Note: Descriptions are shown in the official language in which they were submitted.
,
DOSING REGIMENS FOR THE TREATMENT OF FUNGAL INFECTIONS
TECHNICAL FIELD
[00011 Principles and embodiments of the present invention relate
generally to the
treatment of fungal infections using azoles such as ravuconazole and its
prodrugs.
BACKGROUND
[0002] Fungal infections, also known as mycoses, are common infections
in
animals that can range in severity and invasiveness. Fungal infections are
typically
classified as being superficial, cutaneous, subcutaneous, or systemic. Most
fungal
infections are not life-threatening, but these infections can negatively
impact the patient's
quality of life.
[0003] Onychomycosis, also known as tinea unguium, is an example of a
common fungal infection, particularly in elderly patients and those with
compromised
immune systems. Onychomycosis is a fungal infection of the nail can be caused
by many
different types of fungi, including yeasts, dermatophytes and molds. Members
of the
genuses Candida, Aspergillus and Trichophyton are common causes for
onychomycosis
in humans. Onychomycosis can affect both toenails and fingernails, but toenail
infections
are more common.
[0004] Current treatments for fungal infections such as onychomycosis
include
griseofulvin, terbinafine, fluconazole and itraconazole. However, these
existing therapies
suffer from low clinical and mycological cure rates, high recurrence rates,
and potential
adverse events. Accordingly, there is a need for new therapies for the
treatment of fungal
infections such as onychomycosis.
SUMMARY
[0005] One aspect of the present invention pertains to a method of
treating a
fungal infection in a patient in need thereof, the method comprising
administering to the
patient a therapeutically effective dose of ravuconazole or a pharmaceutically
acceptable
salt, solvate or prodrug thereof. In various embodiments, the therapeutically
effective
1
CA 2986854 2017-11-28
dose is administered daily in an amount equivalent to about 50 mg to about 150
mg of
ravuconazole.
[0006] In one or more embodiments, the fungal infection comprises one or
more
of onychomycosis, oral candidiasis, esophageal candidiasis, vaginal
candidiasis,
aspergillosis, sinusitis, otitis media or dermatophytosis.
[0007] In one or more embodiments, the fungal infection comprises
toenail
onychomycosis.
[0008] In one or more embodiments, the fungal infection is caused by one
or
more fungi selected from Candida, Trichophyton Aspergillus, Malassezia and/or
Cryptococcus.
[0009] In one or more embodiments, the therapeutically effective dose is
administered daily in an amount equivalent to about 75 mg to about 125 mg of
ravuconazole.
[0010] In one or more embodiments, the therapeutically effective dose is
administered daily in an amount equivalent to about 100 mg of ravuconazole.
[0011] In one or more embodiments, the prodrug is fosravuconazole or a
pharmaceutically acceptable salt or solvate thereof
[0012] In one or more embodiments, the prodrug is an L-lysine salt of
fosravuconazole or a solvate thereof
[0013] In one or more embodiments, the prodrug is fosravuconazole L-
lysine
ethanolate (1:1:1).
[0014] In one or more embodiments, the therapeutically effective dose is
administered for at least 4 weeks.
[0015] In one or more embodiments, the therapeutically effective dose is
administered orally.
00161 Another aspect of the present invention pertains to a method of
treating
onychomycosis in a patient in need thereof, the method comprising
administering to the
patient a therapeutically effective dose of fosravuconazole or a
pharmaceutically
acceptable salt or solvate thereof. In various embodiments, the
therapeutically effective
dose is administered daily in an amount equivalent to about 50 mg to about 150
mg of
ravuconazole.
2
CA 2986854 2017-11-28
[0017] In one or more embodiments, the onychomycosis comprises toenail
onychomycosis.
[0018] In one or more embodiments, the onychomycosis is caused by one or
more
fungi selected from Candida, Trichophyton Aspergillus, Malassezia and/or
Cryptococcus.
[0019] In one or more embodiments, the therapeutically effective dose is
administered daily in an amount equivalent to about 75 mg to about 125 mg of
ravuconazole.
[0020] In one or more embodiments, the therapeutically effective dose is
administered daily in an amount equivalent to about 100 mg of ravuconazole.
[0021] In one or more embodiments, the pharmaceutically acceptable salt
or
solvate is an L-lysine salt or a solvate thereof.
[0022] In one or more embodiments, the solvate is fosravuconazole L-
lysine
ethanolate (1:1:1).
[0023] In one or more embodiments, the therapeutically effective dose is
administered for at least 4 weeks.
[0024] Another aspect of the present invention pertains to a method of
treating
onychomycosis in a patient in need thereof, the method comprising orally
administering
to the patient a therapeutically effective dose of fosravuconazole L-lysine
ethanolate
(1:1:1), wherein the therapeutically effective dose is administered daily in
an amount
equivalent to about 100 mg of ravuconazole.
