 1 hour after suprachoroidal drug administration according to the
devices (e.g.,
the device 100) and/or the methods disclosed herein, is substantially the same
TOP, compared
to the TOP of the patient's eye prior to administration of the drug for
treating macular edema
associated with uveitis. In one embodiment, the TOP of the patient's eye
undergoing
treatment for macular edema associated with uveitis (e.g., non-infectious
uveitis), macular
edema associated with RVO or wet AMD, choroidal neovascularization (CNV), wet
AMD
associated with CNV, 2 minutes, 10 minutes, 15 minutes, 30 minutes or 1 hour
after
suprachoroidal drug administration, varies by no more than 10%, compared to
the TOP of the
patient's eye prior to administration of the drug for treating macular edema
associated with
uveitis (e.g., non-infectious uveitis), macular edema associated with RVO or
wet AMD. In
one embodiment, the TOP of the patient's eye undergoing treatment for the
macular edema
associated with uveitis (e.g., non-infectious uveitis), macular edema
associated with RVO or
wet AMD, 2 minutes, 10 minutes, 15 minutes or 30 minutes after suprachoroidal
drug
administration, varies by no more than 20%, compared to the TOP of the
patient's eye prior to
administration of the drug for treating macular edema associated with uveitis
(e.g., non-
infectious uveitis), macular edema associated with RVO. In one embodiment, the
TOP of the
patient's eye undergoing treatment for macular edema associated with uveitis
(e.g., non-
infectious uveitis), macular edema associated with RVO or wet AMD, choroidal
neovascularization (CNV), wet AMD associated with CNV, wet AMD associated with
RVO,
2 minutes, 10 minutes, 15 minutes or 30 minutes after suprachoroidal drug
administration,
varies by no more than 10%-30%, compared to the TOP of the patient's eye prior
to
administration of the drug for treating macular edema associated with uveitis
(e.g., non-
infectious uveitis), macular edema associated with RVO, wet AMD, choroidal
neovascularization (CNV), or wet AMD associated with CNV. In a further
embodiment, the
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
effective amount of the drug for treating macular edema associated with
uveitis (e.g., non-
infectious uveitis), macular edema associated with RVO, wet AMD,
choroidal
neovascularization (CNV), or wet AMD associated with CNV, comprises an
effective
amount of an anti-inflammatory drug (e.g., triamcinolone). In some
embodiments, the drug
formulation includes aflibercept.
[1193] In one
aspect, the methods described herein relate to the administration of a drug
formulation for the treatment of uveitis (infectious or non-infectious),
macular edema,
macular edema associated with non-infectious uveitis, macular edema associated
with
infectious uveitis, macular edema associated with RVO, wherein the majority of
the drug
formulation is retained in the SCS and/or other posterior ocular tissue, in
one or both eyes of
a patient in need of treatment of the posterior ocular disorder, for a period
of time after the
treatment method is completed. Without wishing to be bound by theory, drug
formulation
retention in the SCS contributes to the sustained release profile of the drug
formulations
described herein. As described herein, in some embodiments where a patient is
treated for
macular edema associated with RVO, the patient is further administered a VEGF
modulator
intravitreally in addition to non-surgical or surgical administration of an
anti-inflammatory
compound (e.g., a steroid such as triamcinolone).
[1194] The
method of treating uveitis (e.g., non-infectious uveitis), macular edema
associated with uveitis, macular edema associated with RVO, wet AMD, choroidal
neovascularization (CNV), or wet AMD associated with CNV in a human subject in
need
thereof comprises, in one embodiment, surgically or non-surgically
administering a drug
formulation to the suprachoroidal space of the affected eye of the human
subject, wherein
upon administration, the drug formulation flows away from the insertion site
and is
substantially localized to the posterior segment of the eye, for example to
the posterior ocular
tissue such as the retina and/or choroid. In one embodiment, the methods
provided herein
allow for longer retention of the drug in the eye, e.g., the posterior segment
of the eye, as
compared to intravitreal, topical, parenteral, intracameral or oral
administration of the same
drug dose.
[1195] In one
embodiment, the suprachoroidal drug dose sufficient to achieve a
therapeutic response in a human subject treated with the non-surgical SCS drug
delivery
method is less than the intravitreal, parenteral, intracameral, topical, or
oral drug dose
sufficient to elicit the identical or substantially identical therapeutic
response. In a further
61
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
embodiment, the suprachoroidal drug dose is at least 10 percent less than the
oral, parenteral
or intravitreal dose sufficient to achieve the identical or substantially
identical therapeutic
response. In a further embodiment, the suprachoroidal dose is about 10 percent
to about 25
percent less, or about 10 percent to about 50 percent less than the oral,
parenteral,
intracameral, topical, or intravitreal dose sufficient to achieve the
identical or substantially
identical therapeutic response. Accordingly, in one embodiment, the non-
surgical SCS
administration method of treating macular edema associated with uveitis,
macular edema
associated with RVO achieves a greater therapeutic efficacy than other routes
of
administration. In one embodiment, the non-surgical method provided herein
comprises
inserting a hollow microneedle into the sclera of the eye of the human subject
and infusing a
drug formulation through the hollow microneedle and into the suprachoroidal
space of the
eye. As described in more detail below, the drug formulation, in one
embodiment, is a
solution or suspension of the drug. In some embodiments, the drug formulation
includes
aflibercept.
[1196] In one
embodiment, the amount of therapeutic formulation delivered into the
suprachoroidal space from the devices described herein is from about 10 4 to
about 200 4,
e.g., from about 50 4 to about 150 4. In another embodiment, from about 10 4
to about
500 4, e.g., from about 50 4 to about 250 4, is non-surgically administered to
the
suprachoroidal space.
[1197] The
amount of drug delivered within the SCS also may be controlled, in part, by
the type of microneedle used and how it is used. In one embodiment, a hollow
microneedle
is inserted into the ocular tissue and progressively retracted from the ocular
tissue after
insertion to deliver a fluid drug, where after achieving a certain dosage, the
delivery could be
stopped by deactivating the fluid driving force, such as pressure (e.g., from
a mechanical
device such as a syringe) or an electric field, to avoid leakage/uncontrolled
deliver of drug.
Desirably, the amount of drug being delivered is controlled by driving the
fluid drug
formulation at a suitable infusion pressure. In one embodiment, the infusion
pressure may be
at least 150 kPa, at least 250 kPa, or at least 300 kPa. In another
embodiment, the infusion
pressure is about 150 kPa to about 300 kPa. Suitable infusion pressures may
vary with the
particular patient or species. In another embodiment, the methods provided
herein are carried
out with one of the devices described above (e.g, the injector 100) or in
PCT/US2014/36590,
62
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
filed May 2, 2014 and entitled "Apparatus and Method for Ocular Injection,"
incorporated by
reference herein in its entirety for all purposes.
[1198] It
should be noted that the desired infusion pressure to deliver a suitable
amount of
drug formulation might be influenced by the depth of insertion of the
microneedle and the
composition of the drug formulation. For example, a greater infusion pressure
may be
required in embodiments wherein the drug formulation for delivery into the eye
is in the form
of or includes nanoparticles or microparticles encapsulating the active agent
or microbubbles.
Nanoparticle or microparticle encapsulation techniques are well known in the
art. In one
embodiment, the drug formulation is comprised of drug particles in suspension
with a D99 of
p.m or less. In one embodiment, the drug formulation is comprised of drug
particles in
suspension with a D99 of 7 p.m or less. In another embodiment, the drug
formulation is
comprised of drug particles in suspension with a D99 of 3 p.m or less. In
another embodiment,
the drug formulation is comprised of drug particles in suspension with a D50
of 5 p.m or less.
In one embodiment, the drug formulation is comprised of drug particles in
suspension with a
D50 1 p.m or less. In some embodiments, the drug formulation includes
aflibercept.
[1199] In one
embodiment, the non-surgical method of administering a drug to the SCS
further includes partially retracting the hollow microneedle after insertion
of the microneedle
into the eye, and before and/or during the infusion of the drug formulation
into the
suprachoroidal space. In a particular embodiment, the partial retraction of
the microneedle
occurs prior to the step of infusing the drug formulation into the ocular
tissue. This
insertion/retraction step may form a pocket and beneficially permits the drug
formulation to
flow out of the microneedle unimpeded or less impeded by ocular tissue at the
opening at the
tip portion of the microneedle. This pocket may be filled with drug
formulation, but also
serves as a conduit through with drug formulation can flow from the
microneedle, through
the pocket and into the suprachoroidal space. In some embodiments, the drug
formulation
includes aflibercept and is used to treat a human patient for wet AMD, CNV,
wet AMD
associated with CNV or wet AMD associated with RVO via suprachoroidal
administration.
In some embodiments, the drug formulation includes triamcinolone acetonide and
is
administered via suprachoroidal administration, and is used in conjunction
with aflibercept to
treat a human patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD
associated with RVO.
63
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1200] In one
embodiment, the methods provided herein allow for greater drug retention
in the eye compared to other drug delivery methods, for example, a greater
amount of drug is
retained in the eye when delivered via the methods provided herein as compared
to the same
dose delivered via intracameral, sub-tenon, intravitreal, topical, parenteral
or oral drug
delivery methods. Accordingly, in one embodiment, the intraocular elimination
half life (t1/2)
of the drug when delivered via the methods described herein is greater than
the intraocular till
of the drug when the same drug dose is administered intravitreally,
intracamerally, topically,
parenterally or orally. In another embodiment, the intraocular Cmax of the
drug, when
delivered via the methods described herein, is greater than the intraocular
Cmax of the drug
when the same drug dose is administered intravitreally, intracamerally, sub-
tenonally,
topically, parenterally or orally. In another embodiment, the mean intraocular
area under the
curve (AUCO-t) of the drug, when administered to the SCS via the methods
described herein,
is greater than the intraocular AUCO-t of the drug, when administered
intravitreally,
intracamerally, sub-tenonally, topically, parenterally or orally. In yet
another embodiment,
the intraocular time to peak concentration (tmax) of the drug, when
administered to the SCS
via the methods described herein, is greater than the intraocular tmax of the
drug, when the
same drug dose is administered intravitreally, intracamerally, topically,
parenterally or orally.
In a further embodiment, the drug is aflibercept.
[1201] In one
embodiment, the intraocular till of the drug when administered via the non-
surgical SCS drug delivery methods provided herein, is longer than the
intraocular tv2 of the
drug when the identical dose is administered topically, intracamerally,
intravitreally, orally or
parenterally. In a further embodiment, the intraocular tv2 of the drug when
administered via
the non-surgical SCS drug delivery methods provided herein, is from about 1.1
times to about
times longer, or from about 1.25 times to about 10 times longer, or from about
1.5 times to
about 10 times longer, or about 2 times to about 5 times longer, than the
intraocular t1/2 of
the drug when the identical dosage is administered topically, intracamerally,
sub-tenonally,
intravitreally, orally or parenterally. In a further embodiment, the drug is
aflibercept.
[1202] In
another embodiment, the intraocular Cmax of the drug, when delivered via the
methods described herein, is greater than the intraocular Cmax of the drug
when the same
drug dose is administered intravitreally, intracamerally, topically,
parenterally or orally. In a
further embodiment, the intraocular Cmax of the drug when administered via the
non-surgical
SCS drug delivery methods provided herein, is at least 1.1 times greater, or
at least 1.25 times
64
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
greater, or at least 1.5 times greater, or at least 2 times greater, or at
least 5 times greater, than
the intraocular Cmax of the drug when the identical dose is administered
topically,
intracamerally, intravitreally, orally or parenterally. In one embodiment, the
intraocular
Cmax of the drug when administered via the non-surgical SCS drug delivery
methods
provided herein, is about 1 to about 2 times greater, or about 1.25 to about 2
times greater, or
about 1 to about 5 times greater, or about 1 to about 10 times greater, or
about 2 to about 5
times greater, or about 2 to about 10 times greater, than the intraocular Cmax
of the drug
when the identical dose is administered topically, intracamerally, sub-
tenonally,
intravitreally, orally or parenterally. In a further embodiment, the drug is
aflibercept.
[1203] In
another embodiment, the mean intraocular area under the curve (AUC04) of the
drug, when administered to the SCS via the methods described herein, is
greater than the
intraocular AUC04 of the drug, when administered intravitreally,
intracamerally, sub-
tenonally, topically, parenterally or orally. In a further embodiment, the
intraocular AUCo-t
of the drug when administered via the non-surgical SCS drug delivery methods
provided
herein, is at least 1.1 times greater, or at least 1.25 times greater, or at
least 1.5 times greater,
or at least 2 times greater, or at least 5 times greater, than the intraocular
AUCO-t of the drug
when the identical dose is administered topically, intracamerally, sub-
tenonally,
intravitreally, orally or parenterally. In one embodiment, the intraocular
AUCo_t of the drug
when administered via the non-surgical SCS drug delivery methods provided
herein, is about
1 to about 2 times greater, or about 1.25 to about 2 times greater, or about 1
to about 5 times
greater, or about 1 to about 10 times greater, or about 2 to about 5 times
greater, or about 2 to
about 10 times greater, than the intraocular AUCO-t of the drug when the
identical dose is
administered topically, intracamerally, sub-tenonally, intravitreally, orally
or parenterally. In
a further embodiment, the drug is aflibercept.
[1204] In one
embodiment, the drug formulation comprising the effective amount of the
drug (e.g., an anti-inflammatory drug (e.g., a steroid such as triamcinolone
or NSAID), once
delivered to the SCS, is substantially retained in the SCS over a period of
time. For example,
in one embodiment, about 80% of the drug formulation is retained in the SCS
for about 30
minutes, or about 1 hour, or about 4 hours or about 24 hours or about 48 hours
or about 72
hours. In this regard, a depot of drug is formed in the SCS and/or surrounding
tissue, to
allow for sustained release of the drug over a period of time. In a further
embodiment, the
drug is aflibercept.
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1205] In one
embodiment, the suprachoroidal drug delivery methods provided herein
result in an increased therapeutic efficacy and/or improved therapeutic
response, as compared
to oral, parenteral, sub-tenon, and/or intravitreal drug delivery methods of
the identical or
similar drug dose. In one embodiment, the SCS drug dose sufficient to provide
a therapeutic
response is about 90%, or about 75%, or about one-half (e.g., about one half
or less) the
intravitreal, intracameral, topical, oral or parenteral drug dose sufficient
to provide the same
or substantially the same therapeutic response. In another embodiment, the SCS
dose
sufficient to provide a therapeutic response is about one-fourth the
intravitreal, intracameral,
sub-tenon, topical, oral or parenteral drug dose sufficient to provide the
same or substantially
the same therapeutic response. In yet another embodiment, the SCS dose
sufficient to
provide a therapeutic response is one-tenth the intravitreal, intracameral,
sub-tenon, topical,
oral or parenteral drug dose sufficient to provide the same or substantially
the same
therapeutic response. In one embodiment, the therapeutic response is a
decrease in
inflammation, as measured by methods known to those of skill in the art. In
another
embodiment, the therapeutic response is a decrease in number of ocular
lesions, or decrease
in ocular lesion size. In another embodiment, the therapeutic response is a
decrease in fluid
accumulation and/or intraocular pressure.
[1206]
Therapeutic response is measured at a time point post-treatment, for example 5
days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9
weeks, 10
weeks, 11 weeks or 12 weeks post ¨treatment, and all values in between.
[1207] The
therapeutic efficacy of the drug formulations delivered by the methods
described herein and therapeutic response of the human subject can be assayed
by standard
means in the art, as known to those of skill in the art. In general, the
therapeutic efficacy of
any particular drug can be assessed by measuring the response of the human
subject after
administration of the drug; a drug with a high therapeutic efficacy will show
a greater
amelioration and/or discontinuation of symptoms than a drug with a lower
therapeutic
efficacy. In non-limiting examples, the efficacy of the drug formulations
provided herein can
be measured, for example, by observing changes in pain intensity, changes in
ocular lesions
(size or number), intraocular pressure, fluid accumulation, inflammation
(e.g., by measuring
changes in the Hackett/McDonald ocular score), ocular hypertension, and/or
visual acuity.
[1208] In
another embodiment, the efficacy of the therapeutic formulation is measured by
observing changes in the measurements according to the Hackett/McDonald ocular
scores,
66
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
inflammation, visual acuity, and/or edema. In another embodiment, the efficacy
of the
therapeutic formulation is measured, for example, by observing changes in the
measurements
according to the Hackett/McDonald ocular scores, inflammation, visual acuity,
and/or edema.
[1209] In one
embodiment, the non-surgical administration of an effective amount of a
drug formulation to the SCS results to treat uveitis (e.g., non-infectious
uveitis), macular
edema associated with uveitis, macular edema associated with RVO, wet AMD,
CNV, wet
AMD associated with RVO, or wet AMD associated with CNV results in a decreased
number
of deleterious side effects or clinical manifestations in the treated patient
as compared to the
number of side effects or clinical manifestations caused by the same drug dose
administered
intravitreally, intracamerally, orally or parenterally. In another embodiment,
the non-surgical
administration of an effective amount of a drug formulation to the SCS results
in a decreased
number of one or more deleterious side effects or clinical manifestations, as
compared to the
deleterious side effects or clinical manifestations caused by the same drug
dose administered
intravitreally, intracamerally, sub-tenonally, orally or parenterally.
[1210] Examples
of side effects and clinical manifestations that can be reduced or
ameliorated include, but are not limited to, inflammation, gastrointestinal
side effects (e.g.,
diarrhea, nausea, gastroenteritis, vomiting, gastrointestinal, rectal, and
duodenal hemorrhage,
hemorrhagic pancreatitis, large intestine perforation black or bloody stools,
and/or coughing
up blood); hematologic side effects (e.g., leucopenia, anemia, pancytopenia
and
agranulocytosis, thrombocytopenia, neutropenia, pure red cell aplasia (PRCA),
deep venous
thrombosis easy bruising, and /or unusual bleeding from the nose, mouth,
vagina, or rectum);
immunologic side effects/clinical manifestations (e.g.,
i mmuno suppres si on,
immunosuppression resulting in sepsis, opportunistic infections (herpes
simplex virus ,herpes
zoster, and invasive candidal infections), and/or increased infection);
oncologic side
effects/clinical manifestations (e.g., lymphoma, lymphoproliferative disease
and/or non-
melanoma skin carcinoma); renal side effects/clinical manifestations (e.g.
dysuria, urgency,
urinary tract infections, hematuria, kidney tubular necrosis, and/or BK virus-
associated
nephropathy); metabolic side effects/clinical manifestations (e.g. edema,
hyperphosphatemia,
hypokalemia, hyperglycemia, hyperkalemia. swelling, rapid weight gain, and/or
enlarged
thyroid); respiratory side effects/clinical manifestations (e.g., respiratory
infection, dyspnea,
increased cough, primary tuberculosis dry cough, wheezing, and/or stuffy
nose);
dermatologic side effects/clinical manifestations (e.g., acne, rash,
dyshidrotic eczema,
67
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
papulosquamous psoriatic-like skin eruption rash, blisters, oozing, mouth
sores, and/or hair
loss); muscoskeletal side effects/clinical manifestations (e.g. myopathy
and/or muscle pain),
hepatic side effects/clinical manifestations (e.g. hepatoxicity and/or
jaundice), abdominal
pain, increased incidence of first trimester pregnancy loss, missed menstrual
periods, severe
headache, confusion, change in mental status, vision loss, seizure
(convulsions), increased
sensitivity to light, dry eye, red eye, itchy eye, and/or high blood pressure.
As provided
above, the reduction or amelioration of the side effect or clinical
manifestation is a reduction
or amelioration, as compared to the severity of the side effect or clinical
manifestation prior
to administration of the drug formulation to the SCS of the eye of the
patient, or a reduction
or amelioration of the side effect or clinical manifestation in the patient,
as compared to the
reduction or amelioration experienced upon intravitreal, intracameral,
parenteral or oral
administration of the same drug.
[1211] A wide
range of therapeutic formulations, for example those that include one or
more drugs and/or cellular therapies may be formulated for delivery to the
suprachoroidal
space and posterior ocular tissues with the present microneedle devices and
methods. As
used herein, the term "drug" refers to any prophylactic, therapeutic, or
diagnostic agent, i.e.,
an ingredient useful for medical applications. The drug may be selected from
cellular
therapeutics, small molecules, biologics such as proteins, peptides and
fragments thereof,
nucleic acids including vectors encoding nucleic acid gene therapeutics, which
can be
naturally occurring, synthesized or recombinantly produced. For
example, in one
embodiment, the drug delivered to the suprachoroidal space with the non-
surgical methods
described herein is an antibody or a fragment thereof (e.g., a Fab, Fv or Fc
fragment). In
certain embodiments, the drug is a sub-immunoglobulin antigen-binding
molecule, such as
Fv immunoglobulin fragment, minibody, diabody, and the like, as described in
U.S. Patent
No. 6,773,916, incorporated herein by reference in its entirety for all
purposes. In one
embodiment, the drug is a humanized antibody or a fragment thereof
[1212] In one
embodiment, the non-surgical treatment methods and devices described
herein may be used in gene-based therapy applications. For example, the
method, in one
embodiment, comprises administering a drug formulation into the suprachoroidal
space to
deliver select DNA, RNA, or oligonucleotides to targeted ocular tissues.
Accordingly, in one
embodiment, the drug is selected from a suitable oligonucleotide (e.g.,
antisense
oligonucleotide agents), polynucleotide (e.g., therapeutic DNA), ribozyme,
dsRNA, siRNA,
68
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
RNAi, gene therapy vectors, and/or vaccine. In a further embodiment, the drug
is an aptamer
(e.g., an oligonucleotide or peptide molecule that binds to a specific target
molecule).
[1213] In one
embodiment, a nucleic acid therapeutic is delivered by one of the devices
and/or methods provided herein. In a further embodiment, the nucleic acid
therapeutic is
delivered via a viral particle (viral vector). The virus particle, in one
embodiment, is an
adenovirus, (Ad), adenoassociated virus (AAV), or lentivirus. In another
embodiment, the
viral vector is a self-complementary AAV (scAAV) or helper-dependent
adenovirus (HD-
Ad). In another embodiment, a plasmid vector expressing siRNA or other nucleic
acid
therapeutic is delivered via one of the devices and/or methods described
herein.
Alternatively or additionally, a nucleic acid therapeutic is delivered via a
(1) polymeric, (2)
lipid (e.g., liposomal), (3) protein or (4) dendrimeric nanocarrier delivery
system.
[1214] In
another embodiment, the drug formulation delivered via the methods provided
herein comprises a small molecule drug, an endogenous protein or fragment
thereof, or an
endogenous peptide or fragment thereof
[1215]
Representative examples of types of drugs for delivery to ocular tissues for
the
treatment of uveitis (e.g., non-infectious uveitis), macular edema associated
with uveitis (e.g.,
non-infectious uveitis), macular edema associated with RVO, wet AMD, CNV, wet
AMD
associated with RVO, or wet AMD associated with CNV include anti-inflammatory
drugs,
including, but not limited to steroids (e.g., triamcinolone),
immunosuppressives,
antimetabolites, T-cell inhibitors, alkylating agents, biologics, TNF
antagonists (e.g., TNF-a
antagonists), vascular endothelial growth factor (VEGF) modulators (e.g., VEGF
antagonists), and/or non-steroidal anti-inflammatory drugs (NSAIDs). Non-
limiting
examples of specific drugs and classes of drugs that can be delivered to the
suprachoroidal
space to treat macular edema associated with uveitis include miotics (e.g.,
pilocarpine,
carbachol, physostigmine), sympathomimetics (e.g., adrenaline, dipivefrine),
carbonic
anhydrase inhibitors (e.g., acetazolamide, dorzolamide), VEGF antagonists,
platelet derived
growth factor (PDGF) modulators (e.g., PDGF antagonists), NSAIDs, steroids,
prostaglandins, anti-microbial compounds, including anti-bacterials and anti-
fungals (e.g.,
chloramphenicol, chlortetracycline, ciprofloxacin, framycetin, fusidic acid,
gentamicin,
neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline,
tobramycin,
quinolines), aldose reductase inhibitors, anti-inflammatory and/or anti-
allergy compounds
(e.g., steroidal compounds such as tri amcinol one, betamethas one, cl obetas
one,
69
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
dexamethasone, fluorometholone, hydrocortisone, prednisolone and non-steroidal
compounds
such as antazoline, bromfenac, diclofenac, indomethacin, lodoxamide, saprofen,
sodium
cromoglycate), artificial tear/dry eye therapies, local anesthetics (e.g.,
amethocaine,
lignocaine, oxbuprocaine, proxymetacaine), cyclosporine, diclofenac,
urogastrone and growth
factors such as epidermal growth factor, mydriatics and cycloplegics,
mitomycin C, and
collagenase inhibitors and treatments of age-related macular degeneration such
as pegagtanib
sodium, ranibizumab, and bevacizumab. In one embodiment, the drug delivered by
one of
the devices and/or methods described herein is ranibizumab, axitinib,
bevacizumab and/or
aflibercept.
[1216] In one
embodiment, an angiogenesis inhibitor is administered to the SCS of a
patient in need thereof The angiogenesis inhibitor delivered via the methods
and devices
described herein, in one embodiment, is interferon gamma 1(3, interferon gamma
113
(Actimmune0) with pirfenidone, ACUHTR028, aV135, aminobenzoate potassium,
amyloid P,
ANG1122, ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, anti-CTGF RNAi,
Aplidin, astragalus membranaceus extract with salvia and schisandra chinensis,
atherosclerotic plaque blocker, Azol, AZX100, BB3, connective tissue growth
factor
antibody, CT140, danazol, Esbriet, EXC001, EXC002, EXC003, EXC004, EXC005,
F647,
FG3019, Fibrocorin, Follistatin, FT011, a galectin-3 inhibitor, GKT137831,
GMCT01,
GMCT02, GRMD01, GRMD02, GRN510, Heberon Alfa R, interferon a-213, ITMN520,
JKB119, JKB121, JKB122, KRX168, LPA1 receptor antagonist, MGN4220, MIA2,
microRNA 29a oligonucleotide, MMI0100, noscapine, PBI4050, PBI4419, PDGFR
inhibitor,
PF-06473871, PGN0052, Pirespa, Pirfenex, pirfenidone, plitidepsin, PRM151,
Px102,
PYN17, PYN22 with PYN17, Relivergen, rhPTX2 fusion protein, RXI109, secretin,
STX100, TGF-(3 Inhibitor, transforming growth factor, 13-receptor 2
oligonucleotide,VA999260 or XV615.
[1217] In one
embodiment, the drug delivered to the suprachoroidal space is sirolimus
(RapamycinO, Rapamune0). In one embodiment, the non-surgical drug delivery
methods
disclosed herein are used in conjunction with rapamycin to treat, prevent
and/or ameliorate
macular edema associated with uveitis or macular edema associated with RVO. In
addition,
delivery of rapamycin using the microneedle devices and methods disclosed
herein may be
combined with one or more agents listed herein or with other agents known in
the art. In a
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
further embodiment, the macular edema associated with uveitis is macular edema
associated
with non-infectious uveitis.
[1218] In one
embodiment, the drug delivered to the suprachoroidal space using the non-
surgical methods (e.g., microneedle devices and methods) or surgical methods
(e.g., via a
shunt, stent, or cannula) to treat macular edema associated with uveitis or
macular edema
associated with RVO is triamcinolone (e.g., triamcinolone acetonide). In one
embodiment,
the non-surgical and surgical drug delivery methods disclosed herein are used
in conjunction
with triamcinolone to treat, prevent and/or ameliorate macular edema
associated with uveitis
(e.g., non-infectious uveitis or infectious uveitis). In addition, delivery of
rapamycin using
the microneedle devices and methods disclosed herein may be combined with one
or more
agents listed herein or with other agents known in the art. In a further
embodiment, the
macular edema associated with uveitis is macular edema associated with non-
infectious
uveitis. In some embodiments, the drug formulation includes aflibercept.
[1219] In one
embodiment, a VEGF modulator is delivered via one of the devices
described herein. In one embodiment, the VEGF modulator is a VEGF antagonist.
In one
embodiment, the VEGF modulator is a VEGF-receptor kinase antagonist, an anti-
VEGF
antibody or fragment thereof, an anti-VEGF receptor antibody, an anti-VEGF
aptamer, a
small molecule VEGF antagonist, a thiazolidinedione, a quinoline or a designed
ankyrin
repeat protein (DARPin). As described herein, in some embodiments for the
treatment of
macular edema associated with RVO, an anti-inflammatory drug is delivered to
the SCS of
the eye of a patient in need thereof, in combination with intravitreal
delivery of a VEGF
modulator (e.g., VEGF antagonist) to the same eye. In one embodiment, the VEGF
antagonist is an antagonist of a VEGF receptor (VEGFR), i.e., a drug that
inhibits, reduces, or
modulates the signaling and/or activity of a VEGFR. The VEGFR may be a
membrane-bound
or soluble VEGFR. In a further embodiment, the VEGFR is VEGFR-1, VEGFR-2 or
VEGFR-3. In one embodiment, the VEGF antagonist targets the VEGF-C protein. In
another embodiment, the VEGF modulator is an antagonist of a tyrosine kinase
or a tyrosine
kinase receptor. In another embodiment, the VEGF modulator is a modulator of
the VEGF-A
protein. In yet another embodiment, the VEGF antagonist is a monoclonal
antibody. In a
further embodiment, the monoclonal antibody is a humanized monoclonal
antibody. In some
embodiments, the drug formulation includes aflibercept.
