Note: Descriptions are shown in the official language in which they were submitted.
WO 01/32127 CA 02388333 2002-05-02 pCT/US00/30113
Method and Compositions for Treating Pulmonary Diseases
Area of the Invention
This invention relates compositions and methods for preventing or reducing the
onset of symptoms of pulmonary diseases, or treating or reducing the severity
of pulmonary
diseases. In particular it relates to compositions and methods for treating
pulmonary
diseases mediated by phosphodiesterase 4 (PDE4) by administering a PDE4
inhibitor with
an anti-inflammatory corticosteroid.
Background of the Invention
Identification of novel therapeutic agents for treating pulmonary diseases is
made
difficult by the fact that multiple mediators are responsible for the
development of the
disease. Thus, it seems unlikely that eliminating the effects of a single
mediator could have
a substantial effect on all three components of chronic asthma. An alternative
to the
"mediator approach" is to regulate the activity of the cells responsible for
the
pathophysiology of the disease.
One such way is by elevating levels of cAMP (adenosine cyclic 3',5'-
monophosphate). Cyclic AMP has been shown to be a second messenger mediating
the
biologic responses to a wide range of hormones, neurotransmitters and drugs;
[Krebs
Endocrinology Proceedings of the 4th International Congress Excerpta Medica,
17-29,
1973]. When the appropriate agonist binds to specific cell surface receptors,
adenylate
cyclase is activated, which converts Mg+2-ATP to cAMP at an accelerated rate.
Cyclic AMP modulates the activity of most, if not all, of the cells that
contribute to the
pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP
would
produce beneficial effects including: 1 ) airway smooth muscle relaxation, 2)
inhibition of
mast cell mediator release, 3) suppression of neutrophil degranulation, 4)
inhibition of
basophil degranulation, and 5) inhibition of monocyte and macrophage
activation. Hence,
compounds that activate adenylate cyclase or inhibit phosphodiesterase should
be effective
in suppressing the inappropriate activation of airway smooth muscle and a wide
variety of
inflammatory cells. The principal cellular mechanism for the inactivation of
cAMP is
hydrolysis of the 3'-phosphodiester bond by one or more of a family of
isozymes referred to
as cyclic nucleotide phosphodiesterases (PDEs).
It has been shown that a distinct cyclic nucleotide phosphodiesterase (PDE)
isozyme, PDE4, is responsible for cAMP breakdown in airway smooth muscle and
inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets
for Novel
Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical
Services Ltd.,
1989]. Research indicates that inhibition of this enzyme not only produces
airway smooth
muscle relaxation, but also suppresses degranulation of mast cells, basophils
and
neutrophils along with inhibiting the activation of monocytes and neutrophils.
Moreover,
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WO 01/32127 CA 02388333 2002-05-02 pCT~S00/30113
the beneficial effects of PDE 4 inhibitors are markedly potentiated when
adenylate cyclase
activity of target cells is elevated by appropriate hormones or autocoids, as
would be the
case in vivo. Thus PDE 4 inhibitors would be ef 'we in the lung, where levels
of
prostaglandin EZ and prostacyclin (activators of adenylate cyclase) are
elevated. Such
S compounds would offer a unique approach toward the pharmacotherapy of
bronchial
asthma and possess significant therapeutic advantages over agents currently on
the market.
In addition, it could be useful to combine therapies in light of the fact that
the
etiology of many pulmonary diseases involves multiple mediators. In this
invention there is
presented the combination of a PDE 4 inhibitor and an anti-inflammatory
corticosteroid,
particularly one delivered by inhalation, for treating pulmonary diseases.
This combination
is particularly useful for treating chronic obstructive pulmonary disease
(COPD) or asthma.
Summary of the Invention
In a first aspect this invention relates to a method for treating a pulmonary
disease
in a mammal by administering to a patient in need thereof an effective amount
of a PDE 4-
specific inhibitor and an effective amount of a steroidal anti-inflammatory
agent wherein
the drugs are administered concomitantly together or separately and
sequentially where the
sequential administration is close in time or remote in time.
