Note: Descriptions are shown in the official language in which they were submitted.
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Method for Reducing Exacerbations Associated with COPD
Scope
This invention relates to a method for reducing the incidences and/or the
severity of
exacerbations of COPD by administering a phosphodiesterase 4 (PDE4) inhibitor.
Background
Chronic obstructive pulmonary disease (COPD) is characterized by a
reduction in expiratory flow and slow forced emptying of the lungs which does
not
change markedly over several months (1). The disease is primarily caused by
smoking, has a high incidence of mortality and morbidity and is poorly served
by
existing therapies. In the UK, COPD accounts for approximately 6% of deaths in
men and 4% of deaths in women and is the third most common cause of death (2).
The World Health Organization Global Burden of Disease study showed COPD to
be the sixth leading cause of death worldwide in 1990 and is predicted to rise
to
third position by 2020. COPD is associated with major healthcare costs,
largely due
to expensive treatments such as long-term oxygen therapy and hospital
admissions,
as well as indirect costs including Loss of working capacity. Recent
epidemiological
data suggests that the prevalence of the disease is underestimated. Based on
data
from NHANES III (1988-1994) for subjects in the United States, it was
estimated
that 4.6% of men and 3.7% of women had a diagnosis of COPD and another 24.2%
of men and 16.7% of women had airflow obstruction that was undiagnosed (4).
Patients with COPD frequently develop acute exacerbations of the disease that
are
an important cause of morbidity and mortality and have a significant economic
impact. On average, patients experience one or two exacerbations per year and
the
frequency increases as the disease progresses (Anthonisen NR, Manfreda J,
Warran
CPW et al, Antibiotic therapy in exacerbations of chronic obstructive
pulmonary
disease. Ann Intej~a. Med 1987, 106: 196-204; Fletcher C, Peto R. The natural
history of chronic airflow obstruction. BMJ, 1977; 1: 1645-1648).
Cyclic nucleotide phosphodiesterases (PDEs) represent a family of enzymes that
hydrolyze the ubiquitous intracellular second messengers, adenosine 3',5'-
monophosphate
(CAMP) and guanosine 3',5'-monophosphate (cGMP) to their corresponding
inactive 5'-
monophosphate metabolites. At least seven distinct classes of PDE isozymes are
believed to
exist, each possessing unique physical and kinetic characteristics and each
representing a
product of a different gene family. These are: distinguished using Arabic
numerals 1- 7.
The target enzyme for use of the formulations of this invention is the PDE 4
isozyme in all its various forms and in the full domain of its distributions
in all cells. It is a
low Km (CAMP Km=1-S~,M) cAMP-selective enzyme that has little activity against
cGMP
(Krn~l00~.M). Members of this isozyme class have the interesting
characteristics of
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existing in two or more non-interconvertible or slowly interconvertible forms
that bind
rolipram and other PDE TV inhibitors with distinct rank-order potencies. Thus
the same
gene product can exist in more than one catalytically active conformational
state.
Importantly, the relative proportions of the different binding forms may vary
depending on
the tissue cell type. For example, inflammatory cells may contain a relatively
high
proportion of the form that binds rolipram with a low affinity while brain and
parietal cells
may contain a relatively high proportion of the form that binds rolipram with
a high affinity.
Current 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 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. Although in theory isozyme-selective PDE
inhibitors should
represent an improvement over non-selective inhibitors, the selective
inhibitors tested to
date are not devoid of side effects produced as an extension of inhibiting the
isozyme of
interest in an inappropriate or untargeted tissue. 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. Indications are that side effects of denbufylline, another
PDE 4 inhibitor
targeted for the treatment of mufti-infarct dementia, may include pyrosis,
nausea and emesis
as well. These side effects are thought to occur as a result of inhibiting PDE
4 in specific
areas of the CNS and gastrointestinal system.
But it has been found that certain compounds which potently compete for the
high
affinity rolipram binding form (HPDE 4) have more side effects or more intense
side effects
than those which more potently compete with the LPDE 4 (low affinity rolipram
binding
form). Data is now available which indicate that compounds can be targeted to
the low
affinity binding form of PDE 4 and that this form is distinct from the binding
form for
which rolipram is a high affinity binder. Distinct SARs have been found to
exist for
inhibitors acting at the high affinity rolipram binding form versus the low
affinity rolipram
binding form: In addition, these two forms appear to have different functional
roles. Thus
compounds that interacted with the low affinity rolipram binding form appears
to have anti-
inflammatory activity, whereas those that interact with the high affinity
rolipram binding
form produce side effects or exhibit more intensely those side effects.