71
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1220] In one
embodiment, the VEGF modulator is one or more of the following:
AL8326, 2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin0), ANG3070,
APX003 antibody, APX004 antibody, ponatinib (AP24534), BDM-E, VGX100 antibody
(VGX100 CIRCADIAN), VGX200 (c-fos induced growth factor monoclonal antibody),
VGX300, COSMIX, DLX903/1008 antibody, ENMD2076, sunitinib malate (Sutent0),
INDUS815C, R84 antibody, KDO19, NM3, allogenic mesenchymal precursor cells
combined
with an anti-VEGF antagonist (e.g., anti-VEGF antibody), MGCD265, MG516, VEGF-
Receptor kinase inhibitor, MP0260, NT503, anti-DLL4NEGF bispecific antibody,
PAN90806, Palomid 529, BD0801 antibody, XV615, lucitanib (AL3810, E3810),
AMG706
(motesanib diphosphate), AAV2-sFLT01, soluble Fitt receptor, cediranib
(RecentinTm), AV-
951, tivozanib (KRN-951), regorafenib (Stivarga0), volasertib (BI6727),
CEP11981, KH903,
lenvatinib (E7080), lenvatinib mesylate, terameprocol (EM1421), ranibizumab
(Lucentis0),
pazopanib hydrochloride (VotrientTm), PF00337210, PRS050, SPO1 (curcumin),
carboxyamidotriazole orotate, hydroxychloroquine, linifanib (ABT869, RG3635),
fluocinolone acetonide (Iluvien0), ALG1001, AGN150998, DARPin MP0112, AMG386,
ponatinib (AP24534), AVA101, nintedanib (Vargatefrm), BMS690514, KH902,
golvatinib
(E7050), everolimus (Afinitor0), dovitinib lactate (TKI258, CHIR258), ORA101,
ORA102,
axitinib (Inlyta0, AG013736), plitidepsin (Aplidin0), PTC299, aflibercept
(Zaltrap0,
Eylea0), pegaptanib sodium (MacugenTm, LI900015), verteporfin (Visudyne0),
bucillamine
(Rimatil, Lamin, Brimani, Lamit, Boomiq), R3 antibody, AT001/r84 antibody,
troponin
(BLS0597), EG3306, vatalanib (PTK787), Bmab100, GSK2136773, Anti-VEGFR
Alterase,
Avila, CEP7055, CLT009, ESBA903, HuMax-VEGF antibody, GW654652, HMPL010,
GEM220, HYB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012,
Nova21013, CP564959, Smart Anti-VEGF antibody, AG028262, AG13958, CVX241,
SU14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastaurin
hydrochloride (LY317615), BC194, quinolines, COT601M06.1, C0T604M06.2,
MabionVEGF, SIR-Spheres coupled to anti-VEGF or VEGF-R antibody, Apatinib
(YN968D1), and AL3818. In addition, delivery of a VEGF antagonist using the
microneedle
devices and non-surgical methods disclosed herein may be combined with one or
more agents
listed herein or with other agents known in the art, either in a single or
multiple formulations.
[1221] In one
embodiment, an immunosuppressive agent is delivered via one of the
devices described herein. In a further embodiment, the immunosuppressive agent
is a
glucocorticoid, cytokine inhibitor, cytostatic, alkylating agent, anti-
metabolite, folic acid
72
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
analogue, cytotoxic antibiotic, interferon, opioid, T-cell receptor directed
antibody or an IL-2
receptor directed antibody. In one embodiment, the immunosuppressive agent is
an anti-
metabolite and the anti-metabolite is a purine analog, pyrimidine analogue,
folic acid
analogue or a protein synthesis inhibitor. In another embodiment, the
immunosuppressive
agent is an interleukin-2 inhibitor (e.g., basiliximab or daclizumab).
Other
immunosuppressive agents amenable for use with the methods and formulations
described
herein include, but are not limited to cyclophosphamide, nitrosourea,
methotrexate,
azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracycline,
mitomycin C,
bleomycin, mithramycin, muromonab-CD3, cyclosporine, tacrolimus, sirolimus or
mycophenolate. In one embodiment, the drug formulation comprises an effective
amount
my cophenol ate.
[1222] In one
embodiment, the drug formulation delivered to the SCS of an eye of a
patient in need thereof via the methods described herein comprises an
effective amount of
vascular permeability inhibitor. In one embodiment, the vascular permeability
inhibitor is a
vascular endothelial growth factor (VEGF) antagonist or an angiotensin
converting enzyme
(ACE) inhibitor. In a further embodiment, the vascular permeability inhibitor
is an
angiotensin converting enzyme (ACE) inhibitor and the ACE inhibitor is
captopril.
[1223] In one
embodiment, the drug is a steroid or a non-steroid anti-inflammatory drug
(NSAID). In another embodiment, the anti-inflammatory drug is an antibody or
fragment
thereof, an anti-inflammatory peptide(s) or an anti-inflammatory aptamer(s).
As provided
throughout the specification, the delivery of the anti-inflammatory drug to
the suprachoroidal
space results in benefits over administration of the same drug delivered via
oral, intravitreal,
intracameral, topical and/or a parenteral route of administration. For
example, in one
embodiment, the therapeutic effect of the drug delivered to the suprachoroidal
space is
greater than the therapeutic effect of the same drug, delivered at the same
dosage, when the
drug is delivered via oral, intravitreal, topical or parenteral route. In one
embodiment, the
intraocular elimination half life (t1/2) of the anti-inflammatory drug
administered to the SCS
is greater than the intraocular t1/2 of the anti-inflammatory drug, when the
identical dosage
of the anti-inflammatory drug is administered intravitreally, intracamerally,
topically,
parenterally or orally. In another embodiment, the mean intraocular maximum
concentration
(Cmax) of the anti-inflammatory drug, when administered to the SCS via the
methods
described herein, is greater than the intraocular Cmax of the anti-
inflammatory drug, when
73
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
administered intravitreally, intracamerally, topically, parenterally or
orally. In another
embodiment, the mean intraocular area under the curve (AUCO-t) of the anti-
inflammatory
drug, when administered to the SCS via the methods described herein, is
greater than the
intraocular AUCO-t of the anti-inflammatory drug, when the identical dosage of
the anti-
inflammatory drug is administered intravitreally, intracamerally, topically,
parenterally or
orally.
[1224]
Steroidal compounds that can be administered via the methods provided herein
include hydrocortisone, hydrocortisone- 17-buty rate,
hydrocortisone- 17-aceponate,
hydrocortisone- 17-buteprate, cortisone,
tixocortol pivalate, prednisolone,
methylprednisolone, prednisone, triamcinolone, triamcinolone acetonide,
mometasone,
amcinonide, budesonide, desonide, fluocinonide, halcinonide, bethamethasone,
bethamethasone dipropionate, dexamethasone, fluocortolone, hydrocortisone-17-
valerate,
hal ometas one, al cl ometas one dipropionate, prednicarbate, cl ob etas one-
17-buty rate,
clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate,
fluprednidene
acetate and prednicarbate.
[1225] Specific
classes of NSAIDs that can be administered via the methods provided
herein include salicylates, propionic acid derivatives, acetic acid
derivatives, enolic acid
derivatives, fenamic acid derivatives and cyclooxygenase-2 (COX-2) inhibitors.
In one
embodiment, the methods provided herein are used to deliver one or more of the
following
NSAIDs to the SCS of an eye of a patient in need thereof: acetylsalicylic
acid, diflunisal,
salsalate, ibuprofen, dexibuprofen, naproxen, fenoprofen, keotoprofen,
dexketoprofen,
flurbiprofen, oxaprozin, loxaprofen, indomethacin, tolmetin, sulindac,
etodolac, ketorolac,
diclofenac or nabumetone, piroxicam, meloxicam, tenoxicam, droxicam,
lornoxicam or
isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid,
celecoxib,
refecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib or firocoxib.
[1226] Other
examples of anti-inflammatory drugs, that can be used in the methods
provided herein for treating macular edema associated with uveitis (infectious
or non-
infectious uveitis) include, but are not limited to: mycophenolate, remicase,
nepafenac, 19AV
agonist(s), 19GJ agonists, 2MD analogs, 45C101, 45C102, 57-57, 5-HT2 receptor
antagonist,
64G12, A804598, A967079, AAD2004, AB1010, AB224050, abatacept, etaracizumab
(AbegrinTm), Abevac0, AbGn134, AbGn168, Abki, ABN912, ABR215062, ABR224050,
cyclosporine (Abrammune0), docosanol (behenyl alcohol, Abreva0), ABS15, ABS4,
ABS6,
74
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
ABT122, ABT325, ABT494, ABT874, ABT963, ABXIL8, ABXRB2, AC430, Accenetra,
lysozyme chloride (Acdeam0), ACE772, aceclofenac (Acebloc, Acebid, Acenac),
acetaminophen, chlorzoxazone, serrapeptase, tizanidine hydrochloride, betadex,
Aceclogesic
Plus, Aceclon, Acecloren, Aceclorism, acecrona, Aceffein, acemetacin, asprin
(Acenterine),
Acetal-SP (Aceclofenac - combination, ibuprofen, Acetyl-G, acetylsalicylate dl-
lysine,
acetylsalicylic acid, Acicot, Acifine, Acik, Aclocen, Acloflam-P, Aclomore,
Acton, A-CQ,
ACS15, actarit, Actemra, Acthelea liofilizado, Actifast, Actimab-B, Actiquim,
Actirin, Actis
PLUS, activated leukocyte cell adhesion molecule antibody, Acular X, AD452,
adalimumab,
ADAMTS5 inhibitor, ADC1001, Adco-Diclofenac, Adco-Indomethacin, Adco-
Meloxicam,
Adco-Naproxen, Adco-Piroxicam, Adcort, Adco-Sulindac, adenosine triphosphate
disodium,
AdenosineA2a Receptor Agonist, Adimod, Adinos, Adioct, Adiodol, Adipoplus,
adipose
derived stem and/or regenerative cells, Adizen, Adpep, Advacan, Advagraf,
Advel,
Adwiflam, AEB071, Aental, Afenac, Affen Plus, Afiancen, Afinitor, Aflamin,
Aflazacort,
Aflogen, Afloxan, AFM15, AFM16, AFM17, AFM23, Afpred-Dexa, AFX200, AG011,
Agafen, aganirsen, AGI1096, Agidex, AGS010, Agudol, A-Hydrocort, AIK1, AIN457,
Airtal, AIT110, AJM300, ajulemic acid, AK106, AL-24-2A1, AL4-1A1, Ala Cort,
Alanz,
Albumin immune-globulin, alclometasone dipropionate, ALD518, aldesleukin,
Aldoderma,
alefacept, alemtuzumab, AlequelTM, Alergolon, Alergosone, Aletraxon, Alfenac,
Algason,
Algin vek coat, Algioflex, Algirex, Algivin Plus, alicaforsen sodium, Alin,
Alinia, Aliviodol,
Aliviosin, alkaline phosphatase, ALK56931, allantoin, Allbupen, Allmol,
Allochrysine,
allogeneic endothelial cells, allogeneic mesenchymal precursor cells,
allogeneic
mesenchymal stem cells, alminoprofen, alpha 1 antitrypsin, Alpha 7 nicotinic
agonists, alpha
amylase, alpha chymotrypsin, alpha fetoprotein, alpha linolenic acid, alpha-l-
antitrypsin,
a2431 integrin inhibitors, Alphacort, Alphafen, alpha-hexidine, alpha-trypsin,
Alphintern,
Alpinamed mobility omega 3, Alpoxen, AL-Revl, Alterase, ALX0061, ALX0761,
ALXN1007, ALXN1102, AM3840, AM3876, AMAB, AMAP102, Amason, Ambene,
AmbezimG, amcinonide, AME133v, Amecin, Ameloteks, A-Methapred, Amevive,
AMG108, AMG139, AMG162, AMG181, AMG191, AMG220, AMG623, AMG674,
AMG714, AMG719, AMG729, AMG827, Amidol, amifampridine phosphate, diclofenac
(Emifenac0), Amimethacin, amiprilose hydrochloride, Amiprofen, Ammophos,
Amoflam,
AMP110, Ampikyy, Ampion, ampiroxicam, amtolmetin guacil, AMX256, AN6415,
ANA004, ANA506, Anabu, Anacen, Anaflam, Anaflex ACT, Anaida, anakinra, Analgen
Artritis, Anapan, Anaprox, Anavan, Anax, Anco, andrographis, Aneol, Anergix,
Anervax.RATM (therapeutic peptide vaccine), Anflene, ANG797, Anilixin,
Anmerushin,
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Annexin 1 peptides, annexin A5, Anodyne, Ansaid, Anspirin, Antarene, anti BST2
antibody,
anti C5a MAb, anti ILT7 antibody, anti VLA1 antibody, anti-alphal 1 antibody,
anti-CD4
802-2, anti-CD86 monoclonal antibody, anti-chemokine, anti-DC-SIGN, anti-HMGB-
1
MAb, anti-IL-18 Mab, anti-IL-1R MAb, anti-IL-1R MAb, anti-IL23 BRISTOL, anti-
interleukin-10 antibody, anti-LIGHT antibody, anti-MIF antibody, anti-MIF
antibody, anti-
miR181a, antioxidant inflammation modulators, Antiphlamine, AntiRAGE MAb,
antithrombin III, Anti-TIRC-7 MAb, Anusol-HC, Anyfen, AP105, AP1089, AP1189,
AP401,
AP501, apazone, APD334, Apentac, APG103, Apidone, apilimod mesylate, Apitac,
Apitoxin, Apizel, APN inhibitor, apo-azathioprine, Apo-dexamethasone, ApoE
mimetics,
ApoFasL, apo-Indomethacin, apo-mefenamic, apo-methotrexate, apo-nabumetone,
Apo-
Napro-NA, apo-Naproxen, aponidin, apo-Phenylbutazone, apo-Piroxicam, apo-
Sulin, Apo-
Tenoxicam, apo-Tiaprofenic, Apranax, apremilast, apricoxib, Aprofen, Aprose,
Aproxen,
APX001 antibody, APX007 antibody, APY0201, AqvoDex, AQX108, AQX1125,
AQX131135, AQX140, AQX150, AQX200, AQX356, AQXMN100, AQXMN106,
ARA290, Arava, Arcalyst, Arcoxia, Arechin, Arflur, ARG098, ARG301, arginine
aescin,
arginine deiminase (pegylated), ARGX109 antibody, ARGX110, Arheuma,
Aristocort,
Aristospan, Ark-AP, ARN4026, Arofen, Aroff EZ, Arolef, Arotal, Arpibru,
Arpimune, Arpu
Shuangxin, ARQ101, Arrestin SP, Arrox, ARRY162, ARRY371797, ARRY614, ARRY872,
ART621, Artamin, Arthfree, Artho Tech, Arthrexin, Arthrispray, Arthrotec,
aeterna shark
cartilage extract (ArthrovasTM, NeoretnaTM, PsovascarTm), Artifit, Artigo,
Artin, Artinor,
Artisid, Artoflex, Artren Hipergel, Artridol, Artrilase, Artrocaptin,
Artrodiet, Artrofen,
Artropan, Artrosil, Artrosilene, Artrotin, Artrox, Artyflam, Arzerra,
A5604850, A5605858,
Asacol, ASA-Grindeks, Asazipam, Aseclo, A5F1096, A5F1096, A5K8007, ASKP1240,
ASLAN003, Asmo ID, Asonep, ASP015K, A5P2408, A5P2409, Aspagin, Aspeol,
Aspicam,
Aspirimex, AST120, astaxanthin, AstroCort, Aszes, AT002 antibody, AT007, AT008
antibody, AT008 antibody, AT010, AT1001, atacicept, Ataspin, Atepadene, Atgam,
ATG-
Fresenius, Athrofen, ATIO03, atiprimod, ATL1222, ATN103, ATN192, ATR107, Atri,
Atrmin, Atrosab antibody, ATX3105, AU801, auranofin, Aurobin, Auropan,
Aurothio,
aurotioprol, autologous adipose derived regenerative cells, Autonec, Avandia,
AVE9897,
AVE9940, Avelox, Avent, AVI3378, Avloquin, AVP13546, AVP13748, AVP28225,
AVX002, Axcel Diclofenac, Axcel Papain, Axen, AZ17, AZ175, Azacortid, AZA-DR,
Azafrine, Azamun, Azanin, Azap, Azapin, Azapren, Azaprin, Azaram, Azasan,
azathioprine,
AZD0275, AZD0902, AZD2315, AZD5672, AZD6703, AZD7140, AZD8309, AZD8566,
AZD9056, Azet, Azintrel, azithromycin, Az-od, Azofit, Azolid, Azoran, Azulene,
Azulfidine,
76
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Azulfin, B1 antagonists, Baclonet, BAF312, BAFF Inhibitor, Bages, Baily S.P.,
Baleston,
Balsolone, baminercept alfa, bardoxolone methyl, baricitinib, Barotase,
Basecam,
basiliximab, Baxmune, Baxo, BAY869766, BB2827, BCX34, BCX4208, Becfine,
Beclate-C,
Beclate-N, Beclolab Q, beclomethasone dipropionate, Beclorhin, Becmet-CG,
Begita, Begti,
belatacept, belimumab, Belosalic, Bemetson, Ben, Benevat, Benexam, Benflogin,
Benisan,
Benlysta, Benlysta, benorilate, Benoson, benoxaprofen, Bentol, benzydamine
hydrochloride,
Benzymin, Beofenac, Berafen, Berinert, Berlofen, Bertanel, Bestamine,
Bestofen, Beta Nicip,
Betacort, Betacorten G, Betafoam, beta-glucan, Betalar, Beta-M, Betamed,
Betamesol,
betamethasone, betamethasone dipropionate, betamethasone sodium, betamethasone
sodium
phosphate, betamethasone valerate, Betane, Betanex, Betapanthen, Betapar,
Betapred,
Betason, Betasonate, Betasone, Betatrinta, Betaval, Betazon, Betazone,
Betesil, Betnecort,
Betnesol, Betnovate, Bextra, BFPC13, BFPC18, BFPC21, BFPT6864, BG12, BG9924,
BI695500, BI695501, BIA12, Big-Joint-D, BIIB023 antibody, Bi-ksikam, Bingo,
BioBee,
Bio-Cartilage, Bio-C-Sinkki, Biodexone, Biofenac, Bioreucam, Biosone,
Biosporin,
BIRB796, Bitnoval, Bitvio, Bivigam, BKT140, BKTP46, BL2030, BL3030, BL4020,
BL6040, BL7060, BLI1300, blisibimod, Blokium B12, Blokium Gesic, Blokium,
BMS066,
BMS345541, BMS470539, BMS561392, BMS566419, BMS582949, BMS587101,
BMS817399, BMS936557, BMS945429, BMS-A, BN006, BN007, BNP166, Bonacort,
Bonas, bone marrow stromal cell antigen 2 antibody, Bonflex, Bonifen, Boomiq,
Borbit,
Bosong, BRO2001, BR3-FC, Bradykinin B1 Receptor Antagonist, Bredinin,
Brexecam,
Brexin, Brexodin, briakinumab, Brimani, briobacept, Bristaflam, Britten,
Broben,
brodalumab, Broen-C, bromelains, Bromelin, Bronax, Bropain, Brosiral, Bruace,
Brufadol,
Brufen, Brugel, Brukil, Brusil, BT061, BTI9, BTK kinase inhibitors, BTT1023
antibody,
BTT1507, bucillamine, Bucillate, Buco Reigis, bucolome, Budenofalk,
budesonide, Budex,
Bufect, Bufencon, Bukwang Ketoprofen, Bunide, Bunofen, Busilvex, busulfan,
Busulfex,
Busulipo, Butartrol, Butarut B12, Butasona, Butazolidin, Butesone, Butidiona,
BVX10,
BXL628, BYM338, B-Zone, Cl esterase inhibitor, C243, c4462, c5997, C5aQb,
c7198,
c9101, C9709, c9787, CAB101, cadherin 11 antibody, caerulomycin A, CAL263,
Calcort,
Calmatel, CAM3001, Camelid Antibodies, Camlox, Camola, Campath, Camrox,
Camtenam,
canakinumab, candida albicans antigen, Candin, cannabidiol, CAP1.1, CAP1.2,
CAP2.1,
CAP2.2, CAP3.1, CAP3.2, Careram, Carimune, Cariodent, Cartifix, CartiJoint,
Cartilago,
Cartisafe-DN, Cartishine, Cartivit, Cartril-S, Carudol, CaspaCIDe, CaspaCIDe,
Casyn,
CAT1004, CAT1902, CAT2200, Cataflam, Cathepsin S inhibitor, Catlep, CB0114,
CB2
agonist, CC0478765, CC10004, CC10015, CC1088, CC11050, CC13097, CC15965,
77
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
CC16057, CC220, CC292, CC401, CC5048, CC509, CC7085, CC930, CCR1 antagonist,
CCR6 inhibitor, CCR7 antagonist, CCRL2 antagonist, CCX025, CCX354, CCX634, CD
Diclofenac, CD102, CD103 antibody, CD103 antibody, CD137 antibody, CD16
antibody,
CD18 antibody, CD19 antibody, CD1d antibody, CD20 antibody, CD200Fc, CD209
antibody, CD24, CD3 antibody, CD30 antibody, CD32A antibody, CD32B antibody,
CD4
antibody, CD40 ligand, CD44 antibody, CD64 antibody, CDC839, CDC998, CDIM4,
CDIM9, CDK9-Inhibitor, CDP146, CDP323, CDP484, CDP6038, CDP870, CDX1135,
CDX301, CE224535, Ceanel, Cebedex, Cebutid, Ceclonac, Ceex, CEL2000, Celact,
Celbexx, Celcox, Celebiox, Celebrex, Celebrin, Celecox, celecoxib, Celedol,
Celestone,
Celevex, Celex, CELG4, Cell adhesion molecule antagonists, CellCept, Cellmune,
Celosti,
Celoxib, Celprot, Celudex, cenicriviroc mesylate, cenplace1-1, CEP11004,
CEP37247,
CEP37248, Cephyr, Ceprofen, Certican, certolizumab pegol, Cetofenid,
Cetoprofeno,
cetylpyridinium chloride, CF101, CF402, CF502, CG57008, CGEN15001, CGEN15021,
CGEN15051, CGEN15091, CGEN25017, CGEN25068, CGEN40, CGEN54, CGEN768,
CGEN855, CGI1746, CGI560, CGI676, Cgtx-Peptides, CH1504, CH4051, CH4446,
chaperonin 10, chemokine C-C motif ligand 2, chemokine C-C motif ligand 2
antibody,
chemokine C-C motif ligand 5 antibody, chemokine C-C motif receptor 2
antibody,
chemokine C-C motif receptor 4 antibody, chemokine C-X-C motif ligand 10
antibody,
chemokine C-X-C motif ligand 12 aptamer, Chemotaxis Inhibitor, Chillmetacin,
chitinase 3-
like 1, Chlocodemin, Chloquin, chlorhexidine gluconate, chloroquine phosphate,
choline
magnesium trisalicylate, chondroitin sulfate, Chondroscart, CHR3620, CHR4432,
CHR5154,
Chrysalin, Chuanxinlian, Chymapra, Chymotase, chymotrypsin, Chytmutrip, CI202,
CI302,
Cicloderm-C, Ciclopren, Cicporal, Cilamin, Cimzia, cinchophen, cinmetacin,
cinnoxicam,
Cinoderm, Cinolone-S, Cinryze, Cipcorlin, cipemastat, Cipol-N, Cipridanol,
Cipzen, Citax F,
Citogan, Citoken T, Civamide, CJ042794, CJ14877, c-Kit monoclonal antibody,
cladribine,
Clafen, Clanza, Claversal, clazakizumab, Clearoid, Clease, Clevegen, Clevian,
Clidol,
Clindac, Clinoril, Cliptol, Clobenate, Clobequad, clobetasol butyrate,
clobetasol propionate,
Clodol, clofarabine, Clofen, Clofenal LP, Clolar, Clonac, Clongamma, clonixin
lysine,
Clotasoce, Clovacort, Clovana, Cloxin, CLT001, CLT008, C-MAF Inhibitor,
CMPX1023,
Cnac, CND0201, CNI1493, CNT0136, CNT0148, CNT01959, Cobefen, CoBenCoDerm,
Cobix, Cofenac, Cofenac, C0G241, C0L179, colchicine, Colchicum Dispert,
Colchimax,
Colcibra, Coledes A, Colesol, Colifoam, Colirest, collagen, type V, Comcort,
complement
component (3b/4b) receptor 1, Complement Component Cis Inhibitors, complement
component C3, complement factor 5a receptor antibody, complement factor 5a
receptor
78
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
antibody, complement factor D antibody, Condrosulf, Condrotec, Condrothin,
conestat alfa,
connective tissue growth factor antibody, Coolpan, Copaxone, Copiron,
Cordefla, Corhydron,
Cort S, Cortan, Cortate, Cort-Dome, Cortecetine, Cortef, Corteroid, Corticap,
Corticas,
Cortic-DS, corticotropin, Cortiderm, Cortidex, Cortiflam, Cortinet M,
Cortinil, Cortipyren B,
Cortiran, Cortis, Cortisolu, cortisone acetate, Cortival, Cortone acetate,
Cortopin, Cortoral,
Cortril, Cortypiren, Cosamine, Cosone, cosyntropin, COT Kinase Inhibitor,
Cotilam,
Cotrisone, Cotson, Covox, Cox B, COX-2/5-LO Inhibitors, Coxeton, Coxflam,
Coxicam,
Coxitor, Coxtral, Coxypar, CP195543, CP412245, CP424174, CP461, CP629933,
CP690550,
CP751871, CPSI2364, C-quin, CR039, CR074, CR106, CRA102, CRAC channel
inhibitor,
CRACM ion channel inhibitor, Cratisone, CRB15, CRC4273, CRC4342, C-reactive
protein
2-methoxyethyl phosphorothioate oligonucleotide, CreaVax-RA, CRH modulators,
critic-aid,
Crocam, Crohnsvax, Cromoglycic acid, cromolyn sodium, Cronocorteroid,
Cronodicasone,
CRTX803, CRx119, CRx139, CRx150, CS502, CS670, CS706, CSF1R Kinase Inhibitors,
CSL324, CSL718, CSL742, CT112, CT1501R, CT200, CT2008, CT2009, CT3, CT335,
CT340, CT5357, CT637, CTP05, CTP10, CT-P13, CTP17, Cuprenil, Cuprimine,
Cuprindo,
Cupripen, Curaquin, Cutfen, CWF0808, CWP271, CX1020, CX1030, CX1040, CX5011,
Cx611, Cx621, Cx911, CXC chemokine receptor 4 antibody, CXCL13 antibodies,
CXCR3
antagonists, CXCR4 antagonist, Cyathus 1104 B, Cyclo-2, Cyclocort,
cyclooxygenase-2
inhibitor, cyclophosphamide, Cyclorine, Cyclosporin A Prodrug, Cyclosporin
analogue A,
cyclosporine, Cyrevia, Cyrin CLARIS, CYT007TNFQb, CYT013IL1bQb, CYT015IL17Qb,
CYT020TNFQb, CYT107, CYT387, CYT99007, cytokine inhibitors, Cytopan, Cytoreg,
CZC24832, D1927, D9421C, daclizumab, danazol, Danilase, Dantes, Danzen,
dapsone,
Dase-D, Daypro, Daypro Alta, Dayrun, Dazen, DB295, DBTP2, D-Cort, DD1, DD3,
DE096,
DE098, Debio0406, Debio0512, Debio0615, Debio0618, Debio1036, Decaderm,
Decadrale,
Decadron, Decadronal, Decalon, Decan, Decason, Decdan, Decilone, Declophen,
Decopen,
Decorex, Decorten, Dedema, Dedron, Deexa, Defcort, De-flam, Deflamat, Deflan,