[0025] In one or more embodiments, the onychomycosis comprises toenail
onychomycosis.
[0026] In one or more embodiments, the therapeutically effective dose is
administered for at least 4 weeks.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Further features of the present invention will become apparent
from the
following written description and the accompanying figures, in which:
[0028] FIG. 1 shows the disposition of all subjects from a clinical
trial
investigating the use of fosravuconazole for the treatment of onychomycosis;
3
CA 2986854 2017-11-28
[0029] FIGS. 2A and 2B show the arithmetic mean and geometric mean,
respectively, for plasma ravuconazole concentrations during a clinical trial
investigating
the use of fosravuconazole for the treatment of onychomycosis; and
[0030] FIGS. 3A and 3B show the arithmetic mean and geometric mean,
respectively, for toenail ravuconazole concentrations during a clinical trial
investigating
the use of fosravuconazole for the treatment of onychomycosis.
DETAILED DESCRIPTION
[0031] Before describing several exemplary embodiments of the invention,
it is to
be understood that the invention is not limited to the details of construction
or process
steps set forth in the following description. The invention is capable of
other
embodiments and of being practiced or being carried out in various ways.
[0032] Various embodiments of the present invention pertain to dosing
regimens
for the administration of ravuconazole, its salts, solvates and prodrugs, for
the treatment
of fungal infections. In one or more embodiments, the fungal infection
comprises
onychomycosis, such as toenail onychomycosis.
[0033] It has surprisingly been discovered that dosing regimens using
less than
200 mg (ravuconazole equivalent) per day are effective in treating fungal
infections such
as onychomycosis. Previously, a Phase I/II dose ranging clinical study had
found 200 mg
of ravuconazole to be the most effective dosing regimen for treating
onychomycosis.
However, as described in more detail in Example 1 below, a daily dose of
fosravuconazole equivalent to 100 mg of ravuconazole has now been found to
have a
high complete cure rate and a high mycological cure rate.
Ravuconazole, Salts, Solvates and Prodrugs
[0034] Ravuconazole, also known as 4-[2-[(2R,3R)-3-(2,4-difluoropheny1)-
3-
hydroxy-4-(1 ,2,4-triazol-1 -yl)butan-2-yl] -1,3 -thiazol-4-yl] benzonitrile
or (2R,3R)-3 444
4-cyanophenyl)thiazo 1-2-y1]-2-(2,4-difiuoropheny1)-1- (1 H-1,2,4-triazol-1-
y1)-butan-2-ol,
is a triazole antifungal having the following structure:
4
CA 2986854 2017-11-28
'
OH
N ' S
I /
0 N /
F
CN
[0035] Various prodrugs of ravuconazole are known. For example, U.S.
Patent
Nos. 6,362,172 and 6,448,401 describe phosphate-containing prodrugs of
triazole
antifungal compounds such as ravuconazole.
100361 Fosravuconazole, also known as 442-[(1R,2R)-2-(2,4-
difluoropheny1)-1-
methyl-2-[(phosphonooxy)methoxy]-3-0H-1,2,4-triazol-1-y0propyl]-4-thiazolyl]
benzo-
nitrile or [(2R,3R)-344-(4-cyanopheny1)-1,3-thiazol-2-y1]-2-(2,4-
difluoropheny1)-1-
(1,2,4-triazol-1-y1)butan-2-ylloxymethyl dihydrogen phosphate, is a
phosphonoxymethyl
prodrug of ravuconszole having the following structure:
r
r
0
i
- S
J-, -....1-ir N
1 /
N I ao
.
F
CN
Date recue/Date received 2023-03-10
100371 Various
salts and solvates of fosravuconazole have been previously
described, such as monolysine and dilysine salts, as well as ethanol solvates
of the
monolysine salt. Examples of these salts and solvates can be found in U.S.
Patent App.
Pub. No. 2006/0264406.. Other
pharmaceutically acceptable salts and solvates of ravuconazole and
fosravuconazole are
also encompassed by the present disclosure.
100381 In one
or more embodiments, the solvate is fosravuconazole L-lysine
ethanolate (1:1:1). The molecular formula of fosravuconazole L-lysine
ethanolate (1:1:1)
is C23H20F2N505PS = C6H14N202= C2H60.
100391 As
fosravuconazole, its salts and solvates are prodrugs of ravuconazole,
the doses of fosravuconazole are described herein as amounts equivalent to
ravuconazole.