In a second aspect this invention relates to a composition for treating a
pulmonary
disease in a mammal comprising an effective amount of a PDE4-specific
inhibitor, an
effective amount of a steroidal anti-inflammatory agent and a pharmaceutically
acceptable
excipient.
Detailed Description of the Invention
The combination therapy contemplated by this invention comprises administering
a
PDE4 inhibitor with a steroidal anti-inflammatory agent to prevent onset of a
pulmonary
disease event or to treat an existing condition. The compounds may be
administered
together in a single dosage form. Or they may be administered as two different
formulations which may be the same or different. To illustrate, both drugs may
be provided
separately as oral formulations, or one may be an oral preparation and the
other as an
inhalant, or both may be provided in an inhaled dose form. They may be
administered at the
same time. Or they may be administered either close in time or remotely, such
as where one
drug is administered in the morning and the second drug is administered in the
evening.
The combination may be used prophylactically or after the onset of symptoms.
In
some instances the combinations) may be used to prevent the progression of a
pulmonary
disease or to arrest the decline of a function, such as lung function.
The PDE4-specific inhibitor useful in this invention may be any compound that
is
known to inhibit the PDE4 enzyme or which is discovered to act in as PDE4
inhibitor, and
which are only PDE4 inhibitors, not compounds which inhibit other members of
the PDE
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WO 01/32127 PCT/US00/30113
family as well as PDE4. Generally it is preferred to use a PDE4 antagonists
which has an
IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic
form which
binds rolipram with a high affinity divided by the IC50 for the form which
binds rolipram
with a low affinity.
PDE inhibitors used in treating inflammation and as bronchodilators, drugs
like
theophylline and pentoxyfyllin, inhibit PDE isozymes indiscriminately in all
tissues. These
compounds exhibit side effects, apparently because they non-selectively
inhibit all 5 PDE
isozyme classes in all tissues. The targeted disease state may be effectively
treated by such
compounds, but unwanted secondary effects may be exhibited which, if they
could be
avoided or minimized, would increase the overall therapeutic effect of this
approach to
treating certain disease states. For example, clinical studies with the
selective PDE 4
inhibitor rolipram, which was being developed as an antidepressant, indicate
it has
psychotropic activity and produces gastrointestinal effects, e.g., pyrosis,
nausea and emesis.
For purposes of this disclosure, the CAMP catalytic site which binds R and S
rolipram with a low affinity is denominated the "low affinity" binding site
(LPDE 4) and
the other form of this catalytic site which binds rolipram with a high
affinity is denominated
the "high affinity" binding site (HPDE 4). This term "HPDE4" should not be
confused with
the term "hPDE4" which is used to denote human PDE4.
Initial experiments were conducted to establish and validate a [3H]-rolipram
binding assay. Details of this work are given in Example 1 below.
To determine whether both the high affinity binding activity and the low
affinity
binding activity resided in the same gene product, yeast were transformed by
known
methods and the expression of recombinant PDE 4 was followed over a 6 hour
fermentation
period. Western blot analysis using an antibody directed against PDE 4
indicated that the
amount of PDE 4 expressed increased with time, reaching a maximum after 3 hour
of
growth. In addition, greater than 90% of the immunoreactive product was in the
high speed
(100,000 x g) supernatant of yeast lysates. [3H]R-(-)-Rolipram binding and PDE
activity
were monitored along with protein expression. PDE 4 activity was co-expressed
with
rolipram binding activity, indicating that both functions exist on the same
gene product.
Similar to results with the Western plot analysis, greater than 85% of the
rolipram-
inhibitable PDE activity and [3H]-rolipram binding activity was found to be
present in the
yeast supernatant fraction.
Overall, most of the recombinant PDE 4 expressed in this system exists as LPDE
4
and only a small fraction as HPDE 4. Consequently, inhibition of recombinant
PDE 4
catalytic activity primarily reflects the actions of compounds at LPDE 4.
Inhibition of PDE
4 catalytic activity can thus be used as an index of the potency of compounds
at LPDE 4.