Deflanil,
Deflaren, Deflaz, deflazacort, Defnac, Defnalone, Defnil, Defosalic, Defsure,
Defza,
Dehydrocortison, Dekort, Delagil, delcasertib, delmitide, Delphicort,
Deltacorsolone
prednisolone (Deltacortril), Deltafluorene, Deltasolone, Deltasone, Deltastab,
Deltonin,
Demarin, Demisone, Denebola, denileukin diftitox, denosumab, Denzo,
Depocortin, Depo-
medrol, Depomethotrexate, Depopred, Deposet, Depyrin, Derinase, Dermol,
Dermolar,
Dermonate, Dermosone, Dersone, Desketo, desonide, desoxycorticosterone
acetate, Deswon,
Dexa, Dexabene, Dexacip, Dexacort, dexacortisone, Dexacotisil, dexadic,
dexadrin,
Dexadron, Dexafar, Dexahil, Dexalab, Dexalaf, Dexalet, Dexalgen, dexallion,
dexalocal,
79
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Dexalone, Dexa-M, Dexamecortin, Dexamed, Dexamedis, dexameral, Dexameta,
dexamethasone, dexamethasone acetate, dexamethasone palmitate, dexamethasone
phosphate, dexamethasone sodium metasulfobenzoate, dexamethasone sodium
phosphate,
Dexamine, Dexapanthen, Dexa-S, Dexason, Dexatab, Dexatopic, Dexaval, Dexaven,
Dexazolidin, Dexazona, Dexazone, Dexcor, Dexibu, dexibuprofen, Dexico,
Dexifen,
Deximune, dexketoprofen, dexketoprofen trometamol, Dexmark, Dexomet, Dexon I,
Dexonalin, Dexonex, Dexony, Dexoptifen, Dexpin, Dextan-Plus, dextran sulfate,
Dezacor,
Dfz, diacerein, Diannexin, Diastone, Dicarol, Dicasone, Dicknol, Diclo,
Diclobon,
Diclobonse, Diclobonzox, Diclofast, Diclofen, diclofenac, diclofenac beta-
dimethylaminoethanol, diclofenac deanol, diclofenac diethylamine, diclofenac
epolamine,
diclofenac potassium, diclofenac resinate, diclofenac sodium, Diclogen AGIO,
Diclogen
Plus, Diclokim, Diclomed, Diclo-NA, Diclonac, Dicloramin, Dicloran, Dicloreum,
Diclorism, Diclotec, Diclovit, Diclowal, Diclozem, Dico P, Dicofen, Dicoliv,
Dicorsone,
Dicron, Dicser, Difena, Diffutab, diflunisal, dilmapimod, Dilora, dimethyl
sulfone, Dinac, D-
Indomethacin, Dioxaflex Protect, Dipagesic, Dipenopen, Dipexin, Dipro AS,
Diprobeta,
Diprobetasone, Diproklenat, Dipromet, Dipronova, Diprosone, Diprovate,
Diproxen,
Disarmin, Diser, Disopain, Dispain, Dispercam, Distamine, Dizox, DLT303,
DLT404,
DM199, DM99, DMI9523, dnaJP1, DNX02070, DNX04042, DNX2000, DNX4000,
docosanol, Docz-6, Dolamide, Dolaren, Dolchis, Dolex, Dolflam, Dolfre, Dolgit,
Dolmax,
Dolmina, Dolo Ketazon, Dolobest, Dolobid, Doloc, Dolocam, Dolocartigen,
Dolofit,
Dolokind, Dolomed, Dolonac, Dolonex, Dolotren, Dolozen, Dolquine, Dom0100,
Dom0400,
Dom0800, Domet, Dometon, Dominadol, Dongipap, Donica, Dontisanin, doramapimod,
Dorixina Relax, Dormelox, Dorzine Plus, Doxatar, Doxtran, DP NEC, DP4577,
DP50,
DP6221, D-Penamine, DPIV/APN Inhibitors, DR1 Inhibitors, DR4 Inhibitors,
DRA161,
DRA162, Drenex, DRF4848, DRL15725, Drossadin, DSP, Duexis, Duo-Decadron,
Duoflex,
Duonase, DV1079, DV1179, DWJ425, DWP422, Dymol, DYN15, Dynapar, Dysmen,
E5090, E6070, Easy Dayz, Ebetrexat, EBI007, ECO286, EC0565, EC0746, Ecax,
echinacea
purpurea extract, EC-Naprosyn, Econac, Ecosprin 300, Ecosprin 300, Ecridoxan,
eculizumab,
Edecam, efalizumab, Efcortesol, Effigel, Eflagen, Efridol, EGFR Antibody,
EGS21, eIF5A1
siRNA, Ekarzin, elafin, Eldoflam, Elidel, Eliflam, Elisone, Elmes, Elmetacin,
ELND001,
ELND004, elocalcitol, Elocom, elsibucol, Emanzen, Emcort, Emifen, Emifenac,
emorfazone,
Empynase, emricasan, Emtor, Enable, Enbrel, Enceid, EncorStat, Encortolon,
Encorton,
Endase, Endogesic, Endoxan, Enkorten, Ensera, Entocort, Enzylan, Epanova,
Eparang,
Epatec, Epicotil, epidermal growth factor receptor 2 antibody, epidermal
growth factor
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
receptor antibody, Epidixone, Epidron, Epiklin, EPPA1, epratuzumab, Equi0,
Erac, Erazon,
ERB041, ERB196, Erdon, EryDex, escherichia coli enterotoxin B subunit, Escin,
E-Selectin
Antagonists, Esfenac, ESN603, esonarimod, Esprofen, estetrol, Estopein,
Estrogen Receptor
beta agonist, etanercept, etaracizumab, ETC001, ethanol propolis extract,
ETI511, etiprednol
dicloacetate, Etodin, Etodine, Etodol, etodolac, Etody, etofenamate, Etol
Fort, Etolac, Etopin,
etoricoxib, Etorix, Etosafe, Etova, Etozox, Etura, Eucob, Eufans, eukaryotic
translation
initiation factor 5A oligonucleotide, Eunac, Eurocox, Eurogesic, everolimus,
Evinopon,
EVT401, Exaflam, EXEL9953, Exicort, Expen, Extra Feverlet, Extrapan, Extrauma,
Exudase, F16, F991, Falcam, Falcol, Falzy, Farbovil, Farcomethacin, Farnerate,
Farnezone,
Farnezone, Farotrin, fas antibody, Fastflam, FasTRACK, Fastum, Fauldmetro,
FcgammaRIA
antibody, FE301, Febrofen, Febrofid, felbinac, Feldene, Feldex, Feloran,
Felxicam, Fenac,
Fenacop, Fenadol, Fenaflan, Fenamic, Fenaren, Fenaton, Fenbid, fenbufen,
Fengshi Gutong,
Fenicort, Fenopine, fenoprofen calcium, Fenopron, Fenris, Fensupp, Fenxicam,
fepradinol,
Ferovisc, Feverlet, fezakinumab, FG3019, FHT401, FHTCT4, FID114657,
figitumumab,
Filexi, filgrastim, Fillase, Final, Findoxin, fingolimod hydrochloride,
firategrast, Firdapse,
Fisiodar, Fivasa, FK778, Flacoxto, Fladalgin, Flagon, Flamar, Flamcid,
Flamfort, Flamide,
Flaminase, Flamirex Gesic, Flanid, Flanzen, Flaren, Flaren, Flash Act,
Flavonoid Anti-
inflammatory Molecule, Flebogamma DIF, Flenac, Flex, Flexafen 400, Flexi,
Flexidol,
Flexium, Flexon, Flexono, Flogene, Flogiatrin B12, Flogomin, Flogoral,
Flogosan, Flogoter,
Flo-Pred, Flosteron, Flotrip Forte, Flt3 inhibitors, fluasterone, Flucam,
Flucinar,
fludrocortisone acetate, flufenamate aluminum, flumethasone, Flumidon,
flunixin,
fluocinolone, fluocinolone acetonide, fluocinonide, fluocortolone, Fluonid,
fluorometholone,
Flur, flurbiprofen, Fluribec, Flurometholone, Flutal, fluticasone, fluticasone
propionate,
Flutizone, Fluzone, FM101 antibody, fms-related tyrosine kinase 1 antibody,
Folitrax,
fontolizumab, formic acid, Fortecortin, Fospeg, fostamatinib disodium, FP1069,
FP13XX,
FPA008, FPA031, FPT025, FR104, FR167653, Framebin, Frime, Froben, Frolix,
FROUNT
Inhibitors, Fubifen PAP, Fucole ibuprofen, Fulamotol, Fulpen, Fungifin,
Furotalgin, fusidate
sodium, FX002, FX141L, FX201, FX300, FX87L, Galectin modulators, gallium
maltolate,
Gamimune N, Gammagard, Gamma-TV., GammaQuin, Gamma-Venin, Gamunex, Garzen,
Gaspirin, Gattex, GBR500, GBR500 antibody, GBT009, G-CSF, GED0301, GED0414,
Gefenec, Gelofen, Genepril, Gengraf, Genimune, Geniquin, Genotropin,
Genz29155, Gerbin,
Gerbin, gevokizumab, GF01564600, Gilenia, Gilenya, givinostat, GL0050, GL2045,
glatiramer acetate, Globulin, Glortho Forte, Glovalox, Glovenin-I, GLPG0259,
GLPG0555,
GLPG0634, GLPG0778, GLPG0974, Gluco, Glucocerin, glucosamine, glucosamine
81
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
hydrochloride, glucosamine sulfate, Glucotin, Gludex, Glutilage, GLY079,
GLY145,
Glycanic, Glycefort up, Glygesic, Glysopep, GMCSF Antibody, GMI1010, GMI1011,
GMI1043, GMR321, GN4001, Goanna Salve, Goflex, gold sodium thiomalate,
golimumab,
GP2013, GPCR modulator, GPR15 Antagonist, GPR183 antagonist, GPR32 antagonist,
GPR83 antagonist, G-protein Coupled Receptor Antagonists, Graceptor, Graftac,
granulocyte
colony-stimulating factor antibody, granulocyte-macrophage colony-stimulating
factor
antibody, Gravx, GRC4039, Grelyse, GS101, G59973, GSC100, G5K1605786,
G5K1827771, G5K2136525, G5K2941266, G5K315234, G5K681323, GT146, GT442,
Gucixiaotong, Gufisera, Gupisone, gusperimus hydrochloride, GW274150, GW3333,
GW406381, GW856553, GWB78, GXP04, Gynestrel, Haloart, halopredone acetate,
Haloxin,
HANALL, Harlan Soludacortin, Havisco, Hawon Bucillamin, HB802, HC31496, HCQ
200,
HD104, HD203, HD205, HDAC inhibitor, HE2500, HE3177, HE3413, Hecoria,
Hectomitacin, Hefasolon, Helen, Helenil, HemaMax, Hematom, hematopoietic stem
cells,
Hematrol, Hemner, Hemril, heparinoid, Heptax, HER2 Antibody, Herponil, hESC
Derived
Dendritic Cells, hESC Derived Hematopoietic stem cells, Hespercorbin,
Hexacorton,
Hexadrol, hexetidine, Hexoderm, Hexoderm Salic, HF0220, HF1020, HFT-401, hG-
CSFR
ED Fc, Hiberna, high mobility group box 1 antibody, Hiloneed, Hinocam,
hirudin, Hirudoid,
Hison, Histamine H4 Receptor Antagonist, Hitenercept, Hizentra, HL036, HL161,
HMPL001, HMPL004, HMPL004, HMPL011, HMPL342, HMPL692, honey bee venom,
Hongqiang, Hotemin, HPH116, HTI101, HuCAL Antibody, Human adipose mesenchymal
stem cells, anti-MI-IC class II monoclonal antibody, Human Immunoglobulin,
Human
Placenta Tissue Hydrolysate, HuMaxCD4, HuMax-TAC, Humetone, Humicade, Humira,
Huons Betamethasone sodium phosphate, Huons dexamethasone sodium phosphate,
Huons
Piroxicam, Huons Talniflumate, Hurofen, Huruma, Huvap, HuZAF, HX02, Hyalogel,
hyaluronate sodium, hyaluronic acid, hyaluronidase, Hyaron, Hycocin, Hycort,
Hy-Cortisone,
hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,
hydrocortisone
hemisuccinate, hydrocortisone sodium phosphate, hydrocortisone sodium
succinate,
Hydrocortistab, Hydrocortone, Hydrolin, Hydroquine, Hydro-Rx, Hydrosone HIKMA,
hydroxychloroquine, hydroxychloroquine sulfate, Hylase Dessau, HyMEX, Hypen,
HyQ,
Hysonate, HZN602, I.M.75, TAP Inhibitors, Ibalgin, Ibalgin, Ibex, ibrutinib,
IBsolvMIR, Ibu,
Ibucon, Ibudolor, Ibufen, Ibuflam, Ibuflex, Ibugesic, Ibu-Hepa, Ibukim,
Ibumal, Ibunal,
Ibupental, Ibupril, Ibuprof, ibuprofen, Ibuscent, Ibusoft, Ibusuki Penjeong,
Ibususpen,
Ibutard, Ibutop, Ibutop, Ibutrex, IC487892, ichthammol, ICRAC Blocker,
IDEC131,
IDECCE9.1, Ides, Idicin, Idizone, IDN6556, Idomethine, IDR1, Idyl SR, Ifen,
iguratimod,
82
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
IK6002, IKK-beta inhibitor, IL17 Antagonist, IL-17 Inhibitor, IL-17RC, IL18,
IL1Hyl,
IL1R1, IL-23 Adnectin, IL23 Inhibitor, IL23 Receptor Antagonist, IL-31 mAb, IL-
6
Inhibitor, IL6Qb, Ilacox, Ilaris, ilodecakin, ILV094, ILV095, Imaxetil,
IMD0560, IMD2560,
Imesel Plus, Iminoral, Immodin, IMMU103, IMMU106, Immucept, Immufine, Immunex
Syrup, immunoglobulin, immunoglobulin G, Immunoprin, ImmunoRel, Immurin,
IM08400,
IMP731 antibody, Implanta, Imunocell, Imuran, Imurek, Imusafe, Imusporin,
Imutrex,
IN0701, Inal, INCB039110, INCB18424, INCB28050, INCB3284, INCB3344, Indexon,
Indic, Indo, Indo-A, Indobid, Indo-Bros, Indocaf, Indocarsil, Indocid,
Indocin, Indomehotpas,
Indomen, Indomet, Indometacin, indomethacin, Indomethasone, Indometin,
Indomin,
Indopal, Indoron, Indotroxin, INDUS830, INDU583030, Infladase, Inflamac,
Inflammasome
inhibitor, Inflavis, Inflaxen, Inflectra, infliximab, Ingalipt, Inicox dp,
Inmecin, Inmunoartro,
Innamit, InnoD06006, IN07997, Inocin, Inoten, Inovan, Inpra, Inside Pap,
Insider-P,
Instacyl, Instracool, Intafenac, Intaflam, Inteban, Inteban Spansule,
integrin, alpha 1
antibody, integrin, alpha 2 antibody, Intenurse, interferon alfa, interferon
beta-1a, interferon
gamma, interferon gamma antibody, Interking, interleukin 1 Hy 1, interleukin 1
antibody,
interleukin 1 receptor antibody, interleukin 1, beta antibody, interleukin 10,
interleukin 10
antibody, interleukin 12, interleukin 12 antibody, interleukin 13 antibody,
interleukin 15
antibody, interleukin 17 antibody, interleukin 17 receptor C, interleukin 18,
interleukin 18
binding protein, interleukin 18 antibody, interleukin 2 receptor, alpha
antibody, interleukin 20
antibody, Interleukin 21 mAb, interleukin 23 aptamer, interleukin 31 antibody,
interleukin 34,
Interleukin 6 Inhibitor, interleukin 6 antibody, interleukin 6 receptor
antibody, interleukin 7,
interleukin 7 receptor antibody, interleukin 8, interleukin 8 antibody,
interleukin-18 antibody,
Intidrol, Intradex, Intragam P, Intragesic, Intraglobin F, Intratect, Inzel,
Iomab B, IOR-T3,
IP751, IPH2201, IPH2301, IPH24, IPH33, IP1145, Ipocort, IPP201007, I-Profen,
Iprox,
Ipson, Iputon, IRAK4 Inhibitor, Iremod, Irtonpyson, IRX3, IRX5183, ISA247,
I5I5104838,
ISIS2302, ISISCRPRx, Ismafron, IsoQC inhibitor, Isox, ITF2357, Iveegam EN,
Ivepred,
IVIG-SN, IWO01, Izilox, J607Y, J775Y, JAK Inhibitor, JAK3 inhibitor, JAK3
kinase
inhibitor, JI3292, JI4135, Jinan Lida, JNJ10329670, JNJ18003414, JNJ26528398,
JNJ27390467, JNJ28838017, JNJ31001958, JNJ38518168, JNJ39758979, JNJ40346527,
JNJ7777120, JNT-Plus, Joflam, Joint Glucosamin, Jointec, Jointstem, Joinup,
JPE1375,
J5M10292, J5M7717, J5M8757, JTE051, JTE052, JTE522, JTE607, Jusgo, K412, K832,
Kaflam, KAHR101, KAHR102, KAI9803, Kalymin, Kam Predsol, Kameton, KANAb071,
Kappaproct, KAR2581, KAR3000, KAR3166, KAR4000, KAR4139, KAR4141, KB002,
KB003, KD7332, KE298, keliximab, Kemanat, Kemrox, Kenacort, Kenalog, Kenaxir,
83
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Kenketsu Venoglobulin-IH, Keplat, Ketalgipan, Keto Pine, Keto, Ketobos,
Ketofan, Ketofen,
Ketolgan, Ketonal, Ketoplus Kata Plasma, ketoprofen, Ketores, Ketorin,
ketorolac, ketorolac
tromethamine, Ketoselect, Ketotop, Ketovail, Ketricin, Ketroc, Ketum, Keyi,
Keyven,
KF24345, K-Fenac, K-Fenak, K-Gesic, Kifadene, Kilcort, Kildrol, KIM127,
Kimotab,
Kinase Inhibitor 4SC, Kinase N, Kincort, Kindorase, Kineret, Kineto, Kitadol,
Kitex, Kitolac,
KLK1 Inhibitor, Klofen-L, Klotaren, KLS-40or, KLS-40ra, KM277, Knavon, Kodolo
orabase, Kohakusanin, Koide, Koidexa, Kolbet, Konac, Kondro, Kondromin,
Konshien,
Kontab, Kordexa, Kosa, Kotase, KPE06001, KRP107, KRP203, KRX211, KRX252,
KSB302, K-Sep, Kv 1.3 Blocker, Kv1.3 4SC, Kv1.3 inhibitor, KVK702, Kynol,
L156602,
Labizone, Labohydro, Labopen, Lacoxa, Lamin, Lamit, Lanfetil, laquinimod,
larazotide
acetate, LAS186323, LAS187247, LAS41002, Laticort, LBEC0101, LCP3301, LCP-
Siro,
LCP-Tacro, LCsA, LDP392, Leap-S, Ledercort, Lederfen, Lederlon, Lederspan,
Lefenine,
leflunomide, Leflux, Lefno, Lefra, Leftose, Lefumide, Lefunodin, Lefva,
lenalidomide,
lenercept, LentiRA, LE015520, Leodase, Leukine, Leukocyte function-associated
antigen-1
antagonist, leukocyte immunoglobulin-like receptor, subfamily A, member 4
antibody,
Leukothera, leuprolide acetate, levalbuterol, levomenthol, LFA-1 Antagonist,
LFA451,
LFA703, LFA878, LG106, LG267 Inhibitors, LG688 Inhibitors, LGD5552, Li Life,
LidaMantle, Lidex, lidocaine, lidocaine hydrochloride, Lignocaine
hydrochloride, LIM0723,
LIM5310, Limethason, Limus, Limustin, Lindac, Linfonex, Linola acute, Lipcy,
lisofylline,
Listran, Liver X Receptor modulator, Lizak, LP1207, LJP920, Lobafen, Lobu,
Locafluo,
Localyn, Locaseptil-Neo, Locpren, Lodine, Lodotra, Lofedic, Loflam, Lofnac,
Lolcam,
Lonac, lonazolac calcium, Loprofen, Loracort, Lorcam, Lorfenamin, Lorinden
Lotio,
Lorncrat, lornoxicam, Lorox, losmapimod, loteprednol etabonate, Loteprednol,
Lotirac, Low
Molecular Ganoderma Lucidum Polysaccharide, Loxafen, Loxfenine, Loxicam,
Loxofen,
Loxonal, Loxonin, loxoprofen sodium, Loxoron, LP183A1, LP183A2, LP204A1,
LPCN1019, LT1942, LT1964, LTNS101, LTNS103, LTNS106, LTNS108, LTS1115,
LTZMP001, Lubor, lumiracoxib, Lumitect, LX2311, LX2931, LX2932, LY2127399,
LY2189102, LY2439821, LY294002, LY3009104, LY309887, LY333013, lymphocyte
activation gene 3 antibody, Lymphoglobuline, Lyser, lysine aspirin, Lysobact,
Lysoflam,
Lysozyme hydrochloride, M3000, M834, M923, mAb hG-CSF, MABP1, macrophage
migration inhibitory factor antibody, Maitongna, Majamil prolongatum, major
histocompatibility complex class II DR antibody, major histocompatibility
complex class II
antibody, Malidens, Malival, mannan-binding lectin, mannan-binding lectin-
associated serine
protease-2 antibody, MapKap Kinase 2 Inhibitor, maraviroc, Marlex, masitinib,
Maso,
84
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
MASP2 antibody, MAT304, Matrix Metalloprotease Inhibitor, mavrilimumab,
Maxiflam,
Maxilase, Maximus, Maxisona, Maxius, Maxpro, Maxrel, Maxsulid, Maxy12, Maxy30,
MAXY4, Maxy735, Maxy740, Mayfenamic, MB11040, MBPY003b, MCAF5352A,
McCam, McRofy, MCS18, MD707, MDAM, MDcort, MDR06155, MDT012, Mebicam,
Mebuton, meclofenamate sodium, Meclophen, Mecox, Medacomb, Medafen, Medamol,
Medesone, MEDI2070, MEDI5117, MEDI541, MEDI552, MEDI571, Medicox, Medifen,
Medisolu, Medixon, Mednisol, Medrol, Medrolon, medroxyprogesterone acetate,
Mefalgin,
mefenamic acid, Mefenix, Mefentan, Meflen, Mefnetra forte, Meftagesic-DT,
Meftal,
Megakaryocyte Growth and Development Factor, Megaspas, Megaster, megestrol
acetate,
Meite, Meksun, Melbrex, Melcam, Melcam, Melflam, Melic, Melica, Melix,
Melocam,
Melocox, Mel-One, Meloprol, Melosteral, Melox, Meloxan, Meloxcam, Meloxic,
Meloxicam, Meloxifen, Metoxin, Meloxiv, Melpred, Melpros, Melurjin, Menamin,
Menisone, Menthomketo, Menthoneurin, Mentocin, Mepa, Mepharen, meprednisone,
Mepresso, Mepsolone, mercaptopurine, Mervan, Mesadoron, mesalamine, Mesasal,
Mesatec,
Mesenchymal Precursor Cells, mesenchymal stem cell, Mesipol, Mesren, Mesulan,
Mesulid,
Metacin, Metadaxan, Metaflex, Metalcaptase, metalloenzyme inhibitors,
Metapred, Metax,
Metaz, Meted, Metedic, Methacin, Methaderm, Methasone, Methotrax,
methotrexate,
methotrexate sodium, Methpred, Methyl prednisolone acetate, methyl salicylate,
methyl
sulphonyl methane, Methylon, Methylpred, methylprednisolone,
methylprednisolone acetate,
methylprednisolone sodium succinate, methylprednisolone succinate,
Methylprednisolone,
Methysol, Metindol, Metoart, Metoject, Metolate, Metoral, Metosyn, Metotab,
Metracin,
Metrex, metronidazole, Metypred, Mevamox, Mevedal, Mevilox, Mevin SR, Mexilal,
Mexpharm, Mext, Mextran, MF280, M-FasL, MHC class II beta chain peptide,
Micar,
Miclofen, Miclofenac, Micofenolato Mofetil, Micosone, Microdase, microRNA 181a-
2
oligonucleotide, MIF Inhibitors, MIFQb, MIKA-Ketoprofen, Mikametan,
milodistim, Miltax,
Minafen, Minalfen, Minalfene, Minesulin, Minocort, Mioflex, Miolox, Miprofen,
Miridacin,
Mirloks, Misoclo, Misofenac, MISTB03, MISTB04, Mitilor, mizoribine, MK0359,
MK0812,
MK0873, MK2 Inhibitors, MK50, MK8457, MK8808, MKC204, MLN0002, MLN0415,
MLN1202, MLN273, MLN3126, MLN3701, MLN3897, MLNM002, MM093, MM7XX,
MN8001, Mobic, Mobicam, Mobicox, Mobifen Plus, Mobilat, Mobitil, Mocox,
Modigraf,
Modrasone, Modulin, Mofecept, Mofetyl, mofezolac sodium, Mofilet, Molace,
molgramostim, Motslide, Momekin, Momen Gele, Moment 100, Momesone, Momesun,
Mometamed, mometasone, mometasone furoate, Monimate, monosodium alpha-luminol,
Mopik, MOR103, MOR104, MOR105, M0R208 antibody, MORAb022, Moricam,
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
momiflumate, Mosuolit, Motoral, Movaxin, Mover, Movex, Movix, Movoxicam, Mox
Forte,
Moxen, moxifloxacin hydrochloride, Mozobil, MP, MP0210, MP0270, MP1000,
MP1031,
MP196, MP435, MPA, mPGES-1 inhibitor, MPSS, MRX7EAT, MSL, MT203, MT204,
mTOR Inhibitor, MTRX1011A, Mucolase, Multicort, MultiStem, muramidase,
muramidase,
muramidase hydrochloride, muromonab-CD3, Muslax, Muspinil, Mutaze, Muvera,
MX68,
Mycept, Mycocell, Mycocept, Mycofenolatmofetil Actavis, Mycofet, Mycofit,
Mycolate,
My coldosa, My comun, My conol, my cophenolate mofetil, my cophenolate sodium,
mycophenolic acid, Mycotil, myeloid progenitor cells, Myfenax, Myfetil,
Myfortic, Mygraft,
Myochrysine, Myocrisin, Myprodol, Mysone, nab-Cyclosporine, Nabentac,
nabiximols,
Nabton, Nabuco, Nabucox, Nabuflam, Nabumet, nabumetone, Nabuton, Nac Plus,
Nacta,
Nacton, Nadium, Naklofen SR, NAL1207, NAL1216, NAL1219, NAL1268, NAL8202,
Nalfon, Nalgesin S, namilumab, Namsafe, nandrolone, Nanocort, Nanogam,
Nanosomal
Tacrolimus, Napageln, Napilac, Naprelan, Napro, Naprodil, Napronax, Napropal,
Naproson,
Naprosyn, Naproval, Naprox, naproxen, naproxen sodium, Naproxin, Naprozen,
Narbon,
Narexsin, Naril, Nasida, natalizumab, Naxdom, Naxen, Naxin, Nazovel, NC2300,
ND07,
NDC01352, Nebumetone, NecLipGCSF, Necsulide, Necsunim, Nelsid-S, Neo
Clobenate,
Neo Swiflox FC, Neocoflan, Neo-Drol, Neo-Eblimon, Neo-Hydro, Neoplanta,
Neoporine,
Neopreol, Neoprox, Neoral, Neotrexate, Neozen, Nepra, Nestacort, Neumega,
Neupogen,
Neuprex, Neurofenac, Neurogesic, Neurolab, Neuroteradol, Neuroxicam, Neutalin,
neutrazumab, Neuzym, New Panazox, Newfenstop, NewGam, Newmafen, Newmatal,
Newsicam, NEX1285, sFcRIIB, Nextomab, NF-kappaB Inhibitor, NF-kB inhibitor,
NGD20001, NHP554B, NHP554P, NI0101 antibody, NI0401, NI0501 antibody, NI0701,
NI071, NI1201 antibody, NI1401, Nicip, Niconas, Nicool, NiCord, Nicox,
Niflumate, Nigaz,
Nikam, Nilitis, Nimace, Nimaid, Nimark-P, Nimaz, Nimcet Juicy, Nime, Nimed,
Nimepast,
nimesulide, Nimesulix, Nimesulon, Nimica Plus, Nimkul, Nimlin, Nimnat,
Nimodol,
Nimpidase, Nimsaid-S, Nimser, Nimsy-SP, Nimupep, Nimusol, Nimutal, Nimuwin,
Nimvon-
S, Nincort, Niofen, Nipan, Nipent, Nise, Nisolone, Nisopred, Nisoprex,
Nisulid,
nitazoxanide, Nitcon, nitric oxide, Nizhvisal B, Nizon, NL, NMR1947, NN8209,
NN8210,
NN8226, NN8555, NN8765, NN8828, NNC014100000100, NNC051869, Noak, Nodevex,
Nodia, Nofenac, Noflagma, Noflam, Noflamen, Noflux, Non-antibacterial
Tetracyclines,
Nonpiron, Nopain, Normferon, Notpel, Notritis, Novacort, Novagent, Novarin,
Novigesic,
NOXA12, NOXD19, Noxen, Noxon, NPI1302a-3, NPI1342, NPI1387, NPI1390, NPRCS1,
NPRCS2, NPRCS3, NPRCS4, NPRCS5, NPRCS6, NPS3, NPS4, nPT-ery, NU3450, nuclear
factor NF-kappa-B p65 subunit oligonucleotide, Nucort, Nulojix, Numed-Plus,
Nurokind
86
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Ortho, Nusone-H, Nutrikemia, Nuvion, NVO7alpha, NX001, Nyclobate, Nyox, Nysa,
Obarcort, 00002417, 0C2286, ocaratuzumab, OCTSG815, Oedemase, Oedemase-D,
ofatumumab, Ofgy1-0, Ofvista, OHR118, OKi, Okifen, Oksamen, Olai, olokizumab,
Omeprose E, Omnacortil, Omneed, Omniclor, Omnigel, Omniwel, onercept, 0N04057,
0NS1210, 0NS1220, Ontac Plus, Ontak, 0NX0914, 0PC6535, opebacan, OPN101,
0PN201, 0PN302, 0PN305, 0PN401, oprelvekin, 0PT66, Optifer, Optiflur,
OptiMIRA,
Orabase Hca, Oradexon, Oraflex, OralFenac, Oralog, Oralpred, Ora-sed, Orasone,
orBec,
Orbone forte, Orcl, 0RE10002, 0RE10002, Orencia, 0rg214007, 0rg217993,
0rg219517,
0rg223119, 0rg37663, 0rg39141, 0rg48762, 0rg48775, Orgadrone, Ormoxen, Orofen
Plus,
Oromylase Biogaran, Orfila' Forte, Ortho Flex, Orthoclone OKT3, Orthofen,
Orthoflam,
Orthogesic, Orthoglu, Ortho-II, Orthomac, Ortho-Plus, Ortinims, Ortofen,
Orudis, Oruvail,
0S2, Oscart, Osmetone, Ospain, Ossilife, Ostelox, Osteluc, Osteocerin,