A useful consequence of these findings is that it is now possible to identify
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
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apparently are linked to inhibiting the form which binds rolipram with a high
affinity. This
provides a superior therapeutic index vis-a-vis anti-inflammatory and/or
bronchodilator
activities versus side effects. It has now been found that certain of these
inhibitors, ones
which do not induce unacceptable untoward adverse events when administered at
dosages
which treat COPD per se, will also when given at the same or smaller doses,
reduce the
incidences and/or severity of exacerbations of the disease that oft times
affect COPD
suffers.
Summary of the Invention
Tn a first aspect, this invention relates to a method for reducing the
incidences
IO and/or severity of exacerbations of COPD in a mammal suffering from COPD,
the method
comprising administering an effective amount of a PDE4 inhibitor to a patient
whom is
suffering from COPD.
In a further aspect, this invention relates to the use of a PDE4 inhibitor in
the
manufacture of a medicament for reducing the incidences andlor severity of
exacerbations of COPD.
Description of the Fi ures
Fig 1: Kaplan-Meier Estimates of Percentage of Patients Exacerbation-free
- ITT in Clinical Study A
Fig 2: Kaplan-Meier Estimates of Percentage of Patients Exacerbation-free
- ITT in Clinical Study B
Fig 3: Kaplan-Meier Estimates of Percentage of Patients Exacerbation-free
- ITT in Clinical Study C
Fig 4: Relative Risk (95% CI) of a COPD Exacerbation in Principal Studies.
Detailed Description of the Invention
Acute COPD exacerbations, defined as worsening of COPD symptoms that
required changes in treatment including antimicrobial therapy, a short course
of oral
corticosteroids or other bronchodilator therapy. Exacerbations were
categorized to
three levels:
Level 1: self managed by the patient at home by increasing usual medication
for COPD.
Level 2: requiring additional treatment prescribed by a family or primary
care physician or as a result of a hospital outpatient visit including a visit
to
the Emergency Room.
Level 3: requiring the patient to be admitted to the hospital for treatment.
In certain clinicial studies A and B, patients who received Ariflo~ (cis-4.
cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid),
l5mg
immediate release tablet, BID, had a lower incidence of all categories of
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exacerbations as well as the more severe exacerbations (Levels 2 and 3)
requiring
treatment by a physician or hospitalization than patients who received
placebo.
Clinical trials in COPD patients were carried out to investigate the efficacy
of an 15 mg immediate release tablet, BID of Ariflo. These were placebo-
controlled,
parallel-group, double-blind studies of 6 months duration designed to
demonstrate
the efficacy and safety of Ariflo 15 mg BID in the treatment of COPD.
In one clinical study, A, treatment with Ariflo (l5mg immediate release
tablet, BID) reduced the risk of having an exacerbation by 39% relative to
placebo
(P = 0.002) and reduced the risk of an exacerbation requiring treatment by a
physician or hospitalization by 45% (P = 0.001) based on Kaplan-Meier
estimates
(Figure 1). Similarly, in as second study B, treatment with Ariflo over 26
weeks
reduced the risk of having an exacerbation by 30% relative to placebo (P =
0.005)
and reduced the risk of an exacerbation requiring treatment by a physician or
hospitalization (Levels 2 and 3) by 32% (P = 0.004) (Figure 2). A third
clinical trial
I5 C with Ariflo, ISmg BID, over 6 months gave equivocal results as regards
efficacy
in treating COPD. In this study the affect of Ariflo on exacerbations was
marginal
(Figure 3).
Exacerbation-free survival rates based on Kaplan-Meier estimates of time-to-
first exacerbation are summarized in Table 1.