Ravuconazole has a molecular weight of approximately 437.5 g/mol,
fosravuconazole has
a molecular weight of approximately 547.5 g/mol, and fosravuconazole L-lysine
ethanolate (1:1:1) has a molecular weight of approximately 739.7 g/mol. Thus,
125.1 mg
of fosravuconazole is equivalent to about 100 mg of ravuconazole. Similarly,
an amount
of fosravuconazole L-lysine ethanolate (1:1:1) that is equivalent to 100 mg of
ravuconazole contains about 125.1 mg of fosravuconazole, about 33.4 mg of L-
lysine and
about 10.5 mg of ethanol. Other salts and solvates of ravuconazole and its
prodrugs will
have different conversion factors, depending on the molecular weight of the
salt, solvate
or prodrug.
Fungal Infections
100401
Ravuconazole has broad antimicrobial activity covering a wide range of
fungi, including most Candida and Aspergillus species, some non-Aspergillus
species of
filamentous fungi, Cryptococcus, dermatophytes (e.g. Trichophyton species),
and fungi
that cause the endemic mycoses.
100411 In one
or more embodiments, the fungal infection is caused by one or
more species from the genuses Candida, Aspergillus, Trichophyton, Malassezia
and/or
Cryptococcus. Exemplary species include, but are not limited to, Candida
albicans,
Candida krusei, Candida glabrata, Candida tropical is, Candida parapsilosis,
Cryptococcus
6
Date recue/Date received 2023-03-10
neoformans, Malassezia furfur, Trichophyton mentagrophytes, Trichophyton
rubrum and/or
Aspergillus fumigatus.
[0042] In one or more embodiments, the fungal infection is superficial,
cutaneous, subcutaneous, or systemic. Affected areas can include, but are not
limited to,
skin, hair, nails, mucous membranes (e.g. oral, esophageal and vaginal),
and/or the fungal
infection can involve deeper tissues in the body.
[0043] In one or more embodiments, the ravuconazole, or salt, solvate or
prodrug
thereof (e.g. fosravuconazole), is used to treat a fungal infection such as
onychomycosis,
oral candidiasis, esophageal candidiasis, vaginal candidiasis, aspergillosis,
sinusitis, otitis
media or dermatophytosis.
[0044] In one or more embodiments, the fungal infection comprises
onychomycosis, such as fingernail onychomycosis and/or toenail onychomycosis.
Dosing Regimens
[0045] In various embodiments, an effective amount of ravuconazole, or
salt,
solvate or prodrug thereof, is administered to a patient on a daily basis. In
one or more
embodiments, the effective amount of ravuconazole, or salt, solvate or prodrug
thereof is
equivalent to about 50 mg to about 150 mg of ravuconazole. Exemplary daily
doses
include amounts equivalent to about 50 mg, about 55 mg, about 60 mg, about 65
mg,
about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,
about
100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg,
about
130 mg, about 135 mg, about 140 mg, about 145 mg or about 150 mg of
ravuconazole.
[0046] In one or more embodiments, the patient is administered about 50
mg to
about 150 mg of ravuconazole per day, such as about 50 mg, about 55 mg, about
60 mg,
about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,
about
95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg,
about
125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg or about 150 mg
of
ravuconazole per day.
[0047] In one or more embodiments, the patient is administered about 50
mg to
about 150 mg of ravuconazole per day, provided as fosravuconazole or a salt or
solvate
thereof In one or more embodiments, the effective amount is about 50 mg, about
55 mg,
7
CA 2986854 2017-11-28
about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg,
about
90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg,
about
120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg
or
about 150 mg of ravuconazole per day, provided as fosravuconazole or a salt or
solvate
thereof.
[0048] In one or more embodiments, the patient is administered about
62.6 mg to
about 187.7 mg of fosravuconazole per day, such as about 62.6 mg, about 68.8
mg, about
75.1 mg, about 81.3 mg, about 87.6 mg, about 93.8 mg, about 100.1 mg, about
106.3 mg,
about 112.6 mg, about 118.8 mg, about 125.1 mg, about 131.4 mg, about 137.6
mg, about
143.9 mg, about 150.1 mg, about 156.4 mg, about 162.6 mg, about 168.9 mg,
about 175.1
mg, about 181.4 mg or about 187.7 mg of fosravuconazole per day.
[0049] In one or more embodiments, the patient is administered about
62.6 mg to
about 187.7 mg of fosravuconazole per day, provided as fosravuconazole L-
lysine
ethanolate (1:1:1). In one or more embodiments, the effective amount is about
62.6 mg,
about 68.8 mg, about 75.1 mg, about 81.3 mg, about 87.6 mg, about 93.8 mg,
about 100.1
mg, about 106.3 mg, about 112.6 mg, about 118.8 mg, about 125.1 mg, about
131.4 mg,
about 137.6 mg, about 143.9 mg, about 150.1 mg, about 156.4 mg, about 162.6
mg, about
168.9 mg, about 175.1 mg, about 181.4 mg or about 187.7 mg of fosravuconazole
per
day, provided as fosravuconazole L-lysine ethanolate (1:1:1).