osteopontin, Osteral,
otelixizumab, Otipax, Ou Ning, OvaSave, 0X40 Ligand Antibody, Oxa, Oxagesic
CB,
Oxalgin DP, oxaprozin, OXCQ, Oxeno, Oxib MD, Oxibut, Oxicam, Oxiklorin,
Oximal,
Oxynal, oxyphenbutazone, Oxyphenbutazone, ozoralizumab, P13 peptide, P1639,
P21, P2X7
Antagonists, p38 Alpha Inhibitor, p38 Antagonist, p38 MAP kinase inhibitor,
p38a1pha MAP
Kinase Inhibitor, P7 peptide, P7170, P979, PA401, PA517, Pabi-dexamethasone,
PAC,
PAC10649, paclitaxel, Painoxam, Paldon, Palima, pamapimod, Pamatase,
Panafcort,
Panafcortelone, Panewin, PanGraf, Panimun Bioral, Panmesone, Panodin SR,
Panslay,
Panzem, Panzem NCD, PAP1, papain, Papirzin, Pappen K Pap, Paptinim-D,
paquinimod,
PAR2 Antagonist, Paracetamol, Paradic, Parafen TAJ, Paramidin, Paranac,
Parapar, Parci,
parecoxib, Parixam, Parry-S, Partaject Busulfan, pateclizumab, Paxceed,
PBI0032, PBI1101,
PBI1308, PBI1393, PBI1607, PBI1737, PBI2856, PBI4419, PBI4419, P-Cam,
PCI31523,
PC132765, PC134051, PC145261, PC145292, PC145308, PD360324, PD360324, PDA001,
PDE4 inhibitor, PDE-IV Inhibitor, PDL241 antibody, PDL252, Pediapred, Pefree,
pegacaristim, Peganix, Peg-Interleukin 12, pegsunercept, Pegsunercept,
PEGylated arginine
deiminase, peldesine, pelubiprofen, Penacle, penicillamine, Penostop,
Pentalgin, Pentasa,
Pentaud, pentostatin, Peon, Pepdase, Pepser, Peptirase, Pepzen, Pepzol,
Percutalgine,
Periochip, Peroxisome Proliferator Activated Receptor gamma modulators,
Petizene,
PF00344600, PF04171327, PF04236921, PF04308515, PF05230905, PF05280586,
PF251802, PF3475952, PF3491390, PF3644022, PF4629991, PF4856880, PF5212367,
PF5230896, PF547659, PF755616, PF9184, PG27, PG562, PG760564, PG8395,
PGE3935199, PGE527667, PH5, PH797804, PHA408, Pharmaniaga Mefenamic acid,
Pharmaniaga Meloxicam, Pheldin, Phenocept, phenylbutazone, PHY702, PI3K delta
87
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
inhibitor, PI3K Gamma/Delta Inhibitor, PI3K Inhibitor, Picalm, pidotimod,
piketoprofen,
Pilelife, Pilopil, Pilovate, pimecrolimus, Pipethanen, Piractam, Pirexyl,
Pirobet, Piroc,
Pirocam, Pirofel, Pirogel, Piromed, Pirosol, Pirox, Piroxen, Piroxicam,
piroxicam betadex,
Piroxifar, Piroxil, Piroxim, Pixim, Pixykine, PKC Theta Inhibitor, PL3100,
PL5100
Diclofenac, Placenta Polypeptide, Plaquenil, plerixafor, Plocfen, PLR14,
PLR18, Plutin,
PLX3397, PLX5622, PLX647, PLX-BMT, pms-Diclofenac, pms-Ibuprofen, pms-
Leflunomide, pms-Meloxicam, pms-Piroxicam, pms-Prednisolone, pms-
Sulfasalazine, pms-
Tiaprofenic, PMX53, PN0615, PN100, PN951, podofilox, P0L6326, Polcortolon,
Polyderm,
Polygam S/D, Polyphlogin, Poncif, Ponstan, Ponstil Forte, Porine-A Neoral,
Potaba,
potassium aminobenzoate, Potencort, Povidone, povidone iodine, pralnacasan,
Prandin,
Prebel, Precodil, Precortisyl Forte, Precortyl, Predfoam, Predicort,
Predicorten, Predilab,
Predilone, Predmetil, Predmix, Predna, Prednesol, Predni, prednicarbate,
Prednicort,
Prednidib, Prednifarma, Prednilasca, prednisolone, Deltacortril
(prednisolone), prednisolone
acetate, prednisolone sodium phosphate, prednisolone sodium succinate,
prednisolone
sodium succinate, prednisone, prednisone acetate, Prednitop, Prednol-L,
Prednox, Predone,
Predonema, Predsol, Predsolone, Predsone, Predval, Preflam, Prelon, Prenaxol,
Prenolone,
Preservex, Preservin, Presol, Preson, Prexige, Priliximab, Primacort,
Primmuno, Primofenac,
prinaberel, Privigen, Prixam, Probuxil, Procarne, Prochymal, Procider-EF,
Proctocir,
Prodase, Prodel B, Prodent, Prodent Verde, Proepa, Profecom, Profenac L,
Profenid,
Profenol, Proflam, Proflex, Progesic Z, proglumetacin, proglumetacin maleate,
Prograf,
Prolase, Prolixan, promethazine hydrochloride, Promostem, Promune, PronaB,
pronase,
Pronat, Prongs, Pronison, Prontoflam, Propaderm-L, Propodezas, Propolisol,
Proponol,
propyl nicotinate, Prostaloc, Prostapol, Protacin, Protase, Protease
Inhibitors, Protectan,
Proteinase Activated Receptor 2 Inhibitor, Protofen, Protrin, Proxalyoc,
Proxidol, Proxigel,
Proxil, Proxym, Prozym, PRT062070, PRT2607, PRTX100, PRTX200, PRX106,
PRX167700, Prysolone, PS031291, PS375179, PS386113, PS540446, PS608504,
PS826957,
PS873266, Psorid, PT, PT17, PTL101, P-Transfer Factor peptides, PTX3,
Pulminiq,
Pulsonid, Purazen, Pursin, PVS40200, PX101, PX106491, PX114, PXS2000, PXS2076,
PYM60001, Pyralvex, Pyranim, pyrazinobutazone, Pyrenol, Pyricam, Pyrodex,
Pyroxi-Kid,
QAX576, Qianbobiyan, QPI1002, QR440, qT3, Quiacort, Quidofil, R107s, R125224,
R1295,
R132811, R1487, R1503, R1524, R1628, R333, R348, R548, R7277, R788, rabeximod,
Radix Isatidis, Radofen, Raipeck, Rambazole, Randazima, Rapacan, Rapamune,
Raptiva,
Ravax, Rayos, RDEA119, RDEA436, RDP58, Reactine, Rebif, REC200, Recartix-DN,
receptor for advanced glycation end products antibody, Reclast, Reclofen,
recombinant HSA-
88
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
TIMP-2, recombinant human alkaline Phosphatase, recombinant Interferon Gamma,
Recominant human alkaline phosphatase, Reconil, Rectagel HC, Recticin, Recto
Menaderm,
Rectos, Redipred, Redolet, Refastin, Regenica, REGN88, Relafen, Relaxib,
Relev, Relex,
Relifen, Relifex, Relitch, Rematof, remestemce1-1, Remesulidum, Remicade0
(infliximab),
Remsima, Remsima, Remsima, ReN1869, Renacept, Renfor, Renodapt, Renodapt-S,
Renta,
Reosan, Repare-AR, Reparilexin, reparixin, Repertaxin, Repisprin, Resochin,
Resol, resolvin
El, Resurgil, Re-tin-colloid, Retoz, Reumacap, Reumacon, Reumadolor, Reumador,
Reumanisal, Reumazin, Reumel, Reumotec, Reuquinol, revamilast, Revascor,
Reviroc,
Revlimid, Revmoksikam, Rewalk, Rexalgan, RG2077, RG3421, RG4934 antibody,
RG7416,
RG7624, Rheila, Rheoma, Rheprox, Rheudenolone, Rheufen, Rheugesic, Rheumacid,
Rheumacort, Rheumatrex, Rheumesser, Rheumid, Rheumon, Rheumox, Rheuoxib,
Rhewlin,
Rhucin, RhuDex, Rhulef, Ribox, Ribunal, Ridaura, rifaximin, rilonacept,
rimacalib, Rimase,
Rimate, Rimatil, Rimesid, risedronate sodium, Ritamine, Rito, Rituxan,
rituximab, RNS60,
R01138452, Ro313948, R03244794, R05310074, Rob803, Rocamix, Rocas, Rofeb,
rofecoxib, Rofee, Rofewal, Roficip Plus, Rojepen, Rokam, Rolodiquim, Romacox
Fort,
Romatim, romazarit, Ronaben, ronacaleret, Ronoxcin, ROR Gamma T Antagonist,
ROR
gamma t inverse agonists, Rosecin, rosiglitazone, Rosmarinic acid, Rotan,
Rotec, Rothacin,
Roxam, Roxib, Roxicam, Roxopro, Roxygin DT, RP54745, RPI78, RPI78M, RPI78MN,
RPIMN, RQ00000007, RQ00000008, RTA402, R-Tyflam, Rubicalm, Rubifen, Ruma pap,
Rumalef, Rumidol, Rumifen, Runomex, rusalatide acetate, ruxolitinib,
RWJ445380,
RX10001, Rycloser MR, Rydol, SW Receptor Agonists, SP Receptor Modulators,
S1P1
Agonist, S1P1 receptor agonist, S2474, S3013, SA237, SA6541, Saaz, S-adenosyl-
L-
methionine-sulfate-p-toluene sulfonate, Sala, Salazidin, Salazine,
Salazopyrin, Salcon,
Salicam, salsalate, Sameron, SAN300, Sanaven, Sandimmun, Sandoglobulin,
Sanexon,
SangCya, SAR153191, SAR302503, SAR479746, Sarapep, sargramostim, Sativex,
Savantac,
Save, Saxizon, Sazo, 5B1578, 5B210396, 5B217969, 5B242235, 5B273005, 5B281832,
5B683698, 5B751689, 5BI087, 5C080036, 5C12267, 5C409, Scaflam, SCD ketoprofen,
5CI0323, 5CI0469, SD-15, 5D281, SDP051 antibody, Sd-rxRNA, secukinumab,
Sedase,
Sedilax, Sefdene, Seizyme, 5EL113, Seladin, Selecox, selectin P ligand
antibody,
Glucocorticoid Receptor Agonist, Selectofen, Selektine, SelK1 antibody,
Seloxx, Selspot,
Selzen, Selzenta, Selzentry, semapimod, semapimod hydrochloride, semparatide,
Semparatide, Senafen, Sendipen, Senterlic, SEP119249, Sepdase, Septirose,
Seractil,
Serafen-P, Serase, Seratid D, Seratiopeptidase, Serato-M, Seratoma Forte,
Serazyme,
Serezon, Sero, Serodase, Serpicam, Serra, serrapeptase, Serratin,
Serratiopeptidase,
89
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Serrazyme, Servisone, Seven E P, 5GI1252, SGN30, SGN70, 5GX203, shark
cartilage
extract, Sheril, Shield, Shifazen, Shifazen-Fort, Shincort, Shincort, Shiosol,
ShK186,
Shuanghuangxiaoyan, SI615, SI636, Sigmasporin, Sigmasporin, SIM916, Simpone,
Simulect, Sinacort, Sinalgia, Sinapol, Sinatrol, Sinsia, siponimod, Sirolim,
sirolimus,
Siropan, Sirota, Sirova, sirukumab, Sistal Forte, 5KF105685, 5KF105809,
5KF106615,
5KF86002, Skinalar, Skynim, Skytrip, SLAM family member 7 antibody, Slo-indo,
SM101,
5M201 antibody, 5M401, SMAD family member 7 oligonucleotide, SMART Anti-IL-12
Antibody, SMP114, 5N0030908, 5N0070131, sodium aurothiomalate, sodium
chondroitin
sulfate, sodium deoxyribonucleotide, sodium gualenate, sodium naproxen, sodium
salicylate,
Sodixen, Sofeo, Soleton, Solhidrol, Solicam, Soliky, Soliris, Sol-Melcort,
Solomet, Sotondo,
Solone, Solu-Cort, Solu-Cortef, Solu-Decortin H, Solufen, Solu-Ket, Solumark,
Solu-Medrol,
Solupred, Somaigen, somatropin, Sonap, Sone, sonepcizumab, Sonexa, Sonim,
Sonim P,
Soonil, Soral, Sorenil, sotrastaurin acetate, SP-10, 5P600125, Spanidin, SP-
Cortil, SPD550,
Spedace, sperm adhesion molecule 1, Spictol, spleen tyrosine kinase
oligonucleotide, Sporin,
S-prin, SPWF1501, 5Q641, 5Q922, 5R318B, 5R9025, 5RT2104, 55R150106, 55R180575,
SSSO7 antibody, 5T1959, 5TA5326, stabilin 1 antibody, Stacort, Stalogesic,
stanozolol,
Staren, Starmelox, Stedex IND-SWIFT, Stelara, Stemin, Stenirol, Sterapred,
Steriderm S,
Steno, Sterisone, Steron, stichodactyla helianthus peptide, Stickzenol A,
Stiefcortil, Stimulan,
STNM01, Store Operated Calcium Channel (SOCC) Modulator, 5TP432, STP900,
Stratasin,
Stridimmune, Strigraf, SU Medrol, Subreum, Subuton, Succicort, Succimed,
Sulan, Sulcolon,
Sulfasalazin Heyl, Sulfasalazin, sulfasalazine, Sulfovit, Sulidac, Sulide,
sulindac, Sulindex,
Sulinton, Sulphafine, Sumilu, 5UN597, Suprafen, Supretic, Supsidine, Surgam,
Surgamine,
Surugamu, Suspen, Suton, Suvenyl, Suwei, SW Dexasone, Syk Family Kinase
Inhibitor,
Syn1002, Synacran, Synacthen, Synalar C, Synalar, Synavive, Synercort,
Sypresta, T cell
cytokine-inducing surface molecule antibody, T cell receptor antibody, T5224,
T5226,
TA101, TA112, TA383, TA5493, tabalumab, Tacedin, Tacgraf, TACIFc5, Tacrobell,
Tacrograf, Tacrol, tacrolimus, Tadekinig alpha, Tadolak, TAFA93, Tafirol
Artro, Taizen,
TAK603, TAK715, TAK783, Takfa, Taksta, talarozole, Talfin, Talmain,
talmapimod,
Talmea, Talnif, talniflumate, Tabs, Talpain, Talumat, Tamaigen, Tamceton,
Tamezon,
Tandrilax, tannins, Tannosynt, Tantum, tanzisertib, Tapain-beta, Tapoein,
Tarenac,
tarenflurbil, Tarimus, Tarproxen, Tauxib, Tazomust, TBR652, TC5619, T-cell,
immune
regulator 1, ATPase, H+ transporting, lysosomal VO subunit A3 antibody, TCK1,
T-cort, T-
Dexa, Tecelac, Tecon, teduglutide, Teecort, Tegeline, Tementil, temoporfin,
Tencam,
Tendrone, Tenefuse, Tenfly, tenidap sodium, Tenocam, Tenoflex, Tenoksan,
Tenotil,
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
tenoxicam, Tenoxim, Tepadina, Teracort, Teradol, tetomilast, TG0054, TG1060,
TG20,
TG20, tgAAC94, Th1/Th2 Cytokine Synthase Inhibitor, Th-17 cell inhibitors,
Thalido,
thalidomide, Thalomid, Themisera, Thenil, Therafectin, Therapyace, thiarabine,
Thiazolopyrimidines, thioctic acid, thiotepa, THR090717, THR0921, Threenofen,
Thrombate
III, Thymic peptide, Thymodepressin, Thymogam, Thymoglobulin, Thymoglobuline,
Thymoject thymic peptides, thymomodulin, thymopentin, thymopolypetides,
tiaprofenic acid,
tibezonium iodide, Ticoflex, tilmacoxib, Tilur, T-immune, Timocon, Tiorase,
Tissop,
TKB662, TL011, TLR4 antagonists, TLR8 inhibitor, TM120, TM400, TMX302, TNF
Alpha
inhibitor, TNF alpha-TNF receptor antagonist, TNF antibody, TNF receptor
superfamily
antagonists, TNF TWEAK Bi-Specific, TNF-Kinoid, TNFQb, TNFR1 antagonist,
TNR001,
TNX100, TNX224, TNX336, TNX558, tocilizumab, tofacitinib, Tokuhon happ,
TOL101,
TOL102, Tolectin, ToleriMab, Tolerostem, Tolindol, toll-like receptor 4
antibody, toll-like
receptor antibody, tolmetin sodium, Tongkeeper, Tonmex, Topflame, Topicort,
Topleucon,
Topnac, Toppin Ichthammol, toralizumab, Toraren, Torcoxia, Toroxx, Tory,
Toselac,
Totaryl, Touch-med, Touchron, Tovok, Toxic apis, Toyolyzom, TP4179, TPCA1,
TPI526,
TR14035, Tradil Fort, Traficet-EN, Tramace, tramadol hydrochloride, tranilast,
Transimune,
Transporina, Tratul, Trexall, Triacort, Triakort, Trialon, Triam,
triamcinolone, triamcinolone
acetate, triamcinolone acetonide, triamcinolone acetonide acetate,
triamcinolone
hexacetonide, Triamcort, Triamsicort, Trianex, Tricin, Tricort, Tricortone,
TricOs T,
Triderm, Trilac, Trilisate, Trinocort, Trinolone, Triolex, triptolide,
Trisfen, Trivaris,
TRK170, TRK530, Trocade, trolamine salicylate, Trolovol, Trosera, Trosera D,
Troycort,
TRX1 antibody, TRX4, Trymoto, Trymoto-A, TT301, TT302, TT32, TT32, TT33,
TTI314,
tumor necrosis factor, tumor necrosis factor 2-methoxyethyl phosphorothioate
oligonucleotide, tumor necrosis factor antibody, tumor necrosis factor kinoid,
tumor necrosis
factor oligonucleotide, tumor necrosis factor receptor superfamily, member 1B
antibody,
tumor necrosis factor receptor superfamily 1B oligonucleotide, tumor necrosis
factor
superfamily, member 12 antibody, tumor necrosis factor superfamily, member 4
antibody,
tumor protein p53 oligonucleotide, tumour necrosis factor alpha antibody,
TuNEX, TXA127,
TX-RAD, TYK2 inhibitors, Tysabri, ubidecarenone, Ucerase, ulodesine, Ultiflam,
Ultrafastin, Ultrafen, Ultralan, U-Nice-B, Uniplus, Unitrexate, Unizen,
Uphaxicam,
UR13870, UR5269, UR67767, Uremol-HC, Urigon, U-Ritis, ustekinumab, V85546,
Valcib,
Valcox, valdecoxib, Valdez, Valdixx, Valdy, Valentac, Valoxib, Valtune, Valus
AT, Valz,
Valzer, Vamid, Vantal, Vantelin, VAP-1 SSAO Inhibitor, vapaliximab,
varespladib methyl,
Varicosin, Varidase, vascular adhesion protein-1 antibody, VB110, VB120,
VB201,
91
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
VBY285, Vectra-P, vedolizumab, Vefren, VEGFR-1 Antibody, Veldona, veltuzumab,
Vendexine, Venimmun N, Venoforte, Venoglobulin-IH, Venozel, Vera!, Verax,
vercirnon,
vero-dexamethasone, Vero-Kladribin, Vetazone, VGX1027, VGX750, Vibex MTX,
vidofludimus, Vifenac, Vimovo, Vimultisa, Vincort, Vingraf, Vioform-HC, Vioxl,
Vioxx,
Virobron, visilizumab, Vivaglobin, Vivalde Plus, Vivian-A, VLST002, VLST003,
VLST004,
VLST005, VLST007, Voalla, voclosporin, Vokam, Vokmor, Volmax, Volna-K,
Voltadol,
Voltagesic, Voltanase, Voltanec, Voltaren, Voltarile, Voltic, Voren,
vorsetuzumab, Votan-
SR, VR909, VRA002, VRP1008, VRS826, VRS826, VT111, VT214, VT224, VT310,
VT346, VT362, VTX763, Vurdon, VX30 antibody, VX467, VX5, VX509, VX702, VX740,
VX745, VX745, VX850, W54011, Walacort, Walix, WC3027, Wilgraf, Winflam,
Winmol,
Winpred, Winsolve, Wintogeno, WIP901, Woncox, WSB711 antibody, WSB712
antibody,
WSB735, WSB961, X071NAB, X083NAB, Xantomicin Forte, Xedenol, Xefo, Xefocam,
Xenar, Xepol, X-Flam, Xibra, Xicam, Xicotil, Xifaxan, XL499, XmAb5483,
XmAb5485,
XmAb5574, XmAb5871, X0MA052, Xpress, XPro1595, XtendTNF, XToll, Xtra, Xylex-H,
Xynofen SR, Yang Shu-IVIG, YHB14112, YM974, Youfeline, Youfenac, Yuma,
Yumerol,
Yuroben, YY piroxicam, Z104657A, Zacy, Zaltokin, zaltoprofen, Zap70 Inhibitor,
Zeepain,
Zeloxim Fort, Zema-Pak, Zempack, Zempred, Zenapax, Zenas, Zeno!, Zenos,
Zenoxone,
Zerax, Zerocam, Zerospasm, ZFNs, zinc oxide, Zipsor, ziralimumab, Zitis, Zix-
S, Zocort,
Zodixam, Zoftadex, zoledronic acid, Zolfin, Zolterol, Zopyrin, Zoralone,
ZORprin, Zortress,
ZP1848, zucapsaicin, Zunovate, Zwitterionic polysaccharides, ZY1400, Zybodies,
Zycel,
Zyrofen, Zyrogen Inhibitors, Zyser, Zytrim, and Zywin-Forte. In addition, the
anti-
inflammatory drugs, as listed above, may be combined with one or more agents
listed above
or herein or with other agents known in the art.
[1227] In one
embodiment, the drug is a drug that inhibits, reduces or modulates the
signaling and/or activity of PDGF-receptors (PDGFR). For example, the PDGF
antagonist
delivered to the suprachoroidal space for the treatment of one or more
posterior ocular
disorders such as macular edema associated with uveitis (e.g., non-infectious
uveitis),
macular edema associated with RVO or wet AMD, in one embodiment, is an anti-
PDGF
aptamer, an anti-PDGF antibody or fragment thereof, an anti-PDGFR antibody or
fragment
thereof, or a small molecule antagonist. In one embodiment, the PDGF
antagonist is an
antagonist of the PDGFRa or PDGFRO. In one embodiment, the PDGF antagonist is
the
anti-PDGF-I3 aptamer E10030, dasatinib, sunitinib, axitinib, sorefenib,
imatinib, imatinib
mesylate, nintedanib, pazopanib HC!, ponatinib , MK-2461, pazopanib,
crenolanib, PP-121,
92
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
telatinib, imatinib, KRN 633, CP 673451, TSU-68 (orantinib), Ki8751,
amuvatinib,
tivozanib, masitinib, motesanib diphosphate, dovitinib, dovitinib dilactic
acid, FOVISTA, or
linifanib (ABT-869). As described herein, in one embodimdent, the PDGF
antagonist, for
example, one of the PDGF antagonists described above, can be used in the
methods for
treating macular edema associated with uveitis, macular edema associated with
RVO, wet
AMD, CNV, wet AMD associated with RVO, or wet AMD associated with CNV via SCS
administration. Moreover, in some embodiments, the PDGF antagonist is
administered
intravitreally in conjunction with SCS administration aflibercept, in a method
of treating one
of the aforementioned indications.
[1228] In a
further embodiment, the PDGF antagonist also has VEGF antagonist activity.
For example, an anti-VEGF/PDGF-B darpin, dasatinib, dovitinib, Ki8751,
telatinib, TSU-68
(orantinib) or motesanib diphosphate are known inhibitors of both VEGF and
PDGF, and can
be used in the methods described herein. The dual PDGF/VEGF antagonist can
also be
administered intravitreally in conjunction with non-surgical delivery of
aflibercept to the
SCS.
[1229] Examples
of other suitable drugs for use with the devices and methods described
herein include, but are not limited to: A0003, A36 peptide, AAV2-sFLT01,
ACE041,
ACU02, ACU3223, ACU4429, AdPEDF, aflibercept, AG13958, aganirsen, AGN150998,
AGN745, AL39324, AL78898A, AL8309B, ALN-VEG01, alprostadil, AM1101, amyloid
beta antibody, anecortave acetate, Anti-VEGFR-2 Alterase, Aptocine, APX003,
ARC1905,
ARC1905 with Lucentis, ATG3, ATP-binding cassette, sub-family A, member 4
gene,
ATXS10, Avastin with Visudyne, AVT101, AVT2, bertilimumab, bevacizumab with
verteporfin, bevasiranib sodium, bevasiranib sodium; with ranibizumab,
brimonidine tartrate,
BVA301, canakinumab, Cand5, Cand5 with Lucentis, CERE140, ciliary neurotrophic
factor,
CLT009, CNT02476, collagen monoclonal antibody, complement component 5 aptamer
(pegylated), complement component 5 aptamer (pegylated) with ranibizumab,
complement
component C3, complement factor B antibody, complement factor D antibody,
copper oxide
with lutein, vitamin C, vitamin E, and zinc oxide, dalantercept, DE109,
bevacizumab,
ranibizumab, triamcinolone, triamcinolone acetonide, triamcinolone acetonide
with
verteporfin, dexamethasone, dexamethasone with ranibizumab and verteporfin,
disitertide,
DNA damage inducible transcript 4 oligonucleotide, E10030, E10030 with
Lucentis, EC400,
eculizumab, EGP, EHT204, embryonic stem cells, human stem cells, endoglin
monoclonal
93
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
antibody, EphB4 RTK Inhibitor, EphB4 Soluble Receptor, E5BA1008, ETX6991,
Evizon,
Eyebar, EyePromise Five, Eyevi, Eylea, F200, FCFD4514S, fenretinide,
fluocinolone
acetonide, fluocinolone acetonide with ranibizumab, fms-related tyrosine
kinase 1
oligonucleotide, fms-related tyrosine kinase 1 oligonucleotide with kinase
insert domain
receptor 169, fosbretabulin tromethamine, Gamunex, GEM220, G5101, G5K933776,
HC31496, Human n-CoDeR, HYB676, IBI-20089 with ranibizumab (Lucentis ), iCo-
008,
Iconl, I-Gold, Ilaris, Iluvien, Iluvien with Lucentis, immunoglobulins,
integrin alpha5betal
immunoglobulin fragments, Integrin inhibitor, IRIS Lutein, I-Sense Ocushield,
Isonep,
isopropyl unoprostone, JPE1375, J5M6427, KH902, LentiVue, LFG316, LP590,
LP01010AM, Lucentis, Lucentis with Visudyne, Lutein ekstra, Lutein with
myrtillus extract,
Lutein with zeaxanthin, M200, M200 with Lucentis, Macugen, MC1101, MCT355,
mecamylamine, Microplasmin, motexafin lutetium, MP0112, NADPH oxidase
inhibitors,
aeterna shark cartilage extract (ArthrovasTM, NeoretnaTM, PsovascarTm),
neurotrophin 4 gene,
Nova21012, Nova21013, NT501, NT503, Nutri-Stulln, ocriplasmin, OcuXan, Oftan
Macula,
Optrin, ORA102 with bevacizumab (Avastin0), P144, P17, Palomid 529, PAN90806,
Panzem, Panzem, PARP inhibitors, pazopanib hydrochloride, pegaptanib sodium,
PF4523655, PG11047, piribedil, platelet-derived growth factor beta polypeptide
aptamer
(pegylated), platelet-derived growth factor beta polypeptide aptamer
(pegylated) with
ranibizumab, PLG101, PMX20005, PMX53, POT4, PRS055, PTK787, ranibizumab,
ranibizumab with triamcinolone acetonide, ranibizumabwith verteporfin,
ranibizumab with
volociximab, RD27, Rescula, Retaane, retinal pigment epithelial cells,
RetinoStat, RG7417,
RN6G, RT101, RTU007, 5B267268, serpin peptidase inhibitor, clade F, member 1
gene,
shark cartilage extract, Shefl, 5IR1046, 5IR1076, 5irna027, sirolimus,
SMTD004, Snelvit,
SOD Mimetics, Soliris, sonepcizumab, squalamine lactate, 5T602, StarGen,
T2TrpRS,
TA106, talaporfin sodium, Tauroursodeoxycholic acid, TG100801, TM , TLCx99,
TRC093,
TRC105, Trivastal Retard, TT30, Ursa, ursodiol, Vangiolux, VAR10200, vascular
endothelial growth factor antibody, vascular endothelial growth factor B,
vascular endothelial
growth factor kinoid, vascular endothelial growth factor oligonucleotide, VAST
Compounds,
vatalanib, VEGF antagonist (e.g., as described herein), verteporfin, Visudyne,
Visudyne with
Lucentis and dexamethasone, Visudyne with triamcinolone acetonide, Vivis,
volociximab,
Votrient, XV615, zeaxanthin, ZFP TF, zinc-monocysteine and Zybrestat. In
one
embodiment, one or more of the drugs described above is combined with one or
more agents
listed above or herein or with other agents known in the art.