The potency of compounds at HPDE 4 can be assessed by examining their ability
to
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WO 01/32127 PCT/US00/30113
compete for [3H]R-rolipram. To develop SARs for both the low affinity and high
affinity
rolipram binding sites, the potencies of selected compounds were determined in
two assay
systems. Results from experiments using standard compounds were tabulated. As
expected, certain compounds were clearly more potent in competing with [3H]-
rolipram at
the site for which rolipram demonstrated high affinity binding as compared
with the other
site, the one at which rolipram is a low affinity binder. SAR correlation
between high
affinity binding and low affinity binding was poor and it was concluded that
the SAR for
inhibition of high affinity [3H]-rolipram binding was distinct from the SAR
for binding to
the low affinity rolipram binding site.
It is now known that there are at least two binding forms on human monocyte
recombinant PDE 4 (hPDE 4) with which inhibitors interact. One explanation for
these
observations is that hPDE 4 exists in two distinct forms. One binds the likes
of rolipram
and denbufylline with a high affinity while the other binds these compounds
with a low
affinity. The preferred PDE4 inhibitors of use in this invention will be those
compounds
which have a salutary therapeutic ratio, i.e., compounds which preferentially
inhibit cAMP
catalytic activity where the enzyme is in the form that binds rolipram with a
low affinity,
thereby reducing the side effects which apparently are linked to inhibiting
the form which
binds rolipram with a high affinity. Another way to state this is that the
preferred
compounds will have an IC50 ratio of about 0.1 or greater as regards the IC50
for the PDE
4 catalytic form which binds rolipram with a high affinity divided by the IC50
for the form
which binds rolipram with a low affinity.
A further refinement of this standard is that of one wherein the PDE4
inhibitor has
an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC50
value for competing
with the binding of 1nM of [3H]R-rolipram to a form of PDE 4 which binds
rolipram with a
high affinity over the IC50 value for inhibiting the PDE4 catalytic activity
of a form which
binds rolipram with a low affinity using 1 microM[3H]-cAMP as the substrate. A
further
review explanation with of this test can be found in co-pending U.S.
application 08/456274
filed 31 May 1995, the text of which is incorporated herein by reference to
the extent that
text is necessary to the practice of this invention.
Examples of useful PDE4 inhibitors are:
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-
pyrrolidone;
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-
pyrrolidone,
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N2-cyano-S-methyl-
isothioureido]benzyl)-2-pyrrolidone,
cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid];
ci s-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]
;
(R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-
ylidene]acetate;
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WO 01/32127 PCT/US00/30113
(S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-
ylidene]acetate,
Most preferred are those PDE 4 inhibitors which have an IC50 ratio of greater
than
0.5, and particularly those compounds having a ratio of greater than 1Ø
Preferred
compounds are cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-
carboxylic
acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-
difluoromethoxyphenyl)cyclohexan-1-one, and is-[4-cyano-4-(3-
cyclopropylmethoxy-4-
difluoromethoxyphenyl)cyclohexan-1-of]; these are examples of compounds which
bind
preferentially to the low affinity binding site and which have an IC50 ratio
of 0.1 or greater.
Compounds set out in U.S. patent 5,552,438 issued 03 September, 1996. This
patent and the compounds it discloses are incorporated herein in full by
reference. The
compound of particular interest, which is disclosed in U.S. patent 5,552,438,
is cis-4-cyano-
4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid and its
salts, esters,
pro-drugs or physical forms.
AWD-12-281 from Astra (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept
6-10, Edinburgh) 1998, Abst P.98); a 9-benzyladenine derivative nominated NCS-
613
(INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4
inhibitor identified as CI-1018 (PD-168787; Parke-Davis/Warner-Lambert); a
benzodioxole
derivative Kyowa Hakko disclosed in WO 9916766; V-11294A from Napp (Landells,
L.J.
et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998,
12(Suppl.
28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a
pthalazinone (WO
9947505) from Byk-Gulden; or a compound identified as T-440 (Tanabe Seiyaku;
Fuji, K.
et al. J Pharmacol Exp Ther,1998, 284( 1 ): 162). Any one or all of these
compounds may or
could benefit from the process described herein.