[0050] In one or more embodiments, the patient is administered about
84.5 mg to
about 253.5 mg of fosravuconazole L-lysine ethanolate (1:1:1) per day, such as
about
84.5 mg, about 93 mg, about 101.4 mg, about 109.9 mg, about 118.3 mg, about
126.8
mg, about 135.2 mg, about 143.7 mg, about 152.1 mg, about 160.6 mg, about 169
mg,
about 177.5 mg, about 185.9 mg, about 194.4 mg, about 202.8 mg, about 211.3
mg, about
219.7 mg, about 228.2 mg, about 236.6 mg, about 245.1 mg or about 253.5 mg of
fosravuconazole L-lysine ethanolate (1:1:1) per day.
[0051] In one or more embodiments, the ravuconazole, or salt, solvate or
prodrug
thereof (e.g. fosravuconazole), is administered for a certain treatment
period. In one or
more embodiments, the ravuconazole, or salt, solvate or prodrug thereof (e.g.
fosravuconazole), is administered for at least 2 weeks, such as at least about
2, 3, 4, 5, 6,
7, 8, 9, 10, 11 or 12 weeks or at least about 1, 2, 3, 4, 5 or 6 months.
8
CA 2986854 2017-11-28
Formulation and Administration
100521 The ravuconazole, or salt, solvate or prodrug thereof (e.g.
fosravuconazole) can be administered to the patient via any suitable route.
Exemplary
routes of administration include oral, nasal, buccal, sublingual, topical,
vaginal, rectal,
intravenous and/or parenteral. In one or more embodiments, the ravuconazole,
or salt,
solvate or prodrug thereof (e.g. fosravuconazole) is administered to a patient
orally.
100531 Exemplary oral formulations for ravuconazole, fosravuconazole and
related compounds are described in U.S. Patent App. Pub. Nos. 2010/0249426 and
2015/0118299.
100541 In one or more embodiments, the patient is administered a tablet
or
capsule comprising 125.1 mg of fosravuconazole, 33.4 mg L-lysine, and 10.5 mg
ethanol.
Such tablet or capsule can also include excipients known in the art.
EXAMPLES
Example 1 ¨ Treatment of Onychomycosis
100551 A Phase II clinical pharmacology study was conducted in subjects
with
onychomycosis of the toenail. The study investigated the pharmacokinetics,
efficacy and
safety of three different dosing regimens of fosravuconazole. Fosravuconazole
was
provided as fosravuconazole L-lysine ethanolate (1:1:1) in amounts equivalent
to 100 mg,
200 mg or 400 mg of ravuconazole. The three treatment groups were as follows:
a_ 100 mg group: fosravuconazole 100 mg (ravuconazole equivalent) once
daily for 12 weeks;
b. 200 mg group: fosravuconazole 200 mg (ravuconazole equivalent) once
daily for 7 days (then 21-day washout), 3 cycles
c. 400 mg group: fosravuconazole 400 mg (ravuconazole equivalent) once
daily for 7 days (then 21-day washout), 3 cycles
100561 The dosing regimens of administering 200 mg or 400 mg for 7 days
(21-
day washout), for 3 cycles, are referred to herein as 200 mg (pulse treatment)
or 400 mg
(pulse treatment), respectively.
9
Date recue/Date received 2023-03-10
Pharmacokinetic Endpoints
[0057] The pharmacokinetic endpoints were: (1) toenail ravuconazole
concentrations at Week 12 after study treatment initiation and (2) changes
over time in
plasma and nail ravuconazole concentrations.
Efficacy Endpoints
[0058] The efficacy endpoints were: (1) overall clinical efficacy; (2)
changes over
time in efficacy; (3) confirmation of elements of dermatophytes by direct
microscopy;
and (4) results of identification of dermatophytes by the polymerase chain
reaction (PCR)
method.
Safety Endpoints
[0059] The safety endpoints were: (1) adverse events (AEs); (2) adverse
reactions; and (3) laboratory tests.
Results
Disposition of Subjects
[0060] The disposition of subjects is shown in FIG. 1. Ravueonazole was
given to
94 subjects and 7 subjects were discontinued from the study during the study
treatment
period and 9 subjects during the observation period.
[0061] A total of 7 subjects were discontinued from the study during the
dosing
period. The reason for discontinuation was "The investigator or
subinvestigator
determined that the continuation of the study was inappropriate for other
reasons" in 3
subjects, "AST or ALT level was 2.5-fold or higher of the upper limit of
normal (ULN) at
the laboratory test institute" in 2 subjects, "subject was found to have not
met the
inclusion criteria or have met the exclusion criteria" in 1 subject, and
"continuation of the
study was judged inappropriate due to the onset of adverse events (AEs)" in 1
subject.