94
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1230] In one
embodiment, the drug is interferon gamma lb (Actimmune0) with
pirfenidone, ACUHTR028, AlphaVBeta5, aminobenzoate potassium, amyloid P,
ANG1122,
ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, Anti-CTGF RNAi, Aplidin,
astragalus membranaceus extract with salvia and schisandra chinensis,
atherosclerotic plaque
blocker, Azol, AZX100, BB3, connective tissue growth factor antibody, CT140,
danazol,
Esbriet, EXC001, EXC002, EXC003, EXC004, EXC005, F647, FG3019, Fibrocorin,
Follistatin, FT011, Galectin-3 inhibitors, GKT137831, GMCT01, GMCT02, GRMD01,
GRMD02, GRN510, Heberon Alfa R, interferon alfa-2b, interferon gamma-lb with
pirfenidone, ITMN520, JKB119, JKB121, JKB122, KRX168, LPA1 receptor
antagonist,
MGN4220, MIA2, microRNA 29a oligonucleotide, MMI0100, noscapine, PBI4050,
PBI4419, PDGFR inhibitor, PF-06473871, PGN0052, Pirespa, Pirfenex,
pirfenidone,
plitidepsin, PRM151, Px102, PYN17, PYN22 with PYN17, Relivergen, rhPTX2 Fusion
Proteins, RXI109, secretin, STX100, TGF-beta Inhibitor, transforming growth
factor, beta
receptor 2 oligonucleotide, VA999260 or XV615. In one embodiment, one or more
of the
drugs for treating macular edema associated with uveitis described above is
combined with
one or more agents listed above or herein or with other agents known in the
art.
[1231] In one
embodiment, a drug that treats, prevents and/or ameliorates diabetic
macular edema is used in conjunction with the devices and methods described
herein and is
delivered to the suprachoroidal space of the eye. In a further embodiment, the
drug is
AKB9778, bevasiranib sodium, Cand5, choline fenofibrate, Cortiject, c-raf 2-
methoxyethyl
phosphorothioate oligonucleotide, DE109, dexamethasone, DNA damage inducible
transcript
4 oligonucleotide, F0V2304, iCo007, KH902, MP0112, NCX434, Optina, Ozurdex,
PF4523655, SAR1118, sirolimus, SK0503 or TriLipix. In one embodiment, one or
more of
the diabetic macular edema treating drugs described above is combined with one
or more
agents listed above or herein or with other agents known in the art.
[1232] In one
embodiment, the methods and devices provided herein are used to deliver
triamcinolone or triamcinolone acetonide to the suprachoroidal space of an eye
of a human
subject in need of treatment for treating uveitis (e.g., non-infectious
uveitis), macular edema
associated with uveitis, wet AMD, CNV, wet AMD associated with RVO, or wet AMD
associated with CNV. In another embodiment, triamcinolone or triamcinolone
acetonide is
delivered via one of the methods described herein.
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1233] In one
embodiment, the therapeutic formulation comprises a suspension of cells,
for example, a suspension of rentinal stem cells. In one embodiment, a
suspension of neural
stem cells (NSCs) is administered to the SCS via one of the devices and/or
methods provided
herien. NSCs are self-renewing, multipotent cells that can differentiate into
the main cell
phenotypes of the nervous system. They have been isolated from the adult
mammalian brain
tissue, including humans. In one embodiment, a suspension of retinal stem
cells (RSCs) is
administered to the SCS via one of the devices and/or methods provided herien.
During early
development, retinal stem cells (RSC) are a possible donor source that give
rise to all retinal
cell types. These cells can be isolated, expanded, and differentiated into
retinal neurons by
culturing them in the presence of growth factors, such as epidermal growth
factor and
fibroblast growth factor. In yet another embodiment, a suspension of adult
stem cells or
mesenchymal stem cells (MSCs) is administered to the SCS of a patient in need
thereof via
one of the devices and/or methods provided herein. Other cell types amenable
for
administration via the devices and methods provided herein include but are not
limited to
hematopoietic stem cells (HSCs), human embryonic stem cells (hESCs), retinal
progenitor
cells, endothelial progenitor cells or a combination thereof
[1234] In one
embodiment, one or more of the stem cells described in Arch Ophthalmol.
2004;122(4):621-627, incorporated by reference herein in its entirety for all
purposes, is
delivered to a patient via a device or method described herein.
[1235] The
"therapeutic formulation" delivered via the methods and devices provided
herein in one embodiment, is an aqueous solution or suspension, and comprises
an effective
amount of the drug or therapeutic agent, for example, a cellular suspension.
In some
embodiments, the therapeutic formulation is a fluid drug formulation. The
"drug
formulation" is a formulation of a drug, which typically includes one or more
pharmaceutically acceptable excipient materials known in the art. The term
"excipient"
refers to any non-active ingredient of the formulation intended to facilitate
handling, stability,
dispersibility, wettability, release kinetics, and/or injection of the drug.
In one embodiment,
the excipient may include or consist of water or saline.
[1236] The
therapeutic formulation delivered to the suprachoroidal space of the eye of a
human subject for the treatment of uveitis (e.g., non-infectious uveitis),
macular edema
associated with uveitis (e.g., non-infectious uveitis), wet AMD, CNV, wet AMD
associated
with RVO, or wet AMD associated with CNV may be in the form of a liquid drug,
a liquid
96
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
solution that includes a drug or therapy in a suitable solvent, or liquid
suspension. The liquid
suspension may include microparticles or nanoparticles dispersed in a suitable
liquid vehicle
for infusion. In various embodiments, the drug is included in a liquid
vehicle, in
microparticles or nanoparticles, or in both the vehicle and particles. The
drug formulation is
sufficiently fluid to flow into and within the suprachoroidal space, as well
as into the
surrounding posterior ocular tissues. In one embodiment, the viscosity of the
fluid drug
formulation is about 1 cP at 37 C.
[1237] In one
embodiment, the drug formulation (e.g., fluid drug formulation) includes
microparticles or nanoparticles, either of which includes at least one drug.
Desirably, the
microparticles or nanoparticles provide for the controlled release of drug
into the
suprachoroidal space and surrounding posterior ocular tissue. As used herein,
the term
"microparticle" encompasses microspheres, microcapsules, microparticles, and
beads, having
a number average diameter of from about 1 p.m to about 100 p.m, for example
from about 1 to
about 25 p.m, or from about 1 p.m to about 7 p.m. "Nanoparticles" are
particles having an
average diameter of from about 1 nm to about 1000 nm. The microparticles, in
one
embodiment, have a D50 of about 3 p.m or less. In a further embodiment, the
D50 is about 2
p.m. In another embodiment, the D50 of the particles in the drug formulation
is about 2 p.m or
less. In another embodiment, the D50 of the particles in the drug formulation
is about 1000
nm or less. In one embodiment, the drug formulation comprises microparticles
having a D99
of about 10 p.m or less. The microparticles, in one embodiment, have a D50 of
about 3 p.m or
less. In a further embodiment, the D50 is about 2 p.m. In another embodiment,
the D50 of the
particles in the drug formulation is about 2 p.m or less. In another
embodiment, the D50 of
the particles in the drug formulation is about 1000 nm or less. In one
embodiment, the drug
formulation comprises microparticles having a D99 of about 10 p.m or less. The
microparticles, in one embodiment, have a D50 of about 3 p.m or less. In a
further
embodiment, the D50 is about 2 p.m. In another embodiment, the D50 of the
particles in the
drug formulation is about 2 p.m or less. In another embodiment, the D50 of the
particles in the
drug formulation is about 100 nm to about 1000 nm. In one embodiment, the drug
formulation comprises microparticles having a D99 of about 1000 nm to about 10
p.m. The
microparticles, in one embodiment, have a D50 of about 1 p.m to about 5p.m or
less. In
another embodiment, the drug formulation comprises particles having a D99 of
about 10 p.m.
In another embodiment, the D99 of the particles in the formulation is less
than about 10 p.m, or
less than about 9 p.m, or less than about 7 p.m or less than about 3p.m. In a
further
97
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
embodiment, the microparticles or nanoparticles comprise an anti-inflammatory
drug. In a
further embodiment, the anti-inflammatory drug is triamcinolone.
[1238]
Microparticles and nanoparticles may or may not be spherical in shape.
"Microcapsules" and "nanocapsules" are defined as microparticles and
nanoparticles having
an outer shell surrounding a core of another material. The core can be liquid,
gel, solid, gas,
or a combination thereof In one case, the microcapsule or nanocapsule may be a
"microbubble" or "nanobubble" having an outer shell surrounding a core of gas,
wherein the
drug is disposed on the surface of the outer shell, in the outer shell itself,
or in the core.
(Microbubbles and nanobubles may be respond to accoustic vibrations as known
in the art for
diagnosis or to burst the microbubble to release its payload at/into a select
ocular tissue site.)
"Microspheres" and "nanospheres" can be solid spheres, can be porous and
include a sponge-
like or honeycomb structure formed by pores or voids in a matrix material or
shell, or can
include multiple discrete voids in a matrix material or shell. The
microparticles or
nanoparticles may further include a matrix material. The shell or matrix
material may be a
polymer, amino acid, saccharride, or other material known in the art of
microencapsulation.
[1239] The drug-
containing microparticles or nanoparticles may be suspended in an
aqueous or non-aqueous liquid vehicle. The liquid vehicle may be a
pharmaceutically
acceptable aqueous solution, and optionally may further include a surfactant.
The
microparticles or nanoparticles of drug themselves may include an excipient
material, such as
a polymer, a polysaccharide, a surfactant, etc., which are known in the art to
control the
kinetics of drug release from particles.
[1240] In one
embodiment, the drug formulation further includes an agent effective to
degrade collagen or GAG fibers in the sclera, which may enhance
penetration/release of the
drug into the ocular tissues. This agent may be, for example, an enzyme, such
a
hyaluronidase, a collagenase, or a combination thereof In a variation of this
method, the
enzyme is administered to the ocular tissue in a separate step from¨preceding
or
following¨infusion of the drug. The enzyme and drug are administered at the
same site.
[1241] In
another embodiment, the drug formulation is one which undergoes a phase
change upon administration. For instance, a liquid drug formulation may be
injected through
hollow microneedles into the suprachoroidal space, where it then gels and the
drug diffuses
out from the gel for controlled release.
98
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1242] The
therapeutic substance in one embodiment is formulated with one or more
polymeric excipients to limit therapeutic substance migration and/or to
increase viscosity of
the formulation. A polymeric excipient may be selected and formulated to act
as a viscous
gel-like material in-situ and thereby spread into a region of the
suprachoroidal space and
uniformly distribute and retain the drug. The polymer excipient in one
embodiment is
selected and formulated to provide the appropriate viscosity, flow and
dissolution properties.
For example, carboxymethylcellulose is used in one embodiment to form a gel-
like material
in the suprachoroidal space. The viscosity of the polymer in one embodiment is
enhanced by
appropriate chemical modification to the polymer to increase associative
properties such as
the addition of hydrophobic moieties, the selection of higher molecular weight
polymer or by
formulation with appropriate surfactants.
[1243] The
dissolution properties of the therapeutic formulation in one embodiment is
adjusted by tailoring of the water solubility, molecular weight, and
concentration of the
polymeric excipient in the range of appropriate thixotropic properties to
allow both delivery
through a small gauge needle and localization in the suprachoroidal space. The
polymeric
excipient may be formulated to increase in viscosity or to cross-link after
delivery to further
limit migration or dissolution of the material and incorporated drug.
[1244] Water
soluble polymers that are physiologically compatible are suitable for use as
polymeric excipients in the therapeutic formulations described herein, and for
delivery via the
methods and devices described herein include but are not limited to synthetic
polymers such
as polyvinylalcohol, polyvinylpyrollidone, polyethylene glycol, polyethylene
oxide,
polyhydroxyethylmethacrylate, polypropylene glycol and propylene oxide, and
biological
polymers such as cellulose derivatives, chitin derivatives, alginate, gelatin,
starch derivatives,
hyaluronic acid, chondroiten sulfate, dermatin sulfate, and other
glycosoaminoglycans, and
mixtures or copolymers of such polymers. The polymeric excipient is selected
in one
embodiment to allow dissolution over time, with the rate controlled by the
concentration,
molecular weight, water solubility, crosslinking, enzyme lability and tissue
adhesive
properties of the polymer.
[1245] In one
embodiment, a viscosity modifying agent is present in a therapeutic
formulation delivered by one of the methods and/or devices described herein.
In a further
embodiment, the viscosity modifying agent is polyvinyl alcohol, polyvinyl
pyrrolidone,
methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
hydroxymethyl cellulose
99
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
or hydroxypropyl cellulose. In another embodiment, the formulation comprises a
gelling
agent such as poi y (h y d roxy inethy 'meth acrylate), poly (N-viny py rroli
done ), polyvinyl alcohol
or an acrylic acid polymer such as Carbopol.
[1246] in one
embodiment, the therapeutic formulation is delivered via one of the
methods and or devices described herein as a liposornal formulation.
[1247]
Liposomes can be produced by a variety of methods. Bangham's procedure (J.
Mol. Biol., J Mol Biol. 13(1):238-52, 1965) produces ordinary multilamellar
vesicles
(MLVs). Lenk et al. (U.S. Pat. Nos. 4,522,803, 5,030,453 and 5,169,637),
Fountain et al.
(U.S. Pat. No. 4,588,578) and Cullis et al. (U.S. Pat. No. 4,975,282) disclose
methods for
producing multilamellar liposomes having substantially equal interlamellar
solute distribution
in each of their aqueous compartments. Paphadjopoulos et al., U.S. Pat. No.
4,235,871,
discloses preparation of oligolamellar liposomes by reverse phase evaporation.
Each of the
patents references in this paragraph is incorporated by reference herein in
their entireties for
all purposes.
[1248] In one
embodiment, the liposomal formulation comprises a phosolipid. In a
further embodiment, the liposomal formulation comprises a sterol such as
cholesterol.
[1249] In
another embodiment, the liposomal formulation comprises unilamellar
vesiscles. Unilamellar vesicles can be produced from MLVs by a number of
techniques, for
example, the extrusion of Cullis et al. (U.S. Pat. No. 5,008,050) and Loughrey
et al. (U.S.
Pat. No. 5,059,421). Sonication and homogenization can be used to produce
smaller
unilamellar liposomes from larger liposomes (see, for example, Paphadjopoulos
et al.,
Biochim. Biophys. Acta., 135:624-638, 1967; Deamer, U.S. Pat. No. 4,515,736;
and
Chapman etal., Liposome Technol., 1984, pp. 1-18). A review of these and other
methods
for producing liposomes can be found in the text Liposomes, Marc Ostro, ed.,
Marcel
Dekker, Inc., New York, 1983, Chapter 1, the pertinent portions of which are
incorporated
herein by reference. See also Szoka, Jr. et al., (1980, Ann. Rev. Biophys.
Bioeng., 9:467).
Each of the references in this paragraph is incorporated by reference herein
in their entireties
for all purposes.
[1250] As
described above, the drug formulation delivered to the suprachoroidal space
via the methods described herein, e.g., for treating macular edema associated
with uveitis or
macular edema associated with RVO, can be administered with one or more
additional drugs.
100
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
The one or more additional drugs, in one embodiment, are present in the same
formulation as
the initial drug formulation. In another embodiment, the one or more
additional drugs are
present in a second formulation. In even a further embodiment, the second drug
formulation
is delivered to the patient in need thereof via a non-surgical SCS delivery
method described
herein. Alternatively, the second drug formulation is delivered
intravitreally, intracamerally,
sub-tenonally, orally, topically or parenterally to the human subject in need
of treatment of
macular edema associated with uveitis or macular edema associated with RVO. In
one
embodiment, a VEGF antagonist is delivered to the suprachoroidal space of the
eye of a
human subject in need of treatment of macular edema associated with uveitis or
macular
edema associated with RVO via one of the methods and/or devices disclosed
herein, in
conjunction with an anti-inflammatory compound. . In some embodiments, the
drug
formulation includes aflibercept.
[1251] As
described above, in addition to suprachoroidal delivery, the one or more
additional drugs delivered to the human subject can be delivered via
intravitreal (IVT)
administration (e.g., intravitreal injection, intravitreal implant or eye
drops). Methods of IVT
administration are well known in the art. Examples of classes of drugs that
can be
administered via IVT include, but are not limited to: VEGF modulators, PDGF
modulators,
anti-inflammatory drugs. Examples of drugs that can be administered via IVT
include, but
are not limited to: A0003, A0006, Acedolone, AdPEDF, aflibercept, AG13958,
aganirsen,
AGN208397, AKB9778, AL78898A, amyloid P, Angiogenesis Inhibitor Gene Therapy,
ARC1905, Aurocort, bevasiranib sodium, brimonidine, Brimonidine, brimonidine
tartrate,
bromfenac sodium, Cand5, CERE140, Ciganclor, CLT001, CLT003, CLT004, CLT005,
complement component 5 aptamer (pegylated), complement factor D antibody,
Cortiject, c-
raf 2-methoxyethyl phosphorothioate oligonucleotide, cyclosporine,
triamcinolone, DE109,
denufosol tetrasodium, dexamethasone, dexamethasone phosphate, disitertide,
DNA damage
inducible transcript 4 oligonucleotide, E10030, ecallantide, EG3306, Eos013,
ESBA1008,
ESBA105, Eylea, FCFD4514S, fluocinolone acetonide, fms-related tyrosine kinase
1
oligonucleotide, fomivirsen sodium, fosbretabulin tromethamine, F0V2301,
FOV2501,
ganciclovir, ganciclovir sodium, GS101, GS156, hyaluronidase, IBI20089,
iCo007, Iluvien,
INS37217, Isonep, JSM6427, Kalbitor, KH902, lerdelimumab, LFG316, Lucentis0,
M200,
Macugen, Makyueido, Microplasmin, MK0140, MP0112, NCX434, neurotrophin 4 gene,
0C10X, ocriplasmin, ORA102, Ozurdex, P144, P17, Palomid 529, pazopanib
hydrochloride,
pegaptanib sodium, Plasma Kallikrein Inhibitors, platelet-derived growth
factor beta
101
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
polypeptide aptamer (pegylated), POT4, PRM167, PRS055, QPI1007, ranibizumab,
resveratrol, Retilone, retinal pigment epithelium-specific protein 65kDa gene,
Retisert, rod
derived cone viability factor, RPE65 Gene Therapy, RPGR Gene Therapy, RTP801,
Sd-
rxRNA, serpin peptidase inhibitor clade F member 1 gene, Sirna027, sirolimus,
sonepcizumab, SRT501, STP601, TG100948, Trabio, triamcinolone, triamcinolone
acetonide, Trivaris, tumor necrosis factor antibody, VEGF/rGel-Op,
verteporfin, Visudyne,
Vitrase, Vitrasert, Vitravene, Vitreals, volociximab, Votrient, XG102, Xibrom,
XV615, and
Zybrestat. Accordingly, the methods of the present invention include
administrating via IVT
one or more of the drugs listed above in combination with one or more drugs
disclosed herein
administered into the suprachoroidal space using the microneedle device
described herein.
[1252] In some
embodiments, the methods provided herein comprise administering one
or more drugs via IVT and one or more drugs via SCS. The present inventors
have found that
surprisingly, SCS administration of a drug formulation improves the
effectiveness of a drug
administered IVT to treat one or more of the ocular disorders disclosed
herein. For example,
in some embodiments, SCS administration of an anti-inflammatory drug
concomitantly with
IVT administration of a biologic vastly improves the effectiveness of the
biologic treatment.
In some embodiments, the drug administered via IVT and the drug administered
to the SCS
act synergistically. Two or more compounds that act synergistically interact
such that the
combined effect of the two compounds is greater than the sum of the individual
effects of
each compound when administered alone. For example, in some embodiments, the a
biologic
(e.g., aflibercept) administered IVT combined with a drug (e.g., TA)
administered by SCS
administration act synergistically to treat an ocular disorder (e.g., macular
edema).
EXAMPLES
[1253] The
present invention is further illustrated by reference to the following
Examples. However, it should be noted that these Examples, like the
embodiments described
above, are illustrative and are not to be construed as restricting the scope
of the invention in
any way.
Example 1. Triamcinolone formulations for delivery to the suprachoroidal space
[1254]
Triamcinolone is delivered to the suprachoroidal space using the methods and
devices provided herein. The triamcinolone formulation, in one embodiment, is
selected
from one of the following seven formulations in Table 2.
102
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Table 2. Triamcinolone (TA) formulations.
Formulatio
Formulation Formulation Formulation Formulation Formulation Formulation
Ingredient
n A
Triamcinolo
ne 40 mg/mL
40 mg/mL 40 mg/mL 40 mg/mL 40 mg/mL 40 mg/mL 8 mg/mL
acetonide
D50: -2 D50: -2
D50: -2 gm D50: -2 gm D50: -2
gm D50: -2 gm D50: -2 gm
Particle Illn Illn
Size D99: <10 D99: <10 D99: <10 D99: <10 D99: <10
D99: <10 D99: <10
Inn Inn Inn Inn Inn gni Illn
Sodium
Chloride 0'64%
w/v 0.64% w/v 0.64% w/v 0.55% w/v 0.64% w/v 0.55% w/v 0.55% w/v
Carboxymet
hylcellulose 0.5% w/v 0.5% w/v
0.5% w/v 0.5% w/v 0.5% w/v 0.5% w/v 0.5% w/v
sodium
Poly sorbate 0.015% >0.015% 0.015%
0.02% w/v 0.02%
w/v 0.02% w/v 0.01 % w/v
80 w/v w/v w/v
0.075% 0.075% 0.075% 0.075% 0.075%
KC1
w/v w/v 0.075% w/v w/v w/v
0.075% w/v w/v
CaCl2 0.048% 0.048% 0.048% 0.048% 0.048%
(dihydrate) w/v w/v 0.048% w/v w/v w/v
0.048% w/v w/v
MgCl2
0.030% 0.030% 0' 030% 0.030% 0' 030%
(hexahydrat
w/v w/v 0.030% w/v w/v w/v
0.030% w/v w/v
e)
Sodium
acetate 0.39%
w/v 0.39% w/v 0.39% w/v 0.39% w/v 0.39% w/v 0.39% w/v 0.39% w/v
(trihydrate)
Sodium
citrate 0.17%
w/v 0.17% w/v 0.17% w/v 0.17% w/v 0.17% w/v 0.17% w/v 0.17% w/v
(dihydrate)
Adjust to Adjust to Adjust to Adjust to
Adjust to
Adjust to Adjust to
Na0H/HC1 pH 6.0 - pH 6.0 - pH 6.0 - pH 6.0 - pH 6.0 -
6
7.5 al
7.5 7.5 7.50 75
pH 6.0 - 7.5
7.5
Example 2. Phase 1/2 open-label, safety and tolerability study of
triamcinolone
acetonide administered to the suprachoroidal space in patients with non-
infectious
uveitis.
[1255] A
clinical trial was designed to evaluate the safety and tolerability of a
single
injection of TA (triamcinolone acetonide administered as TRIESCENCETm) into
the SCS in
patients diagnosed with non-infectious uveitis.
[1256] Each mL
of the sterile, aqueous suspension of TRIESENCETm provides 4 mg of
triamcinolone acetonide, with sodium chloride for isotonicity, 0.5% (w/v)
carboxymethylcellulose sodium and 0.015% polysorbate 80. It also contains
potassium
103
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
chloride, calcium chloride (dihydrate), magnesium chloride (hexahydrate),
sodium acetate
(trihydrate), sodium citrate (dihydrate) and water for injection. Sodium
hydroxide and
hydrochloric acid may be present to adjust pH to a target value 6 ¨ 7.5.
[1257] The primary purpose of this trial was to evaluate the overall safety
and tolerability
of treating uveitis patients (non-infectious uveitis ¨ intermediate, posterior
or pan-uveitis) by
administering a triamcinolone into the SCS via a single suprachoroidal
injection. Eligibility
criteria include adult patients with non-infectious uveitis experiencing
either macular edema
or vitreous haze, a common complication of uveitis. This was in order to
determine whether
SCS administration of TA could improve patient vision through reducing the
effects of either
condition. For inclusion in the trial, patients must have TOP (intra-ocular
pressure) of no
greater than 22 mmHg.
[1258] Specifically, the characteristics of the study population were as
follows:
= Male and non-pregnant females, >18 years old
= Non-infectious intermediate, posterior or pan-uveitis
= No glaucomatous damage and not a "steroid responder"
= BCVA > 20/200 OU, worse eye enrolled
= Cystoid macular edema (CME) > 310 u or vitreous have? 1.5+
[1259] Further, the following inclusion/exlusion criteria were applied:
= Stable systemic immunosuppressive therapy (IMT) for 6 months, stable
prednisone
for 1 month
= No Intravitreal triamcinolone or dexamethasone implant for 6 months
= No anti-VEGF intravitreal treatment for 2 months
= No difluprednate drops for 1 month
= No Retisert0 (fluocinolone acetonide intravitreal implant) for 3 years
= No ocular surgery within 6 months.
[1260] Eight patients (six females, two males) were enrolled and treated.
The mean age
of the patient population was 56.0 and the age range of patients was from 42
to 78 years.
Seven of the patients qualified for the study based on the CME criteria, while
four of the
patients qualified for the study based on the vitreous haze criteria of? 1.5.
104
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1261] Each
patient enrolled received a single SCS microinjection of 4.0 mg (100 L) of
triamcinolone acetonide of day 1. Patients returned for a follow-up
examination on the day
after the injection and then for eight additional evaluations at weeks 1, 2,
4, 8, 12, 16, 20 and
26 following the treatment. Patients may receive other treatment at any time
during the trial
with any accepted therapy based on their physician's best medical judgment, if
their
condition deteriorates or if the physician otherwise determines it to be
advisable. In the event
a patient received other treatment, the patient was followed for the duration
of the trial for
safety purposes, but efficacy measures were no longer considered thereafter.
[1262] Patients
received the single SCS injection 4 mm posterior to limbus and received
an ultrasound assessment of scleral thickness immediately after injection.
[1263]
Endpoints. The main safety endpoint was changes from baseline in intraocular
pressure (TOP). Also assessed was an efficacy endpoint relating to changes in
best-corrected
visual acuity, or BCVA, as well as changes in excess retinal thickness.
[1264] Safety
results. All subjects had at least 1 adverse event (AE), and a total of 37
AEs were reported. Most AEs were mild or moderate in severity (95%). Pain was
the most
commonly reported AE. Specifically, eye pain was reported in 4 subjects.
However, all pain
AEs were reported as mild and not related to TA SCS injection. One serious
event (unrelated
pulmonary emboli; SAE) occurred. No deaths have been reported. Approximately
half
(57%) of the reported AEs were ocular adverse events. Nine ocular AEs in four
subjects
were considered possibly related to the TA SCS injection.
[1265] No
significant elevation in TOP was observed in the eight patients, and no
patient
has required TOP lowering medication.
[1266] The
graph in FIG. 22 shows the mean change in TOP for patients in the trial, as
measured at different time points post-treatment. The number of patients
included in the
results for the various measurement time points below varies because the four
patients were
treated on different dates and only two patients have currently completed the
full 26-week
observation period.
[1267] In
addition to these TOP observations, the drug was considered generally well-
tolerated. One patient, who had a history of pulmonary embolisms, was
hospitalized for a
105
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
embolism 10 weeks after the treatment. This serious adverse event was
considered to be
unrelated to the treatment and resolved after three days.
[1268] Visual
Acuity. BCVA (best corrected visual acuity) was measured for all eight
patients. BCVA is a common measurement of a patient's ability to see at
distances and
changes are measured as the difference in number of letters read on a standard
eye chart.
FIG. 23 summarizes the mean improvement in BCVA observed. Four of the eight
patients
showed meaningful improvements in BCVA (a gain of about 3 lines) at 26 weeks
following a
single suprachoroidal injection of TA on Day 1.
[1269] Retinal
Thickness. Seven patients were enrolled with macular edema. Change in
macular edema was evaluated by measuring change in retinal thickness. A
reduction in
retinal thickness in patients with macular edema occurs with the removal of
excess fluid from
the retina, reflecting a reduction of the swelling of the macula and other
parts of the retina,
affected by the edema.
[1270] The
graph in FIG. 24 summarizes the mean change in retinal thickness observed
to date in the trial. The mean reduction in macular edema at week 26 was over
100 microns
with a range from 76 to 154 microns reduction over the 26-week post treatment
observation
period following the single TA injection into the SCS. An average reduction of
about 20
percent in CME was observed for the seven patients.
[1271] One
patient, a 52 year old woman, presented with bilateral uveits with macular
edema in both eyes. She was treated with TA via SCS injection in one eye (4 mg
TA) and
sub-tenon TA injection in the other eye (20 mg TA). FIG. 25 provides OCT
images of the
eyes of this patient prior to and subsequent to the dosing session. results
for this patient
(FIG. 25). The eye treated with TA via suprachoroidal injection provides a
greater decrease
in retinal thickness as compared to the subtenon injection (FIG. 25).
[1272] A 25-
year old male patient presented with bilateral uveitis, with macular edema in
both eyes. The patient was treated with Ozurdex in the left eye and with TA in
the right eye.
Four to six weeks after treatment, the eye treated with TA via suprachoroidal
injection looks
better than the intravitreally Ozurdex treated eye (FIG. 26).
106
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Example 3. A Randomized, masked, multicenter study to assess the safety and
efficacy
of CLS-TA, triamcinolone acetonide injectable suspension in the Treatment of
Subjects
With Macular Edema Followin2 Uveitis
[1273] The
trial described in this Example is a Phase 2, randomized, masked, multicenter
study to assess the safety and efficacy of CLS-TA in the treatment of subjects
with ME
following non-infectious uveitis. The purpose of this study is to evaluate the
safety and
efficacy of CLS-TA in subjects with ME following non-infectious uveitis. Two
different
doses, 4 mg and 0.8 mg, of CLS-TA will each be evaluated for safety and
efficacy.