The several specific compounds set out above which do not have a generic or
trade
name can be made by the processed described in co-pending U.S. patent
applications USSN
862,083 filed 30 October 1992; USSN 862, 111 filed 30 October 1992; USSN
862,030 filed
October 1992; and USSN 862,114 filed 30 October 1992 or their progeny or U.S.
patents) claiming priority from one or more of these applications. Each of
these
applications or related patents is incorporated herein by reference in full as
if set out in this
30 document.
The steroid agents useful in this invention are oral and inhaled
corticosteroids and
their pro-drugs which have anti-inflammatory activity. Examples of these
steroids are
methyl prednisolone, prednisone, dexamethasone, fluticasone, beclomethasone,
budesonide,
flunisolide, mometasone furoate, and triamcinolone acetonide. Methyl
prednisolone and
prednisone are oral and injectable forms of anti-inflammatory corticosteroids;
they are
available from numerous branded and generic pharmaceutical companies.
Beclomethasone
dipropionate is sold as an aerosol for inhalation under the names Beconase~
and Beconase
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WO 01/32127 PCT/US00/30113
AQ~ by Glaxo Wellcome. Fluticasone propionate is sold under the name Flonase~
by
Glaxo Wellcome as well. Triamcinolone acetonide is sold by Rhone-Poulenc Roher
under
the name Nasacort ~ as a nasal spray and aerosol. Flunisolide is sold as a
nasal solution
under the name Nasalide~ and Nasarel TM by Roche Laboratories. Dexamethasone
is sold
as the sodium phosphate salt by Medeva Pharmaceuticals, Inc. under the name
DexacortTM
Phosphate. Mometasone furoate is sold as the monohydrate as a nasal
preparation by
Schering Corp under the name Nasonex~. Budesonide is yet another inhaled
corticosteriod
used in treating pulmonary diseases. It is market by Astra Pharmaceuticals,
L.P. as a
powder in a turbohaler device under the name Pulmicort Turbohaler~. All of
these drugs
and nasal preparations or oral or injectable formulations can be found in the
1999 edition of
the Physicians' Desk Reference~ (PDR), published by Medical Economics
Corporation,
Inc, of New Jersey, USA and is available on the Internet at
http://www.tomescps.com/fraMain.asp?Mnu=0 and linked pages. Additional
corticosteroids
now under development and which could be used in this invention are set out in
Table I.
Table I
Inhaled Corticosteroids
Dru Com an Indication
mometasone furoateSchering-Plough asthma
SAR
rofle onide AstraZeneca asthma
ciclesonide B k-Gulden/ Recordatiasthma
butixocort ro Warner-Lambert/3M asthma/rhinitis
innate
RPR-106541 Rhone-Poulenc Rorer asthma
ST-126 SSP/Torii I asthma
A preferred combination therapy is that of one or more of dexamethasone,
fluticasone, beclomethasone, budesonide, flunisolide, mometasone furoate, and
triamcinolone acetonide administered with cis 4-cyano-4-(3-cyclopentyloxy-4-
methoxyphenyl)cyclohexan-I-carboxylic acid, cilomalast (Ariflo~). A preferred
therapy is
concomitant administration of the steroid as an inhalant and the acid in an
oral dose form,
wherein each drug is administered once or twice a day. In regards to the acid,
a controlled-
release oral tablet is most preferred.
It is contemplated that both active agents would be administered at the same
time,
or very close in time. Alternatively, one drug could be taken in the morning
and one later in
the day. Or in another scenario, one drug could be taken twice daily and the
other once
daily, either at the same time as one of the twice-a-day dosing occurred, or
separately.
Preferably both drugs would be taken together at the same time.
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The present compounds and pharmaceutically acceptable salts which are active
when given orally can be formulated as syrups, tablets, capsules, controlled-
release
preparation or lozenges. A syrup formulation will generally consist of a
suspension or
solution of the compound or salt in a liquid carrier for example, ethanol,
peanut oil. olive
oil, glycerin or water with a flavoring or coloring agent. Where the
composition is in the
form of a tablet, any pharmaceutical carrier routinely used for preparing
solid formulations
may be used. Examples of such carriers include magnesium stearate, terra alba,
talc,
gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the
composition is in the
form of a capsule, any routine encapsulation is suitable, for example using
the
aforementioned carriers in a hard gelatin capsule shell. Where the composition
is in the
form of a soft gelatin shell capsule any pharmaceutical carrier routinely used
for preparing
dispersions or suspensions may be considered, for example aqueous gums,
celluloses,
silicates or oils, and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of a
compound
or salt in a sterile aqueous or non-aqueous carrier optionally containing a
parenterally
acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone,
lecithin, arachis oil
or sesame oil.