Table 1
Summary of Exacerbation-free Survival at 24 Weeks
By Study
Exacerbation-free Survival Rates
Total Number of Estimated
Number Patients Percentage Lower Upper P-
Treatment o~ Exacerbation- Exacerbation- 95% CI 95% CI value
Group Patients free Free ( % ) ( % )
Studv A
All Exacerbations
Placebo 216 141 62.4 55.5 69.3
SB207499 431 336 74.0 69.3 78.6 0.008
Level 2 and 3 Exacerbatiorzs
Placebo 157 69.7 63.1 76.3
SB207499 364 81.7 77.5 85.8 0.003
Study C
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All Exacerbations
Placebo 226 143 56.0 47.8 64.2
SB207499 474 299 58.3 53.5 63.1 0.662
Level 2 and 3 Exacerbations
Placebo 164 71.0 64.7 77.3
SB207499 354 70.9 66.5 75.3 0.793
study B
All Exacerbations
Placebo 242 135 51.1 44.4 57.8
SB207499 469 318 63.9 59.1 68.6 0.004
Level 2 and 3 Exacerbations
Placebo 165 64.3 57.9 70.8
SB207499 367 75.5 71.2 79.7 0.009
Results for the intent-to-treat population are presented.
* Exacerbation-free survival rate is estimated using Kaplan-Meier estimates of
time-to-first exacerbation. P-values
based on log-rank test.
In the two clinical studies A and B where Ariflo (l5mg IR, BID) showed
efficacy in treating COPD, the estimated percentages of patients exacerbation-
free
were significantly greater for patients who received a 15 mg IR tablet BID of
Ariflo
compared to patients who received placebo (P = 0.008 and P = 0. 004,
respectively)
(Figure 4).
The benefit of Ariflo in reducing the risk of COPD exacerbations in two
studies is an important clinical finding, since exacerbations are associated
with a
poor long-term clinical outcome and have significant implications for
healthcare
costs.
A preferred group of inhibitors are those that have an IC50 ratio (high/low
binding)
of about 0.1 or greater, as that IC50 ratio determination is described in U.S.
patent
5,998,428. It is incorporated herein in full by reference as if fully set
forth herein. A
preferred standard for PDE 4-specific inhibitors which can be used in this
invention is one
where the compound has an IC50 ratio of about 0.1 or greater; said ratio being
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 PDE 4
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catalytic activity of a form which binds rolipram with a low affinity using 1
uM[3H]-cAMP
as the substrate.
Specific PDE 4 inhibitors that may be included in these formulations include
those
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. This compound is identified here by its IUPAC name, by its registered
trademark
Ariflo, by its generic name cilomilast, and by an alphanumeric SB207499. Other
PDE 4
inhibitors which may be of interest include: 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; and a
compound
identified as T-440 (Tanabe Seiyaku; Fujii, K. et al. J Pharmacol Exp
Ther,1998, 284(1):
162). Preferred compounds of this invention are those which have an IC50 ratio
of greater
than 0.5, and particularly those compounds having a ratio of greater than 1Ø
The most
preferred compounds are roflumilast and cis-4-cyano-4-[3- (cyclopentyloxy)-4
methoxyphenyl]cyclohexane-1-carboxylic acid.
Other drugs useful in treating PDE4-related diseases can be incorporated into
this
therapy as well. Examples of other therapeutics by category, are drugs which
treat:
inflammatory respiratory diseases such as bronchodilators, leukotriene
receptor antagonists
and leukotriene biosynthesis inhibitors; non-respiratory inflammatory diseases
such as
irntable bowel disease (IBD); immunomodulating drugs, cognition enhancers;
drugs for
treating rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty
arthritis and other
arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative
sepsis; toxic shock
syndrome; adult respiratory distress syndrome; cerebral malaria; silicosis;
pulmonary
sarcoidosis; drugs for treating bone resorption diseases; reperfusion injury;
graft vs. host
reaction; allograft rejections; fever and myalgias due to infection, such as
influenza,
cachexia secondary to infection or malignancy, cachexia secondary to human
acquired
immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex); keloid
formation; scar tissue formation; Crohn's disease; ulcerative colitis;
pyresis; autoimmune
diseases such as multiple sclerosis, autoimmune diabetes and systennic lupus
erythematosis;
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drugs for treating viral infections such as cytomegalovirus (CMV), influenza
virus,
adenovirus, and the herpes virus, and drugs for treating yeast and fungal
infections.
Exemplary types of compounds for treating respiratory diseases are leukotriene
antagonists; mucolytics; antitussives and expectorants; antibiotics; oral or
inhaled beta
s agonists; phosphodiesterase inhibitors other that PDE4-specific inhibitors;
nasal
decongestants; elastase inhibitors; protein therapeutics such as IL4, ILS,
IL8, and IL13
monoclonal antibodies, anti-IgE; or oral or inhaled corticosteriods.