[1274] Oral
corticosteroids remain the main initial choice in treating patients with
uveitis
not responding to topical treatment, however their chronic use can be toxic,
especially for
bones, including osteoporosis or growth retardation. Non-steroidal
immunosuppressive
agents can either be used to treat uveitis directly, or they are used as
corticosteroid sparing
therapy or they are used as agents to control refractory uveitis when the
condition is sight
threatening. Agents commonly used are cyclosporine A, methotrexate,
azathioprine,
cyclophosphamide and chlorambucil. Cyclosporine is efficacious but is
nephrotoxic,
particularly in elderly patients. It is rarely sufficient for use as
monotherapy, and is
infrequently used in uveitis practices. Methotrexate is well tolerated, and
has been the usual
first line steroid sparing agent for many years. Although it is quite
effective in many patients,
its onset of action is very delayed (months), and it carries with it the risks
of liver toxicity and
decreased white blood cell counts (Kalinina 2011). As well, it causes
significant fatigue and
nausea, making it difficult for some patients to tolerate. It is also
absolutely contraindicated
in pregnancy (pregnancy category X). Azathioprine is another drug in the same
class as
methotrexate. It also has a delayed onset of action, and may not be very well
tolerated.
Mycophenolate mofetil is another steroid sparing agent. It has a somewhat
faster onset of
action than the other two agents, but can decrease white blood cell count and
increase blood
pressure. As well, it has significant gastrointestinal side effects.
Cyclophosphamide and
intravenous steroids are helpful for emergency treatment. Chlorambucil is
toxic and
carcinogenic, but might lead to an increased rate of remission and may be
useful for short
term therapy. In short, all of the systemic agents mentioned above carry the
risk of
significant systemic side effects.
[1275] This
clinical trial will be conducted in compliance with the protocol,
International
Conference on Harmonisation (ICH), GCP guidelines, and other applicable
regulatory
107
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
requirements. The study population will include approximately 20 adult
subjects, 18 years or
older, diagnosed with macular edema (ME) following non-infectious uveitis who
meet all of
the inclusion criteria, and none of the Exclusion criteria. All subjects will
receive a single
injection of study drug into a single eye. Approximately 11 U.S. sites will
recruit subjects for
this study.
[1276] The
subjects enrolled in this study will be chosen from subjects with ME in the
study eye with a retinal thickness of at least 310 microns in the central
subfield (average
retinal thickness in the central 1 mm) as measured by SD-OCT, using a
Heidelberg
SPECTRALISO, and confirmed by the Central Reading Center.
[1277] The
formulation of triamcinolone used in this study (CLS-TA, triamcinolone
acetonide injectable suspension) is an unpreserved, terminally sterilized,
aqueous suspension,
formulated for administration into the SCS as a single injection of up to 4 mg
in 100
microliters (pL), or up to 0.8 mg in 100 microliters (pL) using a
microinjector. The drug
product is intended for single use. CLS-TA is supplied as a 1.3 mL fill of a
40 mg/mL or 8
mg/mi. sterile TA suspension in a 2 mL/13 mm TopLyo single use vial, with a
rubber
stopper and an aluminum seal.
[1278] The study has 2 arms randomized 4:1. See Table below.
Subjects are
randomized in a 4:1 ratio to receive a single injection of CLS-TA, 4 mg in a
volume of 100
pL or CLS-TA, 0.8 mg in a volume of 100 pL. Study personnel, study patients,
the sponsor,
and project teams at the Contract Research Organizations (CROs) involved in
the study will
be masked to treatment assignments. Approximately 20 total subjects at
approximately 11
U.S. sites will be enrolled. The study design includes 5 clinic visits over
roughly two (2)
months. Subjects will be in the study for no more than 70 days. Subjects will
receive
treatment at Day 1 (Visit 2), approximately 1-10 days after the initial
screening visit (Visit 1).
They will continue to be monitored for safety and efficacy for 2 months
following their
injection.
[1279]
Eligibility will be established at Visit 1 (Screening Visit). Subjects must
qualify
on SD-OCT readings confirmed by a Central Reading Center prior to being
treated.
Depending on the treatment arm to which subjects are assigned, subjects will
either receive a
single suprachoroidal injection of CLS-TA, up to 4 mg in 100 pL, or a single
suprachoroidal
108
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
injection of CLS-TA, up to 0.8 mg in 100 uL in a single eye. Injection is
carried out as
described in FIG. 21.
[1280] If both
eyes are eligible (see below for inclusion and exclusion criteria), the eye
with worse edema (that with the greater degree of macular thickening per SD-
OCT) will be
selected. If ME is equivalent in both eyes, the right eye will be chosen.
[1281] Subjects
remain at the clinic after treatment for at least 30 minutes for evaluation.
A follow-up examination will be conducted approximately 7-10 days after the
injection
procedure (Visit 3). All subjects will return to the clinic monthly for Visits
4-5 (Months 1
and 2). Visit 4 is 28 days 3 days after treatment at visit 2 and visit 5 is
28 days 3 days
after visit 3. A final evaluation is conducted at Visit 5 ¨ End of Study
(Month 2). The
treatment arms for the study are provided in Table 3, below.
Table 3.
Treatment arm Number of subjects
CLS-TA 4.0 mg ¨16
CLS-TA 0.8 mg ¨4
Total subjects ¨20
Endpoints
[1282] The
primary objective of this study is to determine the safety and efficacy of CLS-
TA, with doses up to 4 mg and 0.8 mg, each in a volume of up to 100 uL, by
determining
change in retinal thickness from baseline in central subfield thickness (CST)
as measured by
spectral domain optical coherence tomography (SD-OCT) in subjects with ME
following
non-infectious uveitis. Accordingly, the primary endpoint is the mean absolute
change from
baseline in CST as measured by SD-OCT after treatment with CLS-TA (4 mg and
0.8 mg) at
2 months in eyes with ME following uveitis.
= The safety endpoints of this study are as follows
= Incidence of treatment-emergent adverse events (TEAEs) and serious
adverse events
(SAEs), grouped by organ system, relatedness to study medication, and severity
= Percentage of subjects whose IOP increase is above 30 mmHg
= Percentage of subjects whose TOP increases > 10 mmHg from their own
baseline TOP.
109
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1283] The secondary endpoints of the study are to:
= Percentage of subjects with a? 20% reduction in CST after treatment with
CLS-TA
(4 mg and 0.8 mg) at 1 and 2 months.
= Percentage of subjects with a CST of < 310 pm at 1 and 2 months.
= Mean change from baseline in BCVA after treatment with CLS-TA (4 mg and
0.8
mg) at 1 and 2 months.
= Percentage of subjects who gain? 5 letters in BCVA at 1 and 2 months
compared
with baseline [BCVA score based on the Early Treatment of Diabetic Retinopathy
Study (ETDRS) visual acuity charts assessed at a starting distance of 4
meters].
= Percentage of subjects who gain? 10 letters in BCVA at 1 and 2 months
compared
with baseline (BCVA score based on the ETDRS visual acuity charts assessed at
a
starting distance of 4 meters).
= Percentage of subjects who gain? 15 letters in BCVA at 1 and 2 months
compared
with baseline (BCVA score based on the ETDRS visual acuity charts assessed at
a
starting distance of 4 meters)
= Percentage of subjects who lose < 15 letters in BCVA at 1 and 2 months
compared
with baseline (BCVA score based on the ETDRS visual acuity charts assessed at
a
starting distance of 4 meters).
[1284] General Inclusion Criteria. Individuals are eligible for
participation in this
study if they meet the following criteria:
= Understand the language of the informed consent and are willing and able
to provide
written informed consent prior to any study procedures.
= Are at least 18 years of age.
= Are willing to comply with the instructions and attend all scheduled
study visits.
= If female, the subject must be non-pregnant, non-lactating and not
planning a
pregnancy. Females of childbearing potential must agree to use an acceptable
method
of contraception throughout participation in the study. Acceptable methods of
contraception include double barrier methods (condom with spermicide or
diaphragm
with spermicide), hormonal methods (oral contraceptives, implantable,
transdermal,
or injectable contraceptives), or an intrauterine contraceptive device (IUCD)
with a
documented failure rate of less than 1% per year. Abstinence may be considered
an
acceptable method of contraception at the discretion of the investigator, but
the
110
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
subject must agree to use one of the acceptable birth control methods if she
becomes
sexually active.
[1285] Ophthalmic Inclusion Criteria
= Only one eye can be treated under this protocol. If both eyes are
eligible, the eye with
worse measurement of ME associated with uveitis will be designated as the
study eye.
Subjects are eligible for participation if their study eye has:
= A history of non-infectious uveitis, including anterior, intermediate,
posterior or
panuveitis.
= ME, with or without subretinal fluid, associated with non-infectious
uveitis.
= A retinal thickness of? 310 microns in the central subfield (average
retinal thickness
in the central 1 mm ring, as measured by SD-OCT (using the Heidelberg
SPECTRALIS ) and confirmed by the Central Reading Center.
= ETDRS BCVA score of? 20 letters read (20/400 Snellen approximate) in each
eye.
[1286] Exclusion Criteria. An individual is not eligible for participation
in this study if
they meet any of the following criteria:
= Has any uncontrolled systemic disease that, in the opinion of the
investigator, would
preclude participation in the study (e.g., unstable medical status including
uncontrolled elevated blood pressure, cardiovascular disease, and glycemic
control) or
put the subject at risk due to study treatment or procedures.
= Has a likely need for hospitalization or surgery within the study period,
including
planned elective surgery or hospitalization that cannot be deferred.
= Has a known human immunodeficiency virus infection, other
immunodeficiency
disease or other medical condition for which corticosteroid therapy would be
contraindicated in the investigator's opinion.
= Has a known hypersensitivity to any component of the formulation of TA,
fluorescein, or to topical anesthetics.
= Has a systemic infection for which prescription anti-infectious
pharmacological
therapy is indicated.
= Is currently enrolled in an investigational drug or device study or have
used an
investigational drug or device within 30 days of entry into this study.
= Is an employee of the site who is directly involved in the management,
administration,
or support of this study or is an immediate family member of the same.
111
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
= History of any serious or active psychiatric illness that, in the opinion
of the
investigator, would interfere with subject treatment, assessment or compliance
with
the protocol.
= Has used acetazolamide (Diamox) in the 2 weeks prior to study treatment.
= Has taken systemic corticosteroids at doses greater than 20 mg per day
for oral
prednisone (or equivalent for other corticosteroids) in the 2 weeks prior to
study
treatment needed to maintain subject care.
= Is currently using prescribed nonsteroidal anti-inflammatory drugs
(excluding over-
the-counter use) or prescribed immunomodulatory therapies, unless the dose has
been
stable for at least 2 weeks, and no change in dosing is anticipated for the
study
duration.
= Has taken any interferon/fingolimod or any other drug in the 6 weeks
prior to study
treatment, where the drug is known to induce or exacerbate ME.
= Has uncontrolled diabetes.
[1287]
Ophthalmic Exclusion Criteria. Subjects are ineligible for participation if
the
subject:
= Is monocular.
= Has uveitis of infectious etiology.
= Has significant media opacity precluding evaluation of the retina and
vitreous in the
study eye.
= Has chronic ME, macular scarring or significant ischemia such that visual
acuity is
unlikely to improve with treatment per the Investigator's judgment.
= Has ME with etiology other than uveitis.
= Has an ocular condition that, in the opinion of the Investigator, would
put the subject
at risk due to study treatment or procedures (i.e. active ocular infection,
history of a
suprachoroidal hemorrhage, etc.).
= Has had uveitis unresponsive to prior systemic corticosteroid treatment
in either eye.
= Has active ocular disease, other than uveitis in the study eye, or
infection including
external ocular infections, such as conjunctivitis, herpetic infection,
chalazion, or
significant blepharitis in either eye.
= Has ocular hypertension (IOP > 22 mmHg) irrespective of topical treatment
or
evidence of glaucomatous optic nerve damage in the study eye. Anyone who has a
112
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
history of clinically significant TOP elevation in response to corticosteroid
treatment
("steroid responder") in the study eye will also be excluded.
= Has had a change in TOP lowering medications in the 30 days prior to
study treatment.
= Has a history of any vitreoretinal surgery (scleral buckle, pars plana
vitrectomy,
retrieval of a dropped nucleus or intraocular lens, etc.; prior
photocoagulation and
IVT injections are acceptable) in the study eye. Prior cataract extraction or
Yttrium-
Aluminum-Garnet (YAG) laser capsulotomy is allowed, but must have been
performed at least 3 months prior to treatment.
= Has a history of cyclodestructive procedures and multiple filtration
surgeries (2 or
more) in the study eye.
= Has evidence of an epiretinal membrane affecting the macula or
vitreomacular
traction in the study eye that in the investigator's opinion could prevent
improvement
in visual acuity.
= Has presence of a staphyloma in the study eye.
= Demonstrates the presence of a toxoplasmosis scar in the study eye.
= Has eye diseases other than uveitis that could compromise central visual
acuity (e.g.
clinically significant diabetic retinopathy, scleritis, ischemic optic
neuropathy or
retinitis pigmentosa) in the study eye.
= Has high myopia defined as a spherical equivalent > -6 diopters or an
axial length?
26 mm in the study eye.
= Has any condition in the study eye that in the opinion of the
Investigator, may
predispose to scleral thinning.
= Has any ocular trauma, within the immediate 6 months prior to study
treatment, in the
study eye.
= Has had photocoagulation or cryotherapy within the 6 months prior to
study treatment in
the study eye.
= Has had any IVT injection of anti-VEGF treatment (bevacizumab,
aflibercept, pegaptanib
or ranibizumab) in the 2 months prior to study treatment in the study eye.
= Has had any ophthalmic topical corticosteroid within 10 days of study
treatment, injection
of periocular or intraocular corticosteroids within 60 days of study
treatment, Ozurdex0
implant in the 120 days prior to the study treatment, or any prior use of
RetisertTM or
IluvienTM implant in the study eye in the past 1 year prior to study
treatment.
= Has had a previous suprachoroidal injection of TA in the study eye in the
past 30 days.
113
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1288]
Randomization Criteria. Subjects are eligible for randomization at Visit 2 if
the
following criteria are met:
= Central Reading Center confirmation of ME by SD-OCT (from Visit 1 OCT
data),
with or without subretinal fluid, caused by non-infectious uveitis (per the
Investigator's judgment) in the study eye.
= Central Reading Center confirmation of a retinal thickness of? 310
microns in the
central subfield (average retinal thickness in the central 1 mm ring, as
measured by
SD-OCT using the Heidelberg SPECTRALIS ) from the Visit 1 OCT data.
= Subject continues to meet inclusion/exclusion criteria.
[1289] Post-
Injection Procedures. The following assessments must occur following the
injection (Visit 2):
= Assess for AEs
= Review changes to concomitant medications
= Measure seated, resting heart rate and blood pressure
= Perform ophthalmic assessments on the study eye only
o Perform slit-lamp biomicroscopy
o Evaluate IOP 30 ( 5) minutes post injection = If TOP remains elevated,
subject
must remain on site until TOP is under control per investigator's best medical
judgment.
o Perform indirect ophthalmoscopy
= Schedule subject to return for Visit 3.
[1290] Visit 3
occurs 7 to 10 days post Visit 2 (Randomization/Treatment). During Visit
3, the following procedures will be performed:
= Assess for AEs
= Review changes to concomitant medications
= Measure seated, resting heart rate and blood pressure
= Perform ophthalmic assessments on the study eye only
o BCVA exams performed by certified site personnel using the ETDRS protocol
o Perform slit-lamp biomicroscopy
o Evaluate TOP
o Perform dilated indirect ophthalmoscopy
114
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
o Obtain FP-4W field color fundus photographs and upload to the Central
Reading Center
o Obtain SD-OCT images and upload to the Central Reading Center
= Schedule subject to return for Visit 4
[1291] Visit 4
occurs approximately 1 month post injection. The visit should be 28 3
days from Visit 2. During Visit 4, the following procedures will be performed:
= Assess for AEs
= Review changes to concomitant medications
= Measure seated, resting heart rate and blood pressure
= Perform ophthalmic assessments on the study eye only
o BCVA exams performed by certified site personnel using the ETDRS protocol
o Perform slit-lamp biomicroscopy
o Evaluate TOP
o Perform indirect ophthalmoscopy
o Obtain SD-OCT images and upload to the Central Reading Center
= Schedule subject to return for next visit
[1292] Visit 5
will be the final evaluation visit and exit from the study. Visit 5 occurs
within 56 4 days from Visit 2. The following procedures will be performed:
= Assess for AEs
= Review changes to concomitant medications
= Measure seated, resting heart rate and blood pressure
= Perform urine pregnancy test on females of childbearing potential
= Perform ophthalmic assessments on both eyes (except FA; study eye only)
o BCVA exams performed by certified site personnel using the ETDRS protocol
o Perform slit-lamp biomicroscopy
o Evaluate TOP
o Perform dilated indirect ophthalmoscopy
o Obtain FP-4W field color fundus photographs and upload to the Central
Reading Center
o Obtain SD-OCT images and upload to the Central Reading Center
o Perform FA with the early series of the study eye and upload to the
Central
Reading Center.
115
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Efficacy Assessments
[1293] Central Subfield Thickness as measured by SD-OCT will be assessed as
a
measure of efficacy. Each site will be provided an imaging protocol and
submission
procedures from the Central Reading Center. The SD-OCT instrument and
technician must
be certified prior to submission of study data. They will be trained on
imaging and uploading
images to EyeKor's Excelsior system for this specific protocol. Retinal
thickness and disease
characterization will be assessed via SD-OCT (Heidelberg SPECTRALISO) at every
visit.
OCT will be performed on both eyes at Visits 1 and 5, and in the study eye
only at Visits 2, 3
and 4.
[1294] The Central Reading Center will evaluate study images in a masked,
independent
manner. At Screening (Visit 1), the Central Reading Center will confirm
subject eligibility
on the basis of retinal thickness criteria prior to subject enrollment. Upon
confirmation from
the Central Reading Center via email, the site may proceed with qualifying the
subject for
Randomization/Treatment which will occur at Visit 2.
[1295] SD-OCT submissions will include a volume (cube) scan consisting of
49 B-scans
of 6 mm length centered on the fovea. An additional Enhanced Depth Imaging
(EDT) scan
will be obtained horizontally through the fovea. SD-OCT scans will be
evaluated for quality
and any segmentation errors affecting the measurement of central subfield
retina thickness
will be corrected. Additional evaluation outputs will include macular grid
volume and
assessment of retinal and choroidal anatomy.
[1296] BCVA assessed using the ETDRS protocol will also be assessed. Each
site will
have at least one certified exam lane that includes all required equipment to
assess BCVA by
one or more certified visual acuity examiner. Training/certification on the
ETDRS protocol
will be completed prior to subject enrollment. In addition, ETDRS
training/certification
documentation will be kept on site and with the sponsor. Site staff will be
masked to
treatment. BCVA will be assessed at every visit. BCVA will be measured on both
eyes at
Visits 1 and 5, and in the study eye only at Visits 2, 3 and 4.
[1297] Safety and tolerability will be evaluated using the following
assessments:
[1298] Intraocular pressure. Tonopen or Goldmann Applanation Tonometer is
allowed
for measuring TOP, however, an average of 3 measurements should be used. Mean
TOP
116
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
values should be rounded up to the next whole number if the value is greater
than or equal to
0.5 mmHg and rounded down if less than 0.5 mmHg. All instruments used to
measure TOP
must be calibrated according to the manufacturer's specifications and
documented (i.e.,
calibration log). The same tool for measuring TOP should be used for every
visit. TOP will
be measured at every visit. It will be measured on both eyes at Visits 1 and 5
and the study
eye only at Visits 2,3 and 4.
[1299] Slit-
lamp biomicroscopy. Slit-lamp biomicroscopy will be performed using the
investigator's standard slit lamp equipment and procedure. This procedure
should be the
same for all subjects observed at the investigator's site. Observations for
each eye should be
made for the following variables (including but not limited to): conjunctiva,
cornea, lens,
anterior chamber, iris, and pupil. Slit-lamp biomicroscopy will be assessed at
every visit. It
will be measured on both eyes at Visits 1 and 5 and the study eye only at
Visits 2, 3 and 4.
[1300] Indirect
ophthalmoscopy. Dilated ophthalmoscopy should be performed
according to the investigator's standard dilation procedure. This procedure
should be the
same for all subjects observed at the investigator's site. The fundus will be
examined
thoroughly and the following variables (including but not limited to):
vitreous haze, vitreous,
retina, choroid, and optic nerve/disc. Dilated indirect ophthalmoscopy will be
assessed at
every visit. It will be measured on both eyes at Visits 1 and 5 and the study
eye only at Visits
2,3 and 4.
[1301]
Fluorescein Angiogram. It is recommended that when both fundus photos and
FA are conducted in the same visit that the Fundus Photos be taken first.
Digital equipment
will be registered and photographers certified for the imaging procedures. The
same
equipment should be used throughout the study. All testing should be carried
out by the same
operator, whenever possible, on all subjects per research site. The designated
person must be
on the site delegation log. It is recommended that a backup also be named. All
data/images
will be uploaded to EyeKor's Excelsior system. As a reminder all images should
be de-
identified before uploading. FA will be performed at Visits 1 and 5 on the
study eye only.
Anatomic assessments will include the area of fluorescein leakage, area of
capillary
nonperfusion, the presence of retinal vascular and optic nerve head staining,
and retinal
pigment epithelium abnormalities.
117
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1302] Fundus
Photographs. FP-4W fields (4 standard Wide Angle Fields). The same
camera should be used throughout the study. All photos should be taken by the
same
photographer, whenever possible, on all subjects per research site. De-
identified images will
be uploaded to EyeKor's Excelsior system. Fundus photographs will be taken at
Visits 1 and
on both eyes and the study eye only at Visit 3. Characteristics graded from
fundus
photographs includes vitreous haze score, lesions consistent with posterior
uveitis, optic disc
swelling, and vascular abnormalities.
[1303] Vitreous
Haze. Photographic vitreous haze will be assessed clinically at every
visit via indirect ophthalmoscopy using a standardized photographic scale
ranging from 0 to
4, with 0 - 4 defined below in Table 4 (Nussenblatt 1985 as modified in Lowder
2011).
Vitreous haze will also be graded from the color fundus photographs according
to a similar
scale. It will be assessed on both eyes at Visits 1 and 5, and in the study
eye only at Visits 2,
3 and 4.
Table 4. Vitreous Haze Scale
Score Description
0 No inflammation
+ 0.5 Trace inflammation (slight blurring of the optic disc
margins
and/or loss of the nerve fiber layer reflex)
+ 1 Mild blurring of the retinal vessels and optic nerve
+ 1.5 Optic nerve head and posterior retina view obsuration
greater
than +1 but less than +2
+ 2 Moderate blurring of the optic nerve head
+ 3 Marked blurring of the optic nerve head
+ 4 Optic nerve head not visible
118
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Example 4. Safety and Efficacy of Suprachoroidal CLS-TA in Combination with
Intravitreal Aflibercept in Subjects with Macular Edema Followin2 Retinal Vein
Occlusion
[1304] This
Phase 2, multicenter, randomized, active-controlled, masked, parallel arm
study seeks to evaluate the safety and efficacy of a single suprachoroidal
injection of CLS-
TA given concomitantly with an intravitreal (IVT) injection of aflibercept
compared to IVT
aflibercept alone in subjects with macular edema (ME) following retinal vein
occlusion
(RVO). RVO is a condition that affects vision, resulting from a blockage in
one of the veins
returning blood flow from the retina. RVO is the second most common cause of
vision loss
due to retinal vascular disease.
[1305] This
study assesses the safety and efficacy of a suprachoroidal injection of CLS-
TA plus IVT aflibercept compared to subjects administered a sham
suprachoroidal procedure
plus IVT aflibercept in the treatment of subjects with ME following retinal
vein occlusion
(RVO). Each subject will receive at least one IVT aflibercept injection and
approximately
half of the subjects will receive a single suprachoroidal injection of CLS-TA.
The subjects
enrolled in this study will be treatment naïve RVO subjects (HRVO, CRVO and
BRVO) with
ME in the study eye. All qualifying subjects will be randomized (Day 1) to
receive an IVT
injection of an anti-VEGF treatment (aflibercept) plus a suprachoroidal
injection of CLS-TA
or an IVT injection of aflibercept plus a sham suprachoroidal procedure.
Subjects will be
followed for approximately 3 months following randomization. The subject,
sponsor, visual
acuity technician and the optical coherence tomography (OCT) reading center
will be masked
to treatment.
[1306]
Approximately 40 subjects at approximately 10 U.S. sites will be enrolled. The
study design includes 5 clinic visits and one safety phone call over
approximately three (3)
months. Subject eligibility will be established at Visit 1 during the
screening process (Day -
14 to -1) where subjects must qualify on spectral-domain optical coherence
tomography (SD-
OCT) readings confirmed by a Central Reading Center (CRC) prior to being
treated. Eligible
subjects will return to the clinic for Visit 2 - Randomization (Day 1) where
subjects will be
randomized via the interactive web response system (IWRS). Subjects will be
randomized to
receive either an IVT aflibercept injection followed by a suprachoroidal CLS-
TA injection or
an IVT aflibercept injection followed by a suprachoroidal sham procedure.
Subjects remain
at the clinic after the suprachoroidal CLS-TA injection or sham for about 30
minutes for
119
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
evaluation. A follow-up safety phone call will be required on Day 2 (24-48
hours following
treatment). Subjects will then receive an IVT aflibercept injection at Visits
3 (Month 1) and 4
(Month 2) only if criteria for additional therapy are met. If subjects do not
qualify for the
IVT injection of aflibercept, they will be given a sham IVT aflibercept
procedure. Subjects
will have their final evaluation conducted at Visit 5 ¨ End of Study (Month
3). No study
injections will occur at Visit 5.
Endpoints
[1307] The primary endpoint is the total number of times subjects qualify
to be
administered IVT aflibercept in each arm through Month 3.
[1308] Safety Endpoints
= Incidence of TEAEs and SAEs, grouped by organ system, relatedness to
study
medication, and severity.
= Incidence of changes in safety parameters as described in Section 8.1,
including: TOP,
slit lamp biomicroscopy, indirect ophthalmoscopy, imaging parameters and vital
signs.
[1309] Secondary Endpoints
= Total number of aflibercept treatments in each arm at Month 1, at Month 2
and at
Month 3.
= Percentage of subjects with a CST of < 310 pm at 1, 2 and 3 months.
= Mean change from baseline in CST at 1, 2 and 3 months.
= Mean reductions in macular edema at 1, 2, and 3 months
= Mean change from baseline in BCVA at 1, 2 and 3 months.
= Percentage of subjects who gain? 15 letters in BCVA at 1, 2 and 3 months
compared
with baseline.
= Percentage of subjects who lose < 15 letters in BCVA at 1, 2 and 3 months
compared
with baseline.
[1310] Trial treatments
[1311] CLS-TA, triamcinolone acetonide injectable suspension, is a sterile
aqueous
suspension formulated for administration into the eye. The drug product is
terminally
120
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
sterilized and is intended for single use. CLS-TA is supplied as a 1.3 mL fill
of 40 mg/mL
sterile CLS-TA suspension in a 2 mL/13 mm TopLyo0 single use vial, with a
rubber stopper
and an aluminum seal. CLS-TA must be stored under ambient temperature
conditions at ca.
20 - 25 C (68 - 77 F); do not freeze. Protect from light by storing in the
kit.
[1312] The 4 mg
dose of CLS-TA contains 40 mg/mL of TA. Subjects will be
randomized 1:1 to receive a single suprachoroidal injection of 40 mg/mL (4 mg
in 100 pL)
CLS-TA (Active arm) or a sham suprachoroidal procedure (Control arm). This
will be based
on the randomization code and what is assigned via the IWRS.
[1313] EYLEAO
(aflibercept) Injection is an FDA approved prescription medicine for
the treatment of RVO. In this study, the dosage for EYLEAO is 2 mg (0.05 mL)
administered
by intravitreal injection. Aflibercept will be acquired commercially by the
clinical sites.
[1314] All
qualifying subjects will be randomized on Day 1 to one of the following arms
and will receive:
[1315] ACTIVE
ARM: an IVT injection of aflibercept [2 mg (0.05 mL)] plus a
suprachoroidal injection of CLS-TA [4 mg (100 pL)] or
[1316] CONTROL
ARM: an IVT injection of aflibercept [2 mg (0.05 mL)] plus a sham
suprachoroidal procedure.
[1317] Subjects
randomized to the Active arm (those receiving CLS-TA) or the Control
arm will be retreated with an IVT injection of aflibercept at Visits 3 (Month
1) and 4 (Month
2) only if criteria for additional therapy are met. If they do not qualify for
the IVT injection
of aflibercept, they will be given a sham IVT aflibercept procedure. The
Clearside
microinjector is designed for suprachoroidal administration of drug through
the SCS. The
microinjector used for injection into the SCS will be supplied to the site.
[1318]
Retreatment Criteria. If any of the following criteria is met in the study eye
at
Month 1 and 2 (Visits 3 and 4), retreatment with an IVT injection of
aflibercept is required.
Dosing is to be done per the current package insert.
= Macular edema or subretinal fluid (new or persistent) in conjunction with
a CST?
340 microns as measured by SD-OCT.
121
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
= A decrease in BCVA of 10 letters (ETDRS) or greater between the current
visit and
the BCVA reading from the previous visit.