[0062] A total of 16 subjects were discontinued from the study during
the entire
study period. The most common reason for discontinuation was "Subject decided
to
prematurely terminate the study" in 7 subjects followed by "AST or ALT level
was 2.5-
fold or higher of the upper limit of normal (ULN) at the laboratory test
institute" in 3
CA 2986854 2017-11-28
subjects" and "The investigator or subinvestigator determined that the
continuation of the
study was inappropriate for other reasons" in 3 subjects, respectively, and
"subject was
found to have not met the inclusion criteria or have met the exclusion
criteria",
"Continuation of the study was judged inappropriate based on the course of the
primary
disease or complications" and "continuation of the study was judged
inappropriate due to
the onset of adverse events (AEs)" in 1 subject, respectively.
Pharmacokinetic Results
[0063] The arithmetic mean and geometric mean for plasma ravuconazole
concentrations are shown in FIGS. 2A and 2B, respectively. Similarly, the
arithmetic
mean and geometric mean for toenail ravuconazole concentrations are shown in
FIGS.
3A and 3B, respectively.
[0064] Both arithmetic mean and geometric mean for toenail ravuconazole
concentrations in the 200 mg (pulse treatment) group did not exceed MIC90 (60
ng/mL),
which were inferior to the 100 mg (once daily dose) and 400 mg (pulse
treatment) groups
in terms of pharmacokinetics.
[0065] Toenail ravuconazole concentrations in the 100 mg (once daily
dose)
group exceeded MIC90 in arithmetic mean at Week 8 and maintained at MIC90 or
higher
until Week 28. Similarly, geometric mean toenail ravuconazole concentrations
in the 100
mg (once daily dose) group exceeded MIC90 at Week 12 after the study treatment
initiation and maintained at MIC90 or higher until Week 24.
[0066] Toenail ravuconazole concentrations in the 400 mg (pulse
treatment)
group exceeded MIC90 in arithmetic mean at Week 8 after the study treatment
initiation
and maintained at MIC90 or higher until Week 24. Similarly, geometric mean
toenail
ravuconazole concentrations in the 400 mg (pulse treatment) group exceeded
MIC90 at
Week 12 after the study treatment initiation and maintained at MIC90 or higher
until
Week 24.
[0067] Toenail ravuconazole concentrations in the 100 mg (once daily
dose)
group maintained at MIC90 or higher for about 4 weeks longer than toenail
ravuconazole
concentrations in the 400 mg (pulse treatment) group.
11
CA 2986854 2017-11-28
[0068] Toenail ravuconazole concentrations in the 100 mg (once daily
dose)
group fluctuated at higher levels than toenail ravuconazole concentrations in
the 400 mg
(pulse treatment) group at Week 20 and onwards after the study treatment
initiation.
100691 Plasma ravuconazole concentrations in the 100 mg (once daily
dose)
group maintained at adjusted MIC90 (3.00 pg/mL) or higher throughout the study
treatment period.
Overall Clinical Efficacy
[0070] Overall clinical efficacy (cure rate and response rate) at Weeks
48 and 24
after the study treatment initiation for the efficacy analysis population (per
protocol set,
PPS) are presented in Tables 1 and 2 below. Overall clinical efficacy (cure
rate and
response rate) at Weeks 48 and 24 after the study treatment initiation for the
full analysis
set (FAS) are presented in Tables 3 and 4 below.
Table 1: Overall clinical evaluation at Week 48 after the study treatment
initiation
(efficacy analysis population: PPS)
Treatment Cured Markedly Improved Slightly Failed Total
Cure rate* and Response rate** and
Group improved improved 95% CI (%) 95% CI
(%)
100 mg 10 14 1 0 0 - 25 40.0(21.2, 61.3) 96.0
(79.7, 99.8)
200 mg 6 12 4 0 0 22 27.3(10.8,50.2) 81.8
(59.8, 94.8)
400 mg 11 12 4 0 0 27 40.7(22.4,61.2) 85.2
(66.3, 95.8)
Table 2: Overall clinical evaluation at Week 24 after the study treatment
initiation
(efficacy analysis population: PPS)
Treatment Cured Markedly Improved Slightly Failed Total
Cure rate* and Response rate** and
Group improved improved 95% CI (%) 95% CI
(%)
100 mg 0 19 6 0 0 25 0.0 (0.0, 13.7) 76.0
(54.9, 90.6)
200 mg 1 14 9 1 0 25 4.0 (0.2, 20.3) 60.0
(38.7, 78.8)
400 mg 0 17 11 3 0 31 0.0 (0.0, 11.2) 54.8
(36.1, 72.6)
12
CA 2986854 2017-11-28
Table 3: Overall clinical evaluation at Week 48 after the study treatment