Typical compositions for inhalation are in the form of a solution, suspension
or
emulsion that may be administered as a dry powder or in the form of an aerosol
using a
conventional propellant such as fluroinated hydrocarbons such as
trichlorofluoromethane.
Preferably the composition for the PDE4 inhibitors is a unit dosage form such
as a
tablet or capsule. For the steroids a metered aerosol dose, metered dry powder
inhaler or
nasal spray is preferred
The active ingredient may be administered from 1 to 6 times a day, sufficient
to
exhibit the desired activity. Preferably, the active ingredient is
administered about once or
twice a day, more preferably twice a day.
The present compounds are useful for the treatment of exercise-induced asthma
(EIA), pollution-induced asthma (PIA) and cold-induced asthma (CIA), both as
chronic
conditions as well as intermittently, in anticipation of the stimulus in
question. Preferably,
the present compounds are used for long-term therapy.
As for the amount of drug administered, it is believed that for the PDE4
inhibitors
will be administered in an amount of between 1 and 200 micrograms per day per
adult
human. Steroids can be administered in conformity with approved labeling.
CA 02388333 2002-05-02
WO 01/32127 PCT/US00/30113
Example 1 -- Phosphodiesterase and Rolipram Binding Assays
Example 1A
Isolated human monocyte PDE 4 and hrPDE (human recombinant PDE4) was
determined to exist primarily in the low affinity form. Hence, the activity of
test
compounds against the low affinity form of PDE 4 can be assessed using
standard assays
for PDE 4 catalytic activity employing 1 microM [3H]CAMP as a substrate
(Torphy et al., J.
ofBiol. Chem., Vol. 267, No. 3 pp1798-1804, 1992).
Rat brain high speed supernatants were used as a source of protein and both
enantionmers of [3H]-rolipram were prepared to a specific activity of 25.6
Ci/mmol.
Standard assay conditions were modified from the published procedure to be
identical to
the PDE assay conditions, except for the last of the cAMP: SOmM Tris HCl (pH
7.5), 5
mM MgCl2, 50 microM 5'-AMP and 1 nM of [3H]-rolipram (Torphy et al., J.
ofBiol.
Chem., Vol. 267, No. 3 pp1798-1804, 1992). The assay was run for 1 hour at
30° C. The
reaction was terminated and bound ligand was separated from free ligand using
a Brandel
cell harvester. Competition for the high affinity binding site was assessed
under conditions
that were identical to those used for measuring low affinity PDE activity,
expect that [3H]-
cAMP was not present.
Example 1 B
~7esasuremcnt of 3'l3osG3hocli,<~stera'roe :tctivltv
PL31::: .ICtivity w 1;lasas-;:El usilt~~ a [31-1]L:1~(T' :~P:~ or [-'1-
tJ~(s~tl' ~l':1 iran-rrl
<ias ay as Eieacribci lay 11:e supplier (all~Il~rsh<ll~~ L..it~L Wierlces).