= A decrease in BCVA of 10 letters (ETDRS) or greater from the best
measurement
(during the study) with an increase in CST of > 50 microns from the previous
visit,
associated with new fluid.
= At month 1 and 2 (Visits 3 and 4), if a subject does not qualify for
retreatment with an
IVT injection of aflibercept, an IVT aflibercept sham procedure will be
performed.
Enrollment Criteria
[1319] General
Inclusion Criteria. An individual is eligible for participation in this
study if he/she meets the following criteria: (1) Understand the language of
the informed
consent and is willing and able to provide written informed consent prior to
any study
procedures; (2) Is at least 18 years of age; (3) Is willing to comply with the
instructions and
attend all scheduled study visits; (4) if female, the subject must be non-
pregnant, non-
lactating and not planning a pregnancy. Females of childbearing potential must
agree to use
an acceptable method of contraception throughout participation in the study.
[1320]
Ophthalmic Inclusion Criteria. Individuals are eligible for participation in
this
study if he/she meet the following criteria: (1) Clinical diagnosis of ME
following RVO in
the study eye; (2) CST of? 310 microns (average retinal thickness in the
central lmm ring)
in the study eye as measured by SD-OCT (using the Heidelberg SPECTRALISO) with
or
without subretinal fluid and confirmed by the CRC; (3) ETDRS BCVA score of? 20
letters
read (20/400 Snellen equivalent) in each eye, and < 70 letters read (20/40
Snellen equivalent)
in the study eye; (4) Macular Edema with the following characteristics: a.
Involving the
fovea, b. Due to any RVO and not due to other causes of ME, c. History of ME <
12 months,
d. Visual acuity decrease due to edema.
[1321] General
Exclusion Criteria. Individuals are ineligible for participation in this
study if he/she meet the following criteria: (1) Has any uncontrolled systemic
disease that, in
the opinion of the investigator, would preclude participation in the study
(e.g., infection
uncontrolled elevated blood pressure, cardiovascular disease, and glycemic
control) or put the
subject at risk due to study treatment or procedures; (2) Myocardial
infarction or stroke
122
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
within 90 days of treatment; (3) Any new or change in an existing prescription
medication
within 30 days of randomization; (4) Has taken systemic corticosteroids at
doses greater than
mg per day for oral prednisone (or equivalent for other corticosteroids) in
the 30 days
prior to study treatment needed to maintain subject care for stable, non-
exclusionary medical
conditions; (5) Has a likely need for hospitalization or surgery within the
study period,
including planned elective surgery or hospitalization; (6) Has a known human
immunodeficiency virus infection, other immunodeficiency disease or other
medical
condition for which corticosteroid therapy would be contraindicated according
to best
medical judgment; (7) Has a known hypersensitivity to any component of the
formulation of
TA, aflibercept, fluorescein, or to topical anesthetics; (8) Is currently
enrolled in an
investigational drug or device study or have used an investigational drug
within 30 days of
entry into this study or participated in an ocular device study in the last 90
days; (9) Is an
employee of the site who is directly involved in the management,
administration, or support
of this study or is an immediate family member of the same.
[1322]
Ophthalmic Exclusion Criteria. An individual is ineligible for participation
in
this study if he/she meets the following criteria: (1) Has had any IVT
injection of anti-VEGF
(bevacizumab, aflibercept, pegaptanib or ranibizumab) for RVO in the study
eye; (2) In the
study eye, any intraocular and periocular corticosteroid injection in the 3
months prior to
treatment, OZURDEX implant in the 6 months prior to treatment, RETISERTTm
implant in
the 1 year prior to treatment or ILUVEIN implant in the 3 years prior to
treatment; (3)
Evidence of or history of any ophthalmic condition in the study eye, other
than RVO, that, in
the investigator's opinion, might compromise visual acuity (e.g., AMD,
diabetic retinopathy,
retinal detachment, central serious chorioretinopathy, scleritis, optic
neuropathy or retinitis
pigmentosa); (4) History of any vitreoretinal surgery (scleral buckle
placement, pars plana
vitrectomy, retrieval of an intraocular lens, sheathotomy) ever, in the study
eye or any ocular
surgery in the 3 months prior to randomization. History of IVT injections are
allowed; (5)
History of an ocular procedure or condition, within the 3 months prior to
randomization, or
condition that, in the investigator's opinion, could compromise globe or
retinal integrity (e.g.,
staphyloma, cryotherapy, high myopia [defined as a spherical equivalent > -8
diopters],
predisposition to scleral thinning, etc.) in the study eye; (6) An ocular
condition that in the
opinion of the Investigator would put the subject at risk due to study
treatment or procedures
in the study eye (e.g., active ocular infection, history of a suprachoroidal
hemorrhage,
chalazion, significant blepharitis); (7) In the study eye, > 3 treatments of
macular laser
123
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
photocoagulation. Previous macular laser photocoagulation must have been > 60
days prior to
injection. Panretinal photocoagulation is allowed; (8) Significant media
opacity precluding
evaluation of retina and vitreous in the study eye. This includes significant
hemorrhage or
cataract that is felt to be a major contributor to reduced visual acuity; (9)
A study eye that, in
the investigator's opinion, would not benefit from resolution of ME, such as
eyes with foveal
atrophy, dense pigmentary changes, chronic ME greater than 12 months or dense
subfoveal
hard exudates; (10) Uncontrolled ocular hypertension (TOP > 22 mmHg)
irrespective of
topical treatment or evidence of glaucomatous optic nerve damage in the study
eye; (11)
Have a history of glaucoma surgery (filtration surgery/trabeculectomy or tube
shunt) in the
study eye; (12) Have a history of clinically significant TOP elevation in
response to
corticosteroid treatment ("steroid responder"); (13) Have used any systemic or
topical
ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) to treat ophthalmic
conditions in
the 1 month prior to treatment; (14) Have had a previous suprachoroidal
injection of TA in
the study eye.
[1323]
Randomization Criteria. Subjects are eligible for randomization at Visit 2 if
the
following criteria are met: (1) CRC confirmation of ME by SD-OCT (from Visit 1
OCT
data), with or without subretinal fluid, caused by RVO in the study eye; (2)
CRC
confirmation of a retinal thickness of? 310 microns in the central subfield
from the Visit 1
SD-OCT data; (3) The study eye gained no more than 10 letters of vision
between the
Screening visit and Randomization (Visit 2) in the study eye; (4) Subject
continues to meet
all of the inclusion and none of the exclusion criteria.
[1324] General
Procedures. The study will consist of 5 study visits and one safety
phone call over a maximum of 101 days (14 weeks). Subjects will attend all
study visits. All
ocular assessments at Visit 1 and Visit 5 will be performed on both eyes
except for
fluorescein angiography (FA) which will be performed on the study eye only.
Ocular
assessments at all other visits (Visits 2-4) will be performed on the study
eye only. Subjects
will be screened for entry (Visit 1) and then return to the clinic within 14
days to be
randomized/treated (Visit 2). At randomization, subjects will receive a single
IVT injection
of aflibercept (per package insert) into the study eye, followed by a single,
unilateral,
suprachoroidal injection of CLS-TA or a suprachoroidal sham procedure in the
study eye,
depending on the randomization code assigned. Subjects will remain in the
clinic for
approximately 30 minutes following the suprachoroidal injection or sham and be
assessed for
124
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
safety. Subjects will receive a Safety Phone Call from the site 24-48 hours
post injection and
then return 1 month post injection for evaluation (Visit 3). Additional follow-
up visits will
occur at Months 2 and 3 (Visits 4 and 5).
[1325] Visit 1
¨ Screening (Day -14 to -1). At Visit 1, subjects will be screened for
eligibility. Before any study-specific assessments are performed, written
informed consent
will be obtained for each subject. During Visit 1, the following assessments
will be
performed:
= Obtain written informed consent
= Assign subject number
= Collect demographics, medical and ocular history
= Review current and past concomitant medications
= Measure seated, resting heart rate and blood pressure
= Collect blood and urine for central lab tests prior to FA
= Perform ophthalmic assessments on both eyes (except FA; study eye only)
o BCVA exams performed by certified site personnel using the ETDRS protocol
o Perform slit-lamp biomicroscopy
o Evaluate TOP
o Perform dilated indirect ophthalmoscopy
o Obtain SD-OCT images and upload to the CRC
o Obtain 4 Wide Field Color Fundus Photographs (FP-4W) and upload to the
CRC
o Perform FA with the early series of the study eye and upload to the CRC
o Verify subject eligibility based on Inclusion/Exclusion requirements
o Determine study eye based upon eligibility criteria. If both eyes are
eligible,
the eye with worse edema (that with the greater degree of macular thickening
per SD-OCT) will be selected. If ME is equivalent in both eyes, the right eye
will be chosen.
o Perform brief physical exam
o Schedule subject to return for Visit 2, Randomization/Treatment.
[1326] Visit 2
¨ Randomization/Treatment (Day 1). Visit 2 must occur within 14 days
of Visit 1 (Screening) and may only occur once subject is eligible for
treatment which
includes central lab results being received and reviewed, and confirmation of
eligibility by
125
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
the CRC. No subject may be treated without CRC confirmation of qualifying
disease and
CST? 310 microns. Once qualification is confirmed, subjects will be randomized
via the
IWRS. All qualifying subjects will be randomized (Day 1) to receive either:
[1327] ACTIVE:
an IVT injection of aflibercept [2 mg (0.05 mL)] plus a suprachoroidal
injection of CLS-TA [4 mg (100 pL)] or CONTROL: an IVT injection of
aflibercept [2 mg
(0.05 mL)] plus a sham suprachoroidal procedure.
[1328] Subjects
randomized to the Active arm (those receiving CLS-TA) or the Control
arm will be retreated with an IVT injection of aflibercept at Visits 3 (Month
1) and 4 (Month
2) only if criteria for additional therapy are met. If they do not qualify for
the IVT injection
of aflibercept, they will be given a sham IVT aflibercept injection.
[1329] Pre-
injection procedures. The following must be performed immediately prior
to the IVT aflibercept injection:
= Assess for AEs
= Review changes to concomitant medications
= Review central lab results for any significant abnormalities that would
exclude the
subject from entry
= Review the results received from the CRC to confirm that subject is
eligible based on
disease and CST
= Review eligibility based on Inclusion/Exclusion and Randomization
criteria
= Measure seated, resting heart rate and blood pressure
= Perform urine pregnancy test on females of childbearing potential
= Perform ophthalmic assessments on the study eye only.
o BCVA exams performed by certified site personnel using the ETDRS protocol
(remember BCVA technician is to be masked to treatment assignment)
o Perform slit-lamp biomicroscopy
o Evaluate TOP
o Perform indirect ophthalmoscopy
o Obtain SD-OCT images and upload to the Central Reading Center (Visit 1
images will be used for qualification; Visit 2 pre-dose images will be used as
baseline)
= Log onto the IWRS system and randomize subject. Kit number will be
assigned.
126
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1330] IVT
Injection of aflibercept: Prepare study eye for IVT injection of aflibercept.
Administer aflibercept IVT injection per package insert. It is recommended
that the
intravitreal injection and the suprachoroidal injection are approximately 2
clock hours apart.
The superior temporal quadrant is the recommended location for suprachoroidal
injections.
[1331]
Suprachoroidal Injection of CLS-TA (ACTIVE KIT): Suprachoroidal injection
should be administered following the IVT injection of aflibercept when the
study eye TOP is
< 30 mmHg, either spontaneously or by treatment, as determined by the
Investigator. The
injection of 100 pL of CLS-TA is administered into the SCS of the study eye
using the
Clearside microinjector approximately 2 clock hours from where the IVT
aflibercept was
administered, preferably in the superior temporal quadrant. See FIG. 21 for
method.
[1332]
Suprachoroidal sham procedure (CONTROL KIT): Sham procedure is
administered following the IVT injection of aflibercept when the study eye TOP
is < 30
mmHg, either spontaneously or by treatment, as determined by the Investigator.
The eye is
prepared as it would for a suprachoroidal CLS-TA injection. A mock
suprachoroidal
injection to the study eye is performed.
[1333] Post-
Injection Procedures. The subjects remain on site for observation for
approximately 30 minutes after injection. The following assessments occur
following the
IVT injection and suprachoroidal injection or sham procedure: (1) Assess
retinal artery for
perfusion; (2) Assess for AEs; (3) Review changes to concomitant medications;
(4) Measure
seated, resting heart rate and blood pressure; (5) Perform ophthalmic
assessments on the
study eye only (a. slit-lamp biomicroscopy; b. Evaluate TOP 10 - 30 minutes
post injection; c.
Perform indirect ophthalmoscopy). If TOP remains elevated, subject must remain
on site until
TOP is under control per investigator's best medical judgment. If TOP is < 30
mmHg, the
subject may leave the clinic.
[1334] Visits 3
(Month 1 Post Injection Follow-Up (Day 28 3)) Visit 4 (2 Month
Post Injection Follow-Up (Day 56 3)). Visit 3 occurs approximately 1 month
post Visit 2
(Randomization/Treatment). The visit is 28 3 days from Visit 2. Visit 4
occurs
approximately 2 months post Visit 2 (Randomization/Treatment). Visit 4 is 56
3 days from
Visit 2. During Visits 3 and 4, the following procedures are performed:
= Assess for AEs
127
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
= Review changes to concomitant medications
= Measure seated, resting heart rate and blood pressure
= Perform ophthalmic assessments on the study eye only
o BCVA exams performed by certified site personnel using the ETDRS protocol
o Perform slit-lamp biomicroscopy
o Evaluate TOP
o Perform dilated indirect ophthalmoscopy
o Obtain SD-OCT images and upload to the CRC
o OPTIONAL: Perform FA with the early series of the study eye and upload to
the CRC only if the investigator feels it is necessary for medical judgment.
= Administer IVT aflibercept to subjects only if they qualify for
additional treatment. If
subject does not qualify for additional treatment, administer an IVT sham
procedure.
[1335] Visit 5 ¨ Month 3; End of Study Visit (Day 84 4 days). Visit 5 is
the final
evaluation visit and exit from the study. Visit 5 occurs within 84 4 days
from Visit 2.
During Visit 5, the following procedures are performed:
= Assess for AEs
= Review changes to concomitant medications
= Measure seated, resting heart rate and blood pressure
= Perform ophthalmic assessments on the study eye only
o BCVA exams performed by certified site personnel using the ETDRS protocol
o Perform slit-lamp biomicroscopy
o Evaluate TOP
o Perform dilated indirect ophthalmoscopy
o Obtain SD-OCT images and upload to the CRC
o OPTIONAL: Perform FA with the early series of the study eye and upload to
the CRC only if the investigator feels it is necessary for medical judgment.
[1336] Assessments of efficacy is as follows.
[1337] Central Subfield Thickness as measured by SD-OCT. Retinal thickness
and
disease characterization will be assessed via SD-OCT (Heidelberg SPECTRALISO)
at every
visit. OCT will be performed on both eyes at Visits 1 and 5, and in the study
eye only at
Visits 2, 3 and 4. The CRC will evaluate study images in a masked, independent
manner. At
128
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Screening (Visit 1), the CRC will confirm subject eligibility on the basis of
retinal thickness
criteria prior to subject enrollment. Upon confirmation from the CRC via
email, the site may
proceed with qualifying the subject for Randomization/Treatment which will
occur at Visit 2.
SD-OCT submissions will include a volume (cube) scan consisting of 49 B-scans
of 6 mm
length centered on the fovea. An additional Enhanced Depth Imaging scan will
be obtained
horizontally through the fovea. SD-OCT scans will be evaluated for quality and
any
segmentation errors affecting the measurement of central subfield retina
thickness will be
corrected. Additional evaluation outputs will include macular grid volume and
assessment of
retinal and choroidal anatomy.
[1338] BCVA assessed using the ETDRS protocol. BCVA is assessed at every
visit.
BCVA will be measured on both eyes at Visits 1 and 5, and in the study eye
only at Visits 2,
3 and 4.
[1339] Safety and tolerability will be evaluated using the following
assessments.
[1340] Intraocular pressure. Tonopen or Goldmann Applanation Tonometer is
allowed
for measuring TOP. Mean TOP values are rounded up to the next whole number if
the value is
greater than or equal to 0.5 mmHg and rounded down if less than 0.5 mmHg. All
instruments
used to measure TOP are calibrated according to the manufacturer's
specifications and
documented (i.e., calibration log). The same tool for measuring TOP should be
used for every
visit. TOP is measured at every visit. It will be measured on both eyes at
Visits 1 and 5 and
the study eye only at Visits 2, 3 and 4.
[1341] Slit-lamp biomicroscopy. Slit-lamp biomicroscopy is performed using
the
investigator's standard slit lamp equipment and procedure. Observations for
each eye are
made for the following variables (including but not limited to): conjunctiva,
cornea, lens,
anterior chamber, iris, and pupil. Slit-lamp biomicroscopy is assessed at
every visit. It will
be measured on both eyes at Visits 1 and 5 and the study eye only at Visits 2,
3 and 4.
[1342] Indirect ophthalmoscopy. The fundus is examined thoroughly and the
following
variables (including but not limited to): vitreous, retina, choroid, and optic
nerve/disc. Dilated
indirect ophthalmoscopy will be assessed at every visit. It will be measured
on both eyes at
Visits 1 and 5 and the study eye only at Visits 2, 3 and 4.
129
CA 03010862 2018-07-06
WO 2017/120601 PCT/US2017/012757
[1343] Fluorescein Angiogram (FA). All data/images are uploaded to EyeKor's
Excelsior system. As a reminder all images should be de-identified before
uploading. FA
will be performed at Visits 1 and 5 on the study eye only. FA may be performed
(it is
optional) at Visits 3 and 4 if the investigator feels it is necessary for
medical judgment only.
Anatomic assessments include the area of fluorescein leakage, area of
capillary nonperfusion,
the presence of retinal vascular and optic nerve head staining, and retinal
pigment epithelium
abnormalities.
[1344] Fundus Photographs. FP-4W (4 Wide Field Color Fundus Photography).
Fundus photographs are taken at Visits 1 and 5 on both eyes. Characteristics
graded from
fundus photographs includes optic disc swelling, and vascular abnormalities.
Results
[1345] Forty-six subjects were randomized into the study (23 into the
CONTROL arm
and 23 into the ACTIVE arm). All 46 studies completed the study. The patient
demographics
are provided below in Table S.
Table 5. Patient demographics
Active
Control
IVT Eylea + TOTAL
IVT Eylea alone
SCS CLS-TA N=46
N=23
N=23
AGE (YEAR)
MEAN 65.8 66.9 66.3
MEDIAN 70.0 67.0 68.0
MIN. MAX 37. 91 41, 80 37, 91
SEX n (/o)
MALE 10 (43.5) 13 (56.5) 23 (50.0)
FEMALE 13 (56.5) 10 (43.5) 23 (50.0)
RACE n (/o)
AMERICAN
INDIAN OR 1 (4.3) 0 1 (2.2)
ALASKA NATIVE
BLACK OR
AFRICAN 4 (17.4) 3 (13.0) 7 (15.2)
AMERICAN
WHITE 18 (78.3) 20 (87.0) 38 (82.6)
130
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1346] As shown
in Figure 41, the primary endpoint was met. In the Control arm (i.e.,
the group that received an IVT injection of aflibercept and did not receive
CLS-TA), 23
additional IVT injections of aflibercept were administered, whereas in the
Active treatment
arm (i.e., the group that received an IVT injection of 2 mg aflibercept and a
SCS injection of
4 mg CLS-TA) only 9 additional IVT injections were administered. Thus, there
were 60%
fewer inejctions in the Active arm relative to the Control arm, indicating
that the treatment is
more effective and/or lasts longer when the IVT injection of the biologic is
coupled with SCS
administration of the anti-inflammatory. The p-values of the difference in the
number of
treatments required were p=0.013 (negative binomial; Wald Chi-square test) and
p= 0.002
(Wilcoxon test, used to evaluate sensitivity).
[1347] In terms
of changes in BCVA at Month 3, subjects in the Active group gained
18.9 letters while subjects in the Control group gained 11.3 letters, showing
an additional
increase in BCVA of 7.6 letters for the Active group over the Congrol group
(Figure 42).
BCVA was also improved as early as months 1 and 2, with a 4.7 number increase
in the
Active group compared to the Control group at month 1, and an 8.5 increase in
the Active
group compared to the Control group at month 2. (Figure 43).
[1348] Macular
edema was also improved in the Active compared to the Control group.
Subjects in the Active group exhibited reduced central subfield thickness
(CST) by 446
microns, while subjects in the Control group exhibited reduced CST by 343
microns,
showing an increased reduction in retinal thickness of 103 microns for the
Active group over
the Control group at month 3 (Figure 44). Macular edema was improved as early
as months 1
and 2 as well. At month 1, subjects in the Active group exhibited CST reduced
by 446
compared to a CST reduction of 405 (Figure 45). At month 2, subjects in the
Active group
exhibited a CST reduced by 459 compared to a CST reduction of 344 in the
Control group
(Figure 45).
[1349] In terms
of safety the Active group was generally safe and well tolerated. There
were no serious adverse events in the study, and there were no adverse events
that led to
discontinuation of the study for any subject.
[1350] Thus,
the results of the study indicate that SCS administration of the CLS-TA
formulation improved treatment of macular edema associated with RVO relative
to
131
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
aflibercept treatment alone. SCS administration of CSS-TA significantly
improved outcomes
in patients relative to patients that received the IVT biologic without SCS
administration
Example S. Study Comparin2 the Effects of SCS and Intravitreal Injections of
Triesence in Rabbits
[1351] A study
was conducted in rabbits to compare the results of SCS injections against
results of intravitreal injections with commercially available TA, Triesence,
related to the
distribution of Triesence through the different tissues of the eye as well as
measuring the drug
levels in the plasma using our microinjector.
[1352] In this
study, each rabbit received a single dose of 4.0 mg of Triesence on day 1 of
the study injected either intravitreally or into the SCS. The rabbits were
then observed for
periods of up to 90 days and the concentration of Triesence in various parts
of the eye was
measured at days 14, 28, 56 and 91.
[1353] FIGS.
27, 28A-28F illustrate the results of this study. The values shown in FIG.
28 for various parts of the eye represent ratios of total drug over the 91-day
time frame of the
study, when comparing the two routes of injection. The measures in FIGS. 28A-
28F
represent the amount of drug found in a specific tissue or area following SCS
injection
expressed as a proportion of the amount found in the same tissue or area
following
intravitreal injection. For example, a ratio of 1.0 indicates that there is an
equal amount of
drug found in the specific tissue following both routes of injection, whereas
a ratio of 10
indicates that there is ten times more drug present in the tissue following
SCS administration
as compared to intravitreal administration. A ratio
of 0.03 indicates that there is
approximately thirty three times more drug in the specific area following
intravitreal injection
as compared to SCS injection.
[1354] In the
case of intravitreal injection, the highest concentrations of Triesence were
present in the iris, ciliary body and lens, all of which are located at the
front of the eye,
throughout the 91-day period. Throughout the period, significantly lower
concentrations of
Triesence were present in the choroid and outer retina, and almost no
Triesence could be seen
in the choroid or outer retina by day 91. By contrast, in the case of SCS
injection,
significantly higher concentrations of Triesence were present in the choroid
and outer retina
132
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
throughout the 91-day period, with only minimal levels present in the iris,
ciliary body and
lens. These results suggest that drug administered through the SCS can remain
localized
away from other parts of the eye and that SCS injection provides significantly
better
bioavailability in the targeted retinal and choroidal tissue than intravitreal
injection.
Example 6. Study Comparin2 the Effects of SCS Administration of CLS-TA with
SCS
Administration of Triesence in Rabbits
[1355] Aspects of the invention are directed to a triamcinolone acetonide
formulation
("CLS-TA") having characteristics as provided in Table 6 below:
Table 6: CLS1001, triamcinolone acetonide injectable suspension
40 m2/mL 8 m2/mL formulation
In2redient
formulation
Triamcinolone acetonide 40 mg/mL 8 mg/mL
Dso: -2 pm Dso: -2 pm
Particle Size
D99: <10 pm D99: <10 pm
Sodium Chloride 0.55% w/v 0.55% w/v
Carboxymethylcellulose sodium 0.5% w/v 0.5% w/v
Polysorbate 80 0.02% w/v 0.01 % w/v
KCI 0.075% w/v 0.075% w/v
CaCl2 (dihydrate) 0.048% w/v 0.048% w/v
MgCl2 (hexahydrate) 0.030% w/v 0.030% w/v
Sodium acetate (trihydrate) 0.39% w/v 0.39% w/v
Sodium citrate (dihydrate) 0.17% w/v 0.17% w/v
Na0H/HCI Adjust to pH 6.0 -7.5 Adjust to pH 6.0 -7.5
[1356] A pharmacokinetic study in rabbits was conducted comparing the
pharmacokinetic profile of CLS-TA with the profile of Triesence, each
administered into the
SCS. Pharmacokinetics refers to the process by which a drug is distributed and
metabolized
in the body, which provides information on drug levels in specific tissues and
how these
levels change over time. Each rabbit received a single dose of 4.0 mg of
either CLS-TA or
Triesence administered through the SCS on day 1 of the study. The rabbits were
then
observed for periods of up to 90 days and the resulting concentration of each
of the two TA
formulations in various parts of the eye was measured at days 15, 29, 58, 63
and 91.
133
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1357] In this
study, CLS-TA and Triesence had comparable distributions throughout the
eye over the 90-day period. As shown in FIGS. 29-30 both CLS-TA and Triesence,
administered into the SCS, remained present in the retina and choroid at high
concentration
levels throughout the 90-day period following injection.
Example 7. Animal Toxic lo2v Studies
[1358]
Toxicology studies in rabbits demonstrated that both CLS-TA and Triesence were
well tolerated when injected to the SCS. In one study, rabbits received a
single injection of
Triesence into the SCS and were evaluated for the following 17 weeks. In the
other study,
rabbits received an injection of CLS- TA into the SCS and were evaluated for
the following
13 weeks; a subgroup of the rabbits then received a second injection of CLS-
TA into the
SCS and the rabbits were evaluated for an additional 13 weeks. Both studies
showed CLS-
TA and Triesence to be generally well-tolerated and safe after single and
repeat dosing,
supporting the administration of CLS- TA and Triesence in clinical studies.
Example 8. Evaluatoion of Suprachoroidal Triamcinolone Injection and Oral
Prednisone in a Porcine Model of Uveitis
[1359] In this
experiment, the anti-inflammatory effects following both high and
maintenance daily dose of oral steroid were evaluated, and compared to the
anti-
inflammatory effects of suprachoroidal steroid injection in a porcine model of
acute posterior
uveitis. The questions asked included whether administration of triamcinolone
to the SCS
demonstrated anti-inflammatory properties in the pig model of acute uveitis,
whether this
effect was comparable to the effect from the most commonly used oral high
daily dose
regimen in uveitis, and whether the anti-inflammatory effect of triamcinolone
matched the
oral daily maintenance low dose regimen also used quite often for longer term
control of
intraocular inflammation. The study design is presented in Table 6 below.
Table 6. Study design.
Group Eyes Treatment Exams Number of pigs
per group
1 (negative OD LPS/ BSS SCS 4
control)
Time -24 hrs.*
2 (oral high OD LPS/ prednisone 1 (prior to 1st 4
134
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
Table 6. Study design.
Group Eyes Treatment Exams Number of pigs
per group
dose mg/kg/day PO injection of LPS),
prednisone) 0* (prior to
treatment),
3 (CLS-TA) OD LPS/ 2 mg CLS-TA 24, 484
and 72 hrs.
4 (oral low OD LPS/ prednisone 0.1 4
dose mg/kg/day PO
prednisone
OD ¨ right eye (Treated) OS ¨ left eye (Untreated)
'50 ul CLS-TA (Clearside product) or BSS injected into the SCS using
microneedles on Day
0, 24 hours after intravitreal LPS, or oral (PO) prednisone on Day 0 and
repeated every 24
hours until euthanasia.
2Examinations consist of Modified Hackett McDonald Inflammation Scores and
IOPs
(TonoVet)
*Examinations at -24 hours (prior to LPS injection) and at day 0 (Prior to
treatment), and at 3
days after injection of CLS-TA, consisted of full-field scotopic
[1360] Twenty
four hours after the induction of acute uveitis by intraocular
lipopolysaccharide (LPS) injection (Day 0) into the vitreous, 50 [IL of
balanced salt solution
(BSS, Group 1) or triamcinolone (CLS-TA) (2 mg, Group 3) was injected into the
suprachoroidal space (SCS). In Groups 2 and 4, oral prednisone (1 mg/kg/day,
Group 2 or
0.1 mg/kg/day, Group 4) was dosed on Day 0, and repeated every 24 hours until
euthanasia
on day 3. Eyes were examined every 24 hours, which included measuring
inflammation
scores (Modified Hackett-McDonald) and intraocular pressure (TOP) until
euthanasia 3 days
after initiation of treatment. Safety assessments and histopathology were
performed on all
eyes. Electroretinography and wide-field fundus photography was performed at -
24 hours,
time 0 (before treatment) and on Day 3. Histopathology was performed on eyes
after
euthanasia.
[1361] The oral
doses chosen for this study reflected the doses typically used to treat
patients with uveitis, for initial dose (1 mg/kg/day) and maintenance dose
(0.1 mg/kg/day).
Only the right eye of each animal was used in the study and the left eye was
unaltered
(n=4/group).