initiation (full
analysis set: FAS)
Treatment Cured Markedly Improved Slightly Failed
Total Cure rate* and Response rate** and
Group improved improved 95% CI (%) 95% CI (%)
100mg 10 15 1 o o 26 38.5(20.3,59.4)
96.2 (80.4, 99.9)
200mg 8 13 4 o o 25 ' 32.0(15.0,53.5)
84.0 (64.0, 95.4)
400mg II 12 4 0 0 27 40.7(22.4,61.2)
85.2 (66.3, 95.8)
Table 4: Overall clinical evaluation at Week 24 after the study treatment
initiation (full
analysis set: FAS)
Treatment Cured Markedly Improved Slightly Failed
Total Cure rate* and Response rate** and
Group improved improved 95% CI (%) 95% CI (%)
100mg o 20 6 o o 26 0.0 (0.0, 13.2)
76.9 (56.4, 91.0)
200mg 1 16 10 1 0 - 28 3.6 (0.1, 18.3)
60.7 (40.6, 78.4)
400mg o 17 11 3 o 31 0.0 (0.0, 11.2)
54.8 (36.1, 72.6)
* Cure rate: Proportion of subjects evaluated as cured
** Response rate: Proportion of subjects evaluated as cured + markedly
improved
[0071] The criteria for assessment of overall clinical response are
provided in
Table 5 below:
Table 5: Criteria for assessment of Overall Clinical Response
Assessment of overall Percent change in the area
Direct microscopic result
clinical efficacy ratio for opacified nail plate
Cured No opacification Negative
Markedly improved >60% decrease Any result
Improved >30% and <60%decrease Any
result
Slightly improved <30% decrease Any result
,
Failed No change or increase Any result
13
CA 2986854 2017-11-28
[0072] The cure rate in the 200 mg (pulse treatment) group was lower
than that in
the other groups in any analysis population. The cure rates in the 100 mg
(once daily
dose) and 400 mg (pulse treatment) groups were comparable. However, the
response rate
(cured + markedly improved) in the 100 mg (once daily dose) group of 96.0% was
higher
than the response rate of 85.2% in the 400 mg (pulse treatment) group.
Changes Over Time in Efficacy
[0073] The changes over time in the ratio for the turbidity area of the
target nail
are shown in Table 6 below:
Table 6: Changes in the turbidity area ratio regarding the target nail (PPS,
%)
Treatment No. of Standard
Timing Mean Minimum Median Maximum
95% CI
Group Subjects Deviation
_
100 mg 28 76.9 13.8 53 75.5 100 (71.6,
82.2)
Start day
of
200 mg 27 76.4 14.7 47 74.0 100 (70.6,
82.1)
treatment _
400 mg 33 74.4 10.7 51 76.0 100 (70.7,
78.2)
100 mg 28 72.9 15.6 40 72.0 100 (66.9,
78.9)
Week 4 200 mg 27 69.6 16.9 44 70.0 100 (62.9,
76.2)
400 mg 33 66.9 13.0 , 46 67.0 92
(62.4, 71.5)
100 mg 27 65.9 17.5 33 67.0 100 (59.0,
72.8)
_
Week 8 200 mg 26 59.8 20.2 26 58.5 100 (51.7,
67.9)
400 mg 33 57.4 17.0 26 59.0 87 (51.4,
63.4)
100 mg 27 55.6 13.9 34 56.0 84 (50.2,
61.0)
_
Week 12 200 mg 25 51.4 20.7 9 49.0 89 (42.9,
59.9)
400 mg 31 49.3 17.0 19 52.0 84 (43.1,
55.4)
100 mg 27 44.2 13.2 _ 19 46.0 70
(39.1, 49.4)
Week 16 200 mg 25 45.0 19.3 10 45.0 84 (37.1,
52.9)
400 mg 31 40.6 17.2 13 41.0 78 (34.4,
46.9)
_
100 mg 25 34.6 11.5 10 36.0 57 (29.9,
39.3)
Week 20 200 mg 25 35.8 19.0 0 34.0 74 (28.0,
43.6)
400 mg 31 31.1 15.2 8 29.0 73 (25.6,
36.7)
100 mg 25 26.5 10.5 10 25.0 57 (22.2,
30.7)
Week 24 200 mg 25 27.9 18.5 0 25.0 71 (20.3,
35.5)
400 mg 31 25.7 18.0 5 20.0 79 (19.2,
32.3)
100 mg 25 19.4 9.0 3 18.0 44 (15.7,
23.1)
Week 28 200 mg 25 23.3 19.0 0 18.0 75 (15.5,
31.1)
400 mg 27 18.3 13.3 0 16.0 46 (13.1,
23.5)
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CA 2986854 2017-11-28
100 mg 25 14.4 8.4 0 15.0 34 (10.9,
17.8)
Week 32 200 mg 25 20.0 18.8 0 9.0 72 (12.3,
27.7)
400 mg 28 14.9 14.1 0 12.0 45 (9.5,
20.3)
100 mg 25 12.0 9.3 0 9.0 33 (8.2,
15.8)
Week 36 200 mg 24 18.2 18.5 0 11.5 62 ,
(10.4,25.9)
400 mg 27 13.5 13.3 0 9.0 42 (8.3,
18.7)
100 mg 25 9.6 9.5 0 12.0 36 (5.7,
13.5)
Week 40 200 mg 23 16.0 15.6 0 10.0 47
(9.3,22.8)
400 mg 27 11.8 13.6 0 6.0 49 (6.5,
17.1)
100 mg 25 8.6 9.6 0 8.0 39 (4.7,
12.5)
Week 44 200 mg 22 13.5 16.0 0 5.0 44
(6.4,20.6)
400 mg 27 11.9 14.6 0 6.0 45 (6.2,
17.6)
100 mg 25 9.3 12.4 0 6.0 51 (4.2,
14.4)
Week 48 200 mg 22 14.6 15.7 0 9.0 46
(7.7,21.5)
400 mg 27 12.7 14.1 0 8.0 45
(6.9,18.4)
[0074] As can be seen from Table 6, the mean ratio for the turbidity
area of the
target nail (Week 40 and onwards after the study treatment initiation) in the
100 mg (once
daily dose) group was lower than that in the 200 mg (pulse treatment) of the
400 mg
(pulse treatment) groups.