The r,mtiE)rls very
cE>IIEIIZCteEI iI~ ~~f~-w-elI p1 Its at roorrl telua~eratut-e. i1~ t7.1 ml E'-
( Ivaet-ioo but't~r cont,.lir1i1~4r
i~Inai cc~r -- ~tr<:t,iE)n~>: ~u Itt'~1 TI-i~-LIt-I. p11 ?.~~. ~. ~ I~r~-i
iI~=C~l_'_ ,.~ tIW1 l~;C;T.1,
G- l l;~.r~tl' i)r ['s-i,l et.s'~II' c_;;llzr<wirrl ply _'t~tit.~
Eipl~ui~377<>1 t, el~rv he ill:ii varli)t;~
E:E?Tli~l~tl'3t(u171 i)~ tI2E; II7~I;iOltO"s, lilt I»,3l ETA-;IS fl~~tYlr: ti
~C1 X71C)iErE~ it)I' ~ !II't~~'Ilt U'<Is
L;.,.x.I~3I?- E~ I>1' I ti:lll';' _',~? 1:! f);' lf;r. \"irltl:i;~If.~."te'
!?i;?<1",!'I tilE' ;)1 C~'v'.ilt c ~. Z11:!u iti~~fa~,
1 ilc ~3~zlt~ , ,~'~I c ~~t<IiCBIt r3Ej Fl~~olV'iCe ~U SalIii' :?t TE),'~I71
1'~Lr3~WI;I(;:L;f1 te?1' ~() 1'37111. ~i<'lt~ti?!t:~7v~a~
r3I't1E~13CL 3QI:::;ltliul :'vF:S <WCC:55E:Ej ~!S' W ttlt;~l~ltlt?Il
4t~~uEtI'()r?ic'"c~~',
~:T11~1~-nolilararr~ los~ci'sa~~ a'fsa~.
The [3H]R-rolipram binding assay was performed by modification of the method
of
Schneider and co-workers. see ~ictril;:r:o. :::... ~l~L E~ 1'i1~.l~:lEac<)
:~;r;._ G <51. 2. .~,~.1~3-
i 3 E)~j! i al ~i \:lel l,ll~~t al., vli)1 fiarzv:::r~cE~?.. v x;:. .~~~. !
(i~?_ ' ; ( 3 f3f> 1 t. R-Rolipram binds to
the catalytic site of PDE4 see Torphy et al., Mol. Pharmacol., Vol. 39, pp.
376-384 ( 1991 ).
Consequently, competition for [3H]R-rolipram binding provides an independent
confirmation of the PDE4 inhibitor potencies of unlabeled competitors. The
assay was
performed at 30°C for 1 hr in 0.5 u1 buffer containing (final
concentrations): 50 mM Tris-
HCI, pH 7.5, 5 mM MgCl2, 0.05% bovine serum albumin, 2 nM ['H]R-rolipram (5.7
x 104
_g_
CA 02388333 2002-05-02
WO 01/32127 PCT/US00/30113
dpm/pmol) and various concentrations of non-radiolabeled inhibitors. The
reaction was
stopped by the addition of 2.5 ml of ice-cold reaction buffer (without ['H]-R-
rolipram) and
rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters
that had
been soaked in 0.3% polyethylenimine. The filters were washed with an
additional 7.5-ml
of cold buffer, dried, and counted via liquid scintillation spectrometry.
Example 2
Cilomalast/Low dose Inhaled Corticosteroid (ICS), Dose-ranging Study
Study Design:
~ This was a phase IIB, randomised, placebo-controlled, dose-ranging study
with a one-week single-blind placebo run-in, a 6-week double-blind
treatment phase and a one-week follow-up phase in patients with
mild/moderate asthma.
~ Study population: Male or female patients aged between 18 and 70 years,
with mild to moderate asthma, who were not adequately controlled on low
doses of inhaled corticosteroids (no greater than 500 mcg beclomethasone
dipropionate/day or equivalent) were eligible. Patients were required to have
a screening FEV 1 of >_ 50% and <_ 80% predicted for height, age, sex and
race and a 12% or greater reversibility after beta-2 agonist administration.
Patients had to have a summary symptom score of 6 or more on 4 out of
7 days preceding the baseline visit to be randomised. The sample size was
300 evaluable patients.
~ cilomalast was dosed at 5 mg, 10 mg 15 mg twice daily for 6 weeks.
~ Subjects were on a median of 500 mcg of beclomethasone equivalent although
the
mean dose of ICS was 652 mcg.
~ Primary endpoint: change from baseline to endpoint in trough clinic
expiratory
volume in 1 second (FEV 1 ), changes in clinic FEV 1 every week and over a 4
hour period following first dose of double-blind medication.
~ Secondary endpoints: use of rescue medicines and overnight symptoms.
~ Tertiarty endpoints: clinic forced vital capacity (FVC), clinic peak
expiratory
flow rate (PEFR), forced expiratory flow at 25-75% (FEF25-75) and 75%
(FEF75), domiciliary PEFR variability, domiciliary PEER, summary symptom
scores.