[1362] Uveitis
Model. Twenty-four hours (Time -24) prior to SCS injection of CLS-TA
or vehicle, or oral administration of prednisone, and with the pigs
anesthetized (intramuscular
Telazol-Ketamine-Xylazine and isoflorane in oxygen via mask), 100 ng of
135
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
lipopolysaccharide (LPS; E. coil 055:B55; Sigma, Inc. St. Louis, MO) in 100 uL
BSS (Alcon
Laboratories, Inc, Forth Worth, TX), was injected using a 27 gauge needle into
the central
posterior vitreous. All injections were performed aseptically. Prior to all
ocular injections,
the eye was prepped with sterile 5% betadine solution then followed by
irrigation with sterile
eyewash. Immediately following the injections, 1 drop of moxifloxacin
ophthalmic solution
(Vigamox0, Alcon Laboratories, Fort Worth, TX) was applied topically, and the
pigs were
allowed to recover from anesthesia.
[1363]
Treatment. Twenty-four hours after the LPS injection (Time 0), 50 uL of CLS-
TA (2 mg) (Group 3) or BSS (Group 1) was injected either into the SCS (30
gauge,
approximately 1100 u.M microneedle) in eyes prepared aseptically. Sterile
microneedles
were used to inject into the SCS of pigs. All injections were made superiorly
(12 o'clock),
approximately 5-6 mm posterior to the limbus. In Groups 2 and 4, oral
prednisone (Roxane
Laboratories, Columbus, Ohio) (1 mg/kg/day PO [Group 21 or 0.1 mg/kg/day PO
[Group 4])
was dosed on recovery from anesthesia on Day 0, and repeated every 24 hours
until
euthanasia.
[1364] Ocular
Inflammation Score. A modified Hackett-McDonald microscopic ocular
inflammation scoring system was used to evaluate the ocular anterior segment,
lens, and
anterior vitreous. Specifically, both eyes of each animal were examined by a
board-certified
veterinary ophthalmologist using a handheld slit lamp and indirect
ophthalmoscope as
follows. Lenticular Examination: Approximately one drop of a short-acting
mydriatic
solution was instilled onto each eye in order to dilate the pupil. After
acceptable dilation has
occurred, the lens of each eye was examined using a slit-lamp biomicroscope.
Hackett, R.B.
and McDonald, T.O. Ophthalmic Toxicology and Assessing Ocular Irritation.
Dermatoxicology, 5th edition. Ed. F.N. Marzulli and H.I. Maibach. Washington,
D.C.:
Hemisphere Publishing Corporation. 1996; 299-305 and 557-566, incorporated by
reference
herein in its entirety.
[1365] Using a
portable slit lamp biomicroscope (Zeiss HSO-10, Carl Zeiss Meditec, Inc.
USA), ocular inflammation scores were evaluated at Time -24 (prior to LPS
injection), at
Time 0 (prior to vehicle or CLS-TA injection, then at times 24, 48 and 72
hours after
injection. Scores were summed to provide a single inflammation score for each
animal for
each examination.
136
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1366]
Intraocular Pressure. Intraocular pressure (TOP) was measured with the pigs
awake and hand restrained at -144, -96, -24, 0, 24, 48, and 72 hours (see
Figure 1) using a
TonoVet Tonometer (iCare, Finland). The measurements were performed with the
pigs
awake and without use of topical anesthetic. The tip of the probe was directed
to contact the
central cornea and 6 measurements were made consecutively. After the six
measurements, the
mean TOP was shown on the display providing the TOP that was recorded.
[1367] Scotopic
Electroretinography (ERG). All animals were dark adapted for 15
minutes prior to ERG. With the pigs anesthetized at times -24, 0 and 72 hours,
and pupils
dilated with 1% tropicamide HC1, whole field scoptic ERGs were recorded from
the right eye
prior to injections. A monopolar contact lens electrode (ERG-jet, La Chair(
des Fonds,
Switzerland) was placed on the cornea to serve as an active electrode. A
subdermal electrode
at the lateral canthus served as the indifferent electrode. A Barraquer eyelid
speculum was
placed to maintain open eyelids and a subdermal needle electrode was inserted
dorsally as the
ground electrode. ERGs were elicited by brief flashes at 0.33 Hz delivered
with a mini-
ganzfeld photostimulator (Roland Instruments, Wiesbaden, Germany) at maximal
intensity.
Twenty responses were amplified, filtered, and averaged (Retiport
Electrophysiologic
Diagnostic Systems, Roland Instruments, Wiesbaden, Germany). B wave amplitudes
were
recorded from each pig at the designated times.
[1368] Wide-
field Ocular Fundus Digital Photography. With the pigs anesthetized at
times -24, 0 and 72 hours, and pupils dilated with tropicamide 1%, the ocular
fundus was
photographed with standardized illumination and focus using a wide-field
digital imaging
system (Retcam II, Clarity Medical Systems, Pleasanton, CA).
[1369] Ocular
Histopathology. The pigs were euthanized at study time 72 hours after
clinical scoring, ERG, and wide-field ocular fundus photography was completed.
After
euthanasia with an overdose of intravenous barbiturate, the right eye was
removed. Aqueous
humor (AH) was aspirated and the globe was then fixed in Davidson's solution
for 24 hours,
followed by alcohol. Central, saggital sections of each globe, including the
optic nerve, were
stained with hematoxylin and eosin and examined by light microscopy. Degree of
inflammatory infiltrate of the ocular anterior and posterior segments was
graded by two
observers masked to the study groups and the final grade was an average of the
two scores.
The grading scale used was modified from Tilton, et al (IOVS 1994):
137
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1370] Anterior chamber tissues including the iris, ciliary body, ciliary
process, corneal
endothelium, and the anterior chamber, were scored for severity of
inflammation as follows:
0 = normal tissue
1 = dilated iris vessels and thickened iris stroma with exudate, protein,
and/or a
few scattered inflammatory cells in the anterior chamber
2= infiltration of inflammatory cells into the stroma of the iris and/or
ciliary body,
with a moderate number of inflammatory cells within the anterior chamber
3 = heavy infiltration of inflammatory cells within the iris stroma and
ciliary body
and a heavy infiltration of inflammatory cells within the anterior chamber
4 = heavy exudation of cells in dense protein aggregation in the anterior
chamber
and inflammatory cell deposits on the corneal endothelium.
[1371] The histologic classification system the retina and posterior
segment was:
0 = normal tissue
1 = minimal infiltration of inflammatory cells within the vitreous cavity
and/or
retina
2 = moderate infiltration of inflammatory cells within the vitreous cavity
and/or
retina.
3 = severe infiltration of inflammatory cells within the vitreous cavity
and/or
retina
[1372] Data and Statistical Analysis. Parametric normally distributed data
(i.e., TOP,
ERG, retinal thickness) were compared by time point for each group using 1-way
ANOVA
models with Tukey-Kramer post-hoc analysis. For non-parametric data (i.e.,
clinical scores,
histologic grades), Wilcoxon tests were conducted per animal by time point.
Differences were
considered significant at P<0.05. Results and probabilities were calculated
using
computerized statistical software (JMP 10, SAS Inc. Cary, NC).
Results
[1373] Injection Procedure Observations. Injections of CLS-TA or BSS into
the SCS
(Groups 1 and 3) were accomplished using microneedles without difficulty or
adverse effect.
Eyes were examined via slit lamp biomicroscopy and indirect ophthalmoscopy
following
each injection. No evidence of backleakage of treatment materials through the
microneedle
138
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
scleral perforation or leakage of drug into the vitreous was observed.
Furthermore, there was
no evidence of injection site or vitreal hemorrhage following any injections
(SCS).
[1374] Ocular Inflammation Scores. Mean
cumulative inflammation scores as
assessed by ophthalmoscopy at time -24 hours ranged between 0 and 1 for all
groups and
were not significantly different. Following intravitreal injection of LPS, by
time 0, mean
cumulative inflammation scores elevated to between 5.5 and 6.25 in all groups
(Fig. 31) and
there were no significant differences between treatment groups. Following
treatment, mean
inflammation scores generally decreased in all groups over the next 3 days. On
Days 1 and 2
(24 and 48 hours after initiation of treatment, respectively), only Group 3
(CLS-TA) had
mean cumulative inflammation scores significantly lower than Group 1 (BSS
treated; P=0.04
and P=0.023 for Days 1 and 2, respectively). After 72 hours of treatment,
Groups 2 (high
dose of prednisone) and Group 3 (CLS-TA) had significantly lower mean
cumulative
inflammation scores than Group 1 (P<0.034). Group 4 (low dose oral prednisone)
mean
cumulative inflammation scores were not significantly different than saline
treated eyes at
any treatment time. These results suggest that 2 mg of CLS-TA injected into
the SCS resulted
in more rapid reduction of inflammation than high dose oral prednisone (one
day vs. three
days) and both CLS-TA and high dose prednisone were more effective than low
dose
prednisone in reduction of ocular inflammation in this model of uveitis.
[1375]
Intraocular Pressure. Mean intraocular pressure ranged from 14.24 to 17 mmHg
during acclimation and increased slightly as pigs became accustomed to being
handled. On
induction of uveitis, the mean TOP decreased by Time 0 to between 11.5 and
14.25 mmHg in
all groups, which were not significantly different. Following treatment, TOP
returned to
baseline by Day 1 in all groups. On Day 3, Group 4 eyes (low dose oral
prednisone) had
significantly lower TOP than all other groups (P<0.0065) suggesting that these
eyes had more
inflammation compared to the other groups. TOP in Group 3 eyes stayed
substantially
constantthroughout the study period (FIG. 32).
[1376]
Electroretinography. At time -24 hours, mean scotopic B wave amplitudes were
not significantly different between groups and ranged from 121.9 +/- 58.7 uV
to 220 +/-
16.04 uV. There were also no significant differences between groups in mean
scotopic B
wave amplitudes at time 0 (after induction of uveitis) with a range of 92.2 +/-
15.3 uV to 204
+/- 62.0 uV. By Day 3 of treatment, a range of 262.7 +/- 26.5 uV and 91.2 uV
+/- 24.5 uV
was measured. On Day 3, mean scotopic B wave amplitude in Group 3 (CLS-TA) was
139
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
significantly lower than other groups (P=0.034). This decreased B-wave
amplitude was
interpreted as biologic variability and not toxicologically significant as
there was no
correlating abnormality observed on ocular fundus examination or retinal
histology.
[1377] Wide-
field Ocular Fundus Digital Photography. Wide-field ocular fundus
images revealed substantial cloudiness of the ocular posterior segment 24
hours after LPS
injection. The cloudiness observed in eyes on Day 0 was a result of
predominantly cellular
infiltrate into the vitreous humor and some changes to the retina. In BSS
treated eyes (Group
1), the cloudiness appeared to worsen from 24 to 72 hours. Treatment with high
dose
prednisone (Group 2) and CLS-TA (Group 3) resulted in fundus images near pre-
treatment
appearance at 72 hours. However, treatment with low dose prednisone (Group 4)
resulted in
images only slightly improved over vehicle treated eyes.
[1378] Ocular
histopathology. No signs of inflammation or degeneration associated
with the SCS injection in Group 3 animals were observed by ocular
histopathology. Each eye
of this group had evidence of TA crystals in the SCS. There was no evidence of
test-article
related toxicity of the ocular anterior or posterior segment in any group.
Mean histologic
scores of the anterior segment of eyes with CLS-TA (Group 3) were
significantly lower
(P=0.018) than eyes treated with saline (Group 1), while mean anterior segment
scores of the
eyes treated with oral prednisone (Groups 2 and 4) were not significantly
different than
Group 1 (FIG. 33). Mean histologic scores of the posterior segment of eyes
treated with
CLS-TA were significantly lower than eyes treated with saline (Group 1) and
eyes treated
with high dose prednisone (Group 2) and CLS-TA (Group 3) were lower than the
mean score
of eyes treated with low dose oral prednisone (Group 4) (P<0.013) (FIG. 33).
These results
suggest that CLS-TA was as effective as high dose and more effective than low
dose oral
prednisone in reduction of histologic inflammation compared to saline treated
eyes.
Example 8. Efficacy of Suprachoroidal Aflibercept in a Laser Induced Choroidal
Neovascularization (CNV) Model
[1379]
Treatment of chronic retinal diseases, such as neovascular (wet) age related
macular degeneration (AMD), often require intravitreal injections of a
biological drug, such
as Lucentis, Eylea (aflibercept) or Avastin to prevent vision loss. The
disease shows new
blood vessel formation from the choroid. The disease affects the choroid and
retina and
specific targeting of these tissues might be more beneficial in modulating
disease
140
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
progression. Specific tissues can be targeted by directly administering the
drug to the choroid
rather than the current method of injecting into the vitreous. Disclosed
herein are methods of
targeting the choroid and the retina via a suprachoroidal injection technique.
This example
demonstrates that a suprachoroidal injection of Eylea can lead to a reduction
in neovascular
area in a validated animal disease model. This experiment shows that this anti-
VEGF agent
can provide the potential for a useful alternative treatment approach.
Further, there is
potential to access the new blood vessels in the choroid, which could reduce
the necessary
frequency of treatment. If this experimental result can be translated into
clinical practice, this
may offer unique options for the treatment of this and other vision
threatening diseases.
[1380] The
efficacy of suprachoroidal administration of aflibercept in reducing
neovascular area in a rat laser induced choroidal neovascularization (CNV)
model was
examined. Reduction in neovascular area in this model could provide evidence
for treating
retinal disease such as wet age related macular degeneration.
[1381] Methods.
Brown Norway rats (4/group) of approximately 8 weeks were used for
this study. Both eyes for each rat were used and 3 laser spots/eye were
applied on day 1. On
day 3 rats were treated using a microneedle to perform a suprachoroidal
injection. The
microneedle was inserted 1-2 mm posterior to the limbus and 5 microliters of
test article was
injected into the suprachoroidal space. Rats were treated with either saline
or aflibercept
(Eylea 40 mg/mL, Regeneron Pharmaceuticals). Eyes were examined using
fluorescein
angiography 3 weeks after laser treatment and images were obtained for
quantitative analysis.
Area of neovascularization was quantified for each laser spot using computer
software.
Statistical analysis was performed using a Mann Whitney t-test. The rats were
sacrificed a
day after fluorescein angiography was conducted to evaluate the CNV lesion
area.
[1382] Results.
As illustrated in FIGS. 34A-34B, saline treated animals exhibited
approximately 4862 192 pixels2 while aflibercept treated animals showed
approximately
3318 353 pixels2 based on evaluation of neovascular leak area. The
difference between
these measurements represents a statistically significant (p<0.001) reduction
in
neovascularization on comparing the aflibercept treated group to the saline
treated group.
[1383]
Conclusions. Suprachoroidal injection of aflibercept lead to a significant
reduction in neovascular area in this 21 day model of laser induced choroidal
neovascularization model in rats. This 3-week treatment effect with a
favorable reduction in
141
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
neovascular area is the first reported evidence provided for duration of
treatment following
suprachoroidal dosing with a soluble biological agent (Eylea). Further, these
results indicate
that suprachoroidal injection of an anti- VEGF agent may provide another
treatment option
for diseases such as wet age related macular degeneration.
Example 9. Demonstration of efficacy of Eylea administered into SCS in a CNV
model
[1384] Methods.
As illustrated in FIGS. 35-36, Brown Norway rats (4/group, 4 groups)
of approximately 8 weeks were used for this study. Both eyes for each rat were
used and 3
laser spots/eye were applied on day 1. On day 3, rats were treated using a
microneedle to
perform a suprachoroidal injection. The microneedle was inserted 1-2 mm
posterior to the
limbus and 5 microliters of test article was injected into the suprachoroidal
space. Rats were
treated with either saline or aflibercept (Eylea (aflibercept) 40 mg/mL,
Regeneron
Pharmaceuticals). On day 10, rats were again treated using a microneedle to
perform a
suprachoroidal injection. The microneedle was inserted 1-2 mm posterior to the
limbus and 5
microliters of test article was injected into the suprachoroidal space. Rats
were treated with
either saline or aflibercept (Eylea 40 mg/mL, Regeneron Pharmaceuticals).
[1385] Eyes
were examined using fluorescein angiography 3 weeks after laser treatment
and images were obtained for quantitative analysis. Area of neovascularization
was
quantified for each laser spot using computer software. Statistical analysis
was performed
using a Mann Whitney t-test. The rats were sacrificed a day after fluorescein
angiography
was conducted to evaluate the CNV lesion area.
[1386] Results.
As illustrated in FIGS. 37A-37B, which also includes the results of
single-injection saline and Eylea treated animals from Example 8, the double-
injection saline
treated animals exhibited approximately 4898 254 pixels2 while the double-
injection
aflibercept treated animals showed approximately 3485 280 pixels2 based on
evaluation of
neovascular leak area. The difference between these measurements represents a
statistically
significant (p<0.001) reduction in neovascularization on comparing the double-
injection
aflibercept treated group to the double-injection saline treated group.
[1387] FIGS. 38-
40 illustrates that there is little statistically significant differences in
the
lesion area between the single-injection saline treated animals and the double-
injection saline
treated animals. FIGS. 38-40 also illustrates the difference in the lesion
area between the
single-injection Eylea (aflibercept) treated animals (200 fig) and the double-
injection Eylea
142
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
(aflibercept) treated animals (400 jig). The lesion area values for saline
(intravitreal
administration) and Eylea (200 jig, intravitreal administration) are also
shown for
comparison. FIG. 39 better illustrates the comparison between the single-
injection Eylea
treatment (200 jig, suprachoroidal space administration), saline treatment
(intravitreal
administration) and Eylea (aflibercept) (200 jig, intravitreal
administration).
Example 10. Efficacy of Suprachoroidal CLS-TA in Combination with Intravitreal
Aflibercept in Subjects with BRVO or CRVO
[1388] The data
collected in the study described above in Example 4 were further
analyzed to further assesses the efficacy of a suprachoroidal injection of CLS-
TA plus IVT
aflibercept compared to subjects administered a sham suprachoroidal procedure
plus IVT
aflibercept in the treatment of subjects with macular edema (ME) following
retinal vein
occlusion (RVO), by stratifying the subjects by RVO type and perfusion type.
As discussed
in Example 4, each subject received at least one IVT aflibercept injection and
half of the
subjects received a single suprachoroidal injection of CLS-TA. The subjects
enrolled in this
study were treatment naive RVO subjects (HRVO, CRVO and BRVO) with ME in the
study
eye. All qualifying subjects were randomized (Day 1) to receive an IVT
injection of an anti-
VEGF treatment (aflibercept) plus a suprachoroidal injection of CLS-TA or an
IVT injection
of aflibercept plus a sham suprachoroidal procedure. Subjects were followed
for
approximately 3 months following randomization. The subject, sponsor, visual
acuity
technician and the optical coherence tomography (OCT) reading center were
masked to
treatment.
[1389] The
design of scheduled visits for the 46 total enrolled subjects was described in
Example 4. The following assessments were made: the total number of times
subjects
qualified to be administered IVT aflibercept in each arm through month 3; mean
central
subfoveal thickness (CST) at 1, 2, and 3 months; mean change in central
subfoveal thickness
(CST) at 1, 2, and 3 months; mean best corrected visual acity (BCVA) at 1, 2,
and 3 months;
and mean change in best corrected visual acity (BCVA) at 1, 2, and 3 months.
As described
above, subjects were stratified based on RVO type (BRVO or CRVO) and perfusion
type
(ischemic or non-ischemic) to determine if any differences could be detected
in the
effectiveness of active arm treatment (IVT aflibercept + SCS Zuprata) relative
to control
treatment (IVT aflibercept + sham SCS).
143
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
[1390] The
trial treatments, retreatment criteria, enrollment criteria, visit schedules,
injection procedures and assessment of efficacy were described in Example 4.
Results
[1391] Patients
were stratified by type of RVO and persusion type (ischemic vs. non-
ischemic) as set forth in Table 7.
Table 7. Study design ¨ stratficiation of subjects
Control Active
TOTAL NUMBER OF IVT aflibercept IVT aflibercept +
TOTAL
SUBJECTS alone SCS CLS-TA
N=23 (%) N=23 ("/0)
TYPE OF RETINAL
VEIN OCCULUSION
BRVO 5 (21.7) 14 (60.9) 19 (41.3)
HRVO 1(4.3) 0 1(2.2)
CRVO 17 (73.9) 9 (39.1) 26 (56.5)
PERFUSION TYPE
ISCHEMIC 5(21.7) 6 (26.1) 11 (23.9)
NON-ISCHEMIC 18 (78.3) 17 (73.9) 35 (76.1)
[1392] The
purpose of the study was to assess CST, BVCA, and the number of
administrations of aflibercept required (as measured by subjects qualifying
for retreatment
with IVT aflibercept based on CST or BCVA criteria described above in Example
4) in
subjects in each group category (BRVO v. CRVO; and ischemic vs. non-ischemic).
FIG. 46
shows the qualification for retreatment with aflibercept of the enrolled
patients from both
arms. As shown in the figure, a lower percentage of Active arm (IVT
aflibercept + SCS TA)
144
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
patients qualified for retreatment with aflibercept in both BRVO and CRVO
groups (21% and
22%, respectively) compared to the percentage qualifying for additional
aflibercept in the
Control arm (aflibercept alone) in BRVO and CRVO patients (67% and 71%,
respectively).
Therefore, the combination of aflibercept + Zuprata (SCS TA) represented a
more effective
treatment for both BRVO and CRVO patients.
[1393] As shown
in FIG. 47, the mean central subfoveal thickness (CST) was 638 p.m in
the BRVO subjects treated with aflibercept + Zuprata (Active group) and was
586 p.m in the
BRVO subjects in the Control group at baseline. The mean CST was reduced to
approximately 300 p.m in both treatment groups at month 1. At month 2, while
mean CST
was increased to 455 p.m in Control group, the mean CST in the subjects
treated with Active
group remained at 295 p.m. At month 3, the mean CST was approximately 300 p.m
for the
subjects in both groups. The Active group was more consistently effective in
reducing CST.
[1394] In terms
of mean changes in CST, BRVO subjects in the aflibercept + Zuprata
(Active group) had a reduction of 347 p.m at month 2 while BRVO subjects in
the Control
group only had a reduction of 130 p.m, showing 217 p.m differences between the
groups. In
addition, at both month 1 and month 3, the mean CST was reduced more in the
subjects
treated with Active group compared to the mean CST in the Control group,
showing that the
IVT injection of aflibercept coupled with a SCS injection of the anti-
inflmmatory were more
effective to reduce CST (FIG. 48).
[1395] As shown
in FIG. 49, the mean best corrected visual acuity (BCVA) in BRVO
subjects was improved in both Active and Control groups from baseline to month
3. In terms
of changes in BCVA (FIG. 50), subjects in the BRVO Active group consistently
exhibited
increased BCVA from month 1 to month 3 (13 to 16 to 17) whereas although BCVA
in the
control group also increased in month 1, it decreased at month 2 and increased
again at month
3), indicating that the Active group was more consistently effective in
improving BCVA in
BRVO subjects.
[1396] For CRVO
patients, the treatment of aflibercept + Zuprata (Active group) also
resulted in more reduction of CST (for instance, Baseline to month 1: 876 p.m
to 268 p.m)
compared to Control group (Baseline to month 1: 778 p.m to 326 p.m) (FIG. 51),
indicating
that aflibercept + Zuprata is also a more effective treatment for CRVO
patients. In terms of
changes in CST, subjects in the Active group exhibited a 607 p.m reduction at
month 1 while
145
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
subjects in Control group exhibited a 452 p.m reduction, showing an additional
reduction in
CST of 156 p.m for the Active group over the Control group (FIG. 52).
Similarly, the Active
group had an additional 212 p.m reduction in CST at month 2 and an additional
238 p.m
reduction in CST at month 3 over the Control group.
[1397] Further,
as shown in FIG. 53, aflibercept + Zuprata (Active group) also improved
the mean score of BCVA more compared to subjects in the Control group from
baseline to
month 3 in CRVO patients. In terms of the changes in BCVA, subjects in the
Active group
gained 21 socres while subjects in the Control group gained 10 scores, showing
an additional
increase in BCVA of 11 scores for the Active group over the Control group at
month 1 (FIG.
54). Simialrly, BCVA was also improved at month 2 and month 3, with 18 scores
increase in
the Active group compared to the Control group at month 2, and a 16 scores
increase in the
Active group compared to the Control group at month 3.
[1398] The data
were also assessed to determine the effect of perfusion type (ischemic vs.
non-ischemic patients) on qualification for aflibercept, BVCA, and CST.
Pateints were
stratified into ischemic RVO or non-ischemic RVO, and further stratified into
BRVO or
CRVO; qualification for additional aflibercept administration, BVCA, and CST
was assessed
for each subgroup of patients.
[1399] A
greater proportion of non-ischemic patients qualified for aflibercept
retreatment,
independent of Control vs. Active group (FIG. 55). Within the ischemic group
(independent
of RVO type), no active arm patients qualified for aflibercept retreatment,
while 40% of
Control group patients qualified for aflibercpet retreatment (FIG. 56). Within
the non-
ischemic group (independent of RVO type), far more patients in the control arm
required
aflibercept retreatment relative to active arm (13 (72%) vs. 5 (29%) of total
patients in each
group; FIG. 57).
[1400] FIG. 58A-
D shows the BVCA and CST data for ischemic versus non-ischemic
patients independent of treatment, at months 1, 2, and 3 of the study. FIG.
58A shows BVCA
in ischemic versus non-ischemic patients. There was little difference in BVCA
between non-
schemic and ischemic groups. FIG. 58B shows that the change in BVCA remained
the same
(13 or 14) in the non-ischemic group but increased (to 16, 21, and 20 at
months 1, 2, and 3,
respectively) in the ischemic group. FIG. 58C shows that CST in non-ischemic
patients was
reduced from 715 p.m at baseline to 352 p.m at month 3; and CST in ischemic
patients was
146
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
reduced from 773 um at baseline to 280 um at month 3. FIG. 58D shows the
change in CST,
and indicates that ischemic patients consistenly exhibited more of a reduction
in CST over the
3 month study period.
[1401] The
patients were next stratified into treatment groups to assess any differences
in
BVCA and CST data in the ischemic vs. non-ischemic subgroups.
[1402] FIG. 59A-
D shows the BVCA and CST data for non-ischemic patients in each
treatment group, at months 1, 2, and 3 of the study. FIG. 59A shows that for
non-ischemic
patients, BVCA increased from about 52 at baseline to about 69 at month 3 in
the Active
treatment group, whereas BVCA increased from about 48 at baseline to only
about 58 in the
control group. The change in BVCA over time in these patients was about 3
letters better in
the the Active group versus the control group at month 1, and about 8 letters
better in the
Active group versus the control group at months 2 and 3 (FIG. 59B). FIG. 59C
shows that
CST was reduced in the Active arm relative to the control arm by month 2 and
remained
reduced compared to control at month 3. Similarly, FIG. 59D shows that at
months 2 and 3,
the active arm exhibited more of a reduction in CST relative to the control
arm.
[1403] FIG. 60A-
D shows the BVCA and CST data for ischemic patients in each
treatment group, at months 1, 2, and 3 of the study. FIG. 60A shows that for
ischemic
patients, BVCA for the group was similar at each month of the study in both
groups.
However, FIG. 60B shows the change in BVCA in ischemic patients in the control
arm was
reduced compared to the change in BVCA in the active arm; active arm patients
gained about
9 more letters at months 1 and 2, and about 7 more letters at month 3,
relative to control
patients. FIG. 60C shows that CST was reduced in the Active arm relative to
the control arm
by month 1. FIG. 60D shows the change in CST, and indicates that active arm
patients
consistenly exhibited more of a reduction in CST over the 3 month study
period.
[1404] Patients
were further categorized into BRVO or CRVO and ischemic or non-
ischemic subgroups. FIG. 61A-D shows the BVCA data for each treatment group,
stratified
into ischemic or non-ischemic and BRVO or CRVO groups, at months 1, 2, and 3
of the
study. FIG. 61A shows BVCA in ischemic BRVO patients in the control arm
(aflibercept +
sham) versus the active arm, and indicates that the patients in the active arm
exhibited an
increase in BVCE at each month of the study. In contrast, FIG. 61B shows that
while patients
in the active arm exhibited a consistent increase in BVCA, patients in the
control arm
147
CA 03010862 2018-07-06
WO 2017/120601
PCT/US2017/012757
exhibited higher BVCA than active arm patients at both month 1 and month 3.
Strikingly, in
both ischemic CRVO patients and non-ischemic CRVO groups, active arm patients
exhibited
far higher BVCA at months 1, 2, and 3 compared to control arm patients (FIGS.
61C and
61D). In particular, ischemic CRVO patients exhibited an unexpectedly high
increase of
about 27 letters at month 1, about 36 letters at month 2, and about 33 letters
at month 3,
which was a vast improvement over the control arm (in which the increase in
letters was
about 13, about 19, and about 21 at months 1, 2, and 3, respectively; FIG.
61D). In summary,
the data showed that the combination of aflibercept with Zupata provided a
superior clinical
benefit in CRVO patients, particularly ischemic CRVO patients. FIG. 62
provides a
summary of the data provided in FIGS. 61A-D.
* * * * * * *
[1405]
Publications, patents and patent applications cited herein are specifically
incorporated by reference in their entireties. While the described invention
has been
described with reference to the specific embodiments thereof it should be
understood by
those skilled in the art that various changes may be made and equivalents may
be substituted
without departing from the true spirit and scope of the invention. In
addition, many
modifications may be made to adopt a particular situation, material,
composition of matter,
process, process step or steps, to the objective spirit and scope of the
described invention. All
such modifications are intended to be within the scope of the claims appended
hereto.
148