[0075] The clinical cure rate for the target nail at Week 48 after the
study
treatment initiation is shown in Table 7 below:
Table 7: Clinical cure rate for the target nail at Week 48 after the study
treatment
initiation (PPS, %)
Treatment Clinical cure (no Remaining of Total Clinical
cure rate
group visual sign of the visual sign and 95%
CI(%)
infection) of infection
,
100 mg group 11 14 25
44.0(24.5,65.0)
200 mg group 7 _ 15 25
31.8(13.9,54.8)
300 mg group 11 16 27
40.7(22.4,61.2)
[0076] While relapse/reinfection occurred in 4 subjects in the 200 mg
(pulse
treatment) group and 1 subject in the 400 mg group, there was no subject in.
the 100 mg
(once daily dose) group who had relapse/reinfection.
CA 2986854 2017-11-28
[0077] The response rates (cured + markedly improved) in the 100 mg
(once daily
dose) group (Weeks 24 and 48 after the study treatment initiation) were higher
than those
in the 400 mg (pulse treatment) group.
Mycological Cure (Results of search for fungal elements by direct microscopy)
[0078] Presence or absence of fungal elements by direct microscopy at
the each
evaluation timing is shown in Table 8. At screening, fungal elements were
found by
direct microscopy in all treatment groups.
Table 8: Presence or absence of fungal elements by direct microscopy (PPS)
Observation timing Presence or 100 mg 200 mg 400 mg
absence of fungal group group group
elements
At screening Absence (%) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)
Presence (%) 28 (100.0) 27 (100.0) 33
(100.0)
Week 12 after the study Absence (%) 9 (33.3) 13 (50.0) 6 (19.4)
treatment initiation Presence (%) 18 (16.7) 13 (50.0) 25
(80.6)
Week 24 after the study Absence (%) 12 (48.0) 12 (48.0) 14
(45.2)
treatment initiation Presence (%) 13 (52.0) 13 (52.0) 17
(54.8)
Week 48 after the study Absence (%) 18 (72.0) 8 (36.4) 17
(63.0)
treatment initiation Presence (%) 7 (28.0) 14 (63.6) 10
(37.0)
[0079] As can be seen from Table 8, negative rate of fungal elements at
Week 48
after the study treatment initiation was highest in the 100 mg (once daily
dose) group
followed by the 400 mg (pulse treatment) group and 200 mg (pulse treatment)
group.
[0080] Disappearance rate of Trichophyton rubruni, which was frequently
identified at patient screening, was highest in the 100 mg (once daily dose)
group at
57.1%, followed by 52.1% for the 400 mg (pulse treatment) group and 36.8% for
the 200
mg (pulse treatment) group.
[0081] Table 9 below shows the cure rate for various identified species:
16
CA 2986854 2017-11-28
Table 9: Overall clinical evaluation at Week 48 after the study
Species Treatment Cured Markedly Improved Slightly
Failed Total Cure rate*
Group improved improved and 95%
CI
(0/0)
100 mg 10 10 1 0 0 21 47.6
(25.8,
70.2)
Trichophyton 200 mg 6 11 2 0 0 19 31.6
(12.6,
rubrum 56.5)
400 mg 11 10 4 0 0 25 44.0
(24.5,
65.0)
100 mg 0 4 0 0 0 4 0.0 (
0.0,
60.2)
Trichophyton 200 mg 0 0 2 0 0 2 0.0 (
0.0,
mentagrophytes 84.1)
400 mg 0 2 0 0 o 2 0.0 (
0.0,
84.1)
100 mg - - - - - - - ( - , - )
Trichophyton 200 mg 0 1 0 o 0 1 0.0 (0.0, 97.5)
species
400 mg - - - - - ( - , - )
* Cure rate: Proportion of subjects evaluated as cured
[0082] As can be seen from Table 9, the cure rate of subjects infected
with
Trichophyton rubrum was higher in the 100 mg (pulse treatment) group than in
the 400
mg (pulse treatment) group or the 200 mg (pulse treatment) group.