Evaluation Criteria
The primary efficacy measure was defined as the change from baseline to
endpoint in trough clinic forced expiratory volume in 1 second (FEV 1 ).
Changes in
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WO 01/32127 PCT/US00/30113
clinic FEV 1 were also analysed at each week of the double-blind treatment
phase
and over a 4-hour period immediately following the first dose of double-blind
medication. Secondary efficacy variables were use of inhaled/nebulised beta-2
agonist and overnight asthma symptoms. Tertiary efficacy variables were forced
vital
capacity (FVC), clinic peak expiratory flow rate (PEFR), forced expiratory
flow at
25-75% (FEF25-75) and 75% (FEF75), domiciliary PEFR variability, domiciliary
PEFR (morning and evening), summary symptom score (a composite score of
overnight, morning and overall daytime asthma), morning asthma, overall
daytime
asthma, inhaled corticosteroid use, cough, wheeze, breathlessness/chest
tightness,
asthma exacerbation rates and global assessments by the physician and the
patient.
Study Results:
~ No statistical improvement in trough FEV 1 at endpoint ITT analysis 15 mg
cilomalast BID vs placebo ( 0.16 L; p=0.062)
~ Response was dose-ordered for trough FEV 1 at endpoint ITT analysis
~ Significant improvement in trough FEV 1 (0.21 L; p=0.033) if excluded
patients on
ICS doses > 500 mcg of beclamethasone while on cilomalast 15 mg BID
~ Corroborating support for cilomalast 15 mg BID included 4 hour FEV 1,
domicillary
PEFR, FEF25-75 and physician and patient global assessment scores
Example 3
Cilomalast/High dose Inhaled Corticosteriod (ICS) Study
Study Desig-nn:
~ R, DB, PC, DR in patients with mild/moderate asthma on _> 800 mcg of
beclomethasone
~ cilomalast~ doses were 5, 10 and 15 mg twice daily for 4 weeks.
~ 2 week run-in.
~ Primary endpoint: trough clinic FEV 1.
~ Secondary endpoints: morning PEFR, symptoms, PEFR variability, evening PEFR,
clinic PEFR, FEF25-75, FEF75, rescue medication used.
Study Results:
~ No statistically significant change in clinic trough FEV 1 in any dose group
was
noted in the ITT analysis
~ No dose ordering was observed for the primary endpoint
~ Trough FEV 1 statistically improved at 10 mg of cilomalast BID using
repeated
measures analysis is patients excluded on < 800 mcg of ICS (0.16 L; p=0.009)
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CA 02388333 2002-05-02
WO 01/32127 PCT/US00/30113
~ ICS (beclamethasone) dose ranged from 100 to 4000 mcg and averaged 1136 mcg
~ Corroborative support for the 10 mg of cilomalast BID as the effective dose
also
came from numerically superior results in the 4 hour clinic FEV 1, clinic FVC,
PEFR
~ No dose-response relationship could be determined, trough concentrations
were
dose proportional and similar to previous studies.
Table 1
Comparison between compounds in selected studies
Allergen challenge studies
Comuarative Data: Allergen Challenge Studies
,l~ti
. r
4'i7.y
Y ~y
'i&
d, r .
1.3 12.3 10.7 22.9 +6.9
NONE 36.4 30.8 32 NO
FALL
3.5 63.5 42.4 not done
NONE 56.9 42.6 not done
Legend: Data on cilomalast was taken from the protocol analysis in asthma
patients on <
652 mcg of ICS. Data on montelukast (MT), budesonide (BDP) and both was taken
from a
single study in the Singulair SBA that examined the effect of Singulair
relative to inhaled
corticosteroids.
There are significant differences between the behavior of the placebo (Pbo)
groups
in both studies. Conclusion is that cilomalast outperformed Singulair when
added to low
dose ICS, despite the fact that the Pbo group also improved in the cilomalast
study.
The foregoing statements and examples are intended to illustrate the
invention, not
to limit it. Reference is made to the claims for what is reserved to the
inventors hereunder.
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