Particularly preferred
combination therapies are the use of a therapeutic amount of a corticosteriod,
a beta agonist,
an anticholinergic, an inhaled cromone, a leukotriene antagonist, or an
antibiotic to treat
secondary infections.
The amount of inhibitor that is effective in this treatment method falls
between 100
micrograms and 100 mg per dose, administered as needed from one to four times
per day.
A preferred range is 1-60 mg per dose administered once or twice a day. More
preferred is
a S-30 mg dose administered one or twice a day. Most preferred is a 10-20, or
10-ISmg
dose administered once or twice per day, e.g. a twice-a-day 15 mg dose, or
once-a-day 30 or
60 mg dose. The dose for reducing exacerbations and/or the severity of them
can be smaller
than that which is used to treat COPD per se.
The inhibitor will be administered by conventional means. For example, it will
be
administered orally or as an inhaled powder or aerosol. It may be possible to
formulate
some of these inhibitors in the form of a topical patch, a sustained release
injectable or a
suppository, it is believed that an oral preparation or one administered as an
inhalant will be
the superior route of delivery.
For the purposes of this invention, the preferred formulation will be an
immediate
release or controlled release oral tablet containing between about lmg to 200
mg of Ariflo,
more preferably 5 to 100mg, and most preferably between 5, or 10 to 60mg of
the active
ingredient. Additional preferred dosage amounts within these ranges are 10,
I5, 20, 30, 40,
50, 60, 70, 80 or 90mg per preparation.
Specific Examples
The clinical studies protocol were carried out generally as follows:
Eligible patients had a clinical diagnosis of COPD (according to international
treatment guidelines), a % predicted FEV 1 >_ 30% and _< 70% post-
bronchodilator, a
FEV1/FVC of S 0.7, and fixed airway obstruction defined by <_ 15%
reversibility
following administration of a beta-agonist. In each of the studies, patients
with
COPD entered a 4-week placebo run-in period and were then randomized to
receive
Ariflo 15 mg twice daily or placebo in a ratio of 2 to 1. Patients were
monitored
following 1, 2 and 4 weeks of treatment and subsequently at 4-week intervals.
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Patients were permitted to receive concomitant salbutamol (prn) and/or short
acting
anticholinergic therapy at a stable dose during these studies.
Study B included a 2-week, randomised, double-blind, run-out phase to
examine the effects of discontinuation of treatment. Patients who received
Ariflo
during the initial 24 week period, were randomized (1:1 ratio) to Ariflo l5mg
BID
or placebo for the run-out phase; patients who received placebo during the
initial 24
weeks, continued on placebo during the run-out phase.
Pulmonary function measurements were performed at each visit (with the
exception of Week 1). The St. George's Respiratory Questionnaire (SGRQ) was
administered at Baseline, and Weeks 12 and 24 (or at the time of withdrawal).
Routine compliance, vital sign, and laboratory assessments were performed at
each
visit. These studies included frequent ECG assessments and extensive
monitoring of
patients reporting gastrointestinal adverse experiences of potential clinical
concern
to address concerns about possible effects of SB 207499 on both cardiovascular
and
gastrointestinal body systems. 12-lead ECG assessments were conducted at
screening, prior to dosing at Baseline, and prior to dosing at each visit
during the
double-blind treatment period. In addition, 12-lead ECGs were performed 3
hours
after the administration of drug on the first and last day of dosing. In a
subset of
patients, 24-hour Holter ECG monitoring was conducted during Run-in and at
Weeks 1 and 20. Orthostatic vital signs and faecal occult blood tests were
determined for all patients in order to obtain a general incidence of abnormal
assessments in this patient population. Orthostatic vital signs were
determined at
Screening, Baseline and the end of double-blind treatment. Faecal occult blood
tests
were performed between Screening and Baseline and between 20 weeks and the end
of double-blind treatment (24 weeks).
All efficacy measures were analyzed for the ihteht-to-treat population (ITT),
defined as all patients who received randomized study medication and had a
baseline
evaluation and at least one on-therapy efficacy evaluation during the double-
blind
period. Efficacy analyses for the per protocol populatiorz (PP) (defined as
patients
who did not significantly violate the protocol) were limited to trough FEV 1,
and the
total score of the SGRQ, the co-primary measures of efficacy, and the
secondary
parameters, exercise tolerance test, post-exercise breathlessness, summary
symptom
score, and trough FVC.
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