Safety Results
[0083] Patients treated with fosravuconazole were well-tolerated in all
dosing
groups.
[0084] The incidence of AEs was 89.7% in the 100 mg (once daily does)
group,
64.5% in the 200 mg (pulse treatment) group, and 85.3% in the 400 mg (pulse
treatment)
group. There was no significant difference in AEs between the 100 mg (once
daily dose)
and 400 mg (pulse treatment) groups.
[0085] While tinea pedis occurred in 2 subjects in the 400 mg (pulse
treatment)
group, there was no new AE derived from fungal infection in the 100 mg (once
daily
dose) group).
[0086] No death or other serious AEs occurred in any of the treatment
groups.
AEs resulted in the discontinuation of the study treatment in 1 subject in the
100 mg
(once daily dose) group and 4 subjects in the 400 mg (pulse treatment) group.
Of the 4
17
CA 2986854 2017-11-28
subjects who discontinued the study treatment in the 400 mg (pulse treatment)
group, the
AEs were assessed as not related to the study drug in 2 subjects.
[0087] Moderate AEs occurred in 3 subjects in the 100 mg (once daily
dose)
group, 12 subjects in the 200 mg (pulse treatment) group, and 12 subjects in
the 400 mg
(pulse treatment) group. Thus, the number of moderate AEs was lowed in the 100
mg
(once daily dose) group than either of the pulse treatment groups (200 mg or
400 mg).
[0088] As AEs with high incidences, y-glutamyl transferase increased and
liver
function test abnormal were observed. In the detailed degree of changes in
liver function
test values, AST or ALT elevated to Grade 2 after the start of study treatment
in 4
subjects in total; 2 subjects in the 100 mg (once daily dose) group, 1 subject
in the 200
mg (pulse treatment) group, and 1 subject in the 400 mg (pulse treatment)
group (Table
3.2-26, Table 3.2-27). Of the 4 subjects, AST or ALT increased after the
completion of
the study treatment in 2 subjects and either recovered or abated in the liver
function test
performed about 2 weeks later. Grade 2 AST or ALT increased recovered by
discontinuing the study treatment in the other 2 subjects in the liver
function test
performed about 6 or 7 weeks later. In these 4 subjects, no other AEs
suggesting liver
disorder occurred.
Conclusions
[0089] The 100 mg (once daily dose) had the best overall results. The
Week 48
cure rate for the 100 mg (once daily dose) group of 40.0% was comparable to
the 400 mg
(pulse treatment) group of 40.7%, and both were higher than the 27.3% cure
rate for the
200 mg (pulse treatment) group. The 100 mg (once daily dose) group had a
higher
response rate at Week 48 of 96.0% than either the 200 mg (pulse treatment)
group or the
400 mg (pulse treatment) groups, which were 81.8% and 85.2%, respectively.
[0090] The Week 48 mycological cure rate of 72.0% in the 100 mg (once
daily
dose) group was higher than either the 200 mg (pulse treatment) group or the
400 mg
(pulse treatment) group, which were 36.4% and 63.0%, respectively. Moreover,
the
disappearance rate of fungal elements (Trichophyton rubrum) determined by a
PCR method
at Week 48 was 57.1% in the 100 mg (once daily dose) group, versus 52.0% in
the 400 mg
(pulse treatment) group and 36.8% in the 200 mg (pulse treatment) group.
18
CA 2986854 2017-11-28
100911 Reference throughout this specification to "one embodiment,"
"certain
embodiments," "various embodiments," "one or more embodiments" or "an
embodiment"
means that a particular feature, structure, material, or characteristic
described in
connection with the embodiment is included in at least one embodiment of the
disclosure.
Thus, the appearances of the phrases such as "in one or more embodiments," "in
certain
embodiments," "in various embodiments," "in one embodiment" or "in an
embodiment"
in various places throughout this specification are not necessarily referring
to the same
embodiment of the disclosure. Furthermore, the particular features,
structures, materials,
or characteristics may be combined in any suitable manner in one or more
embodiments.
100921 Although the disclosure herein provided a description with
reference to
particular embodiments, it is to be understood that these embodiments are
merely
illustrative of the principles and applications of the disclosure. It will be
apparent to those
skilled in the art that various modifications and variations can be made to
the present
disclosure without departing from the spirit and scope thereof.
19
Date recue/Date received 2023-03-10
