CZ2003141A3 - Medicament for reducing the incidences and/or the severity of exacerbations of COPD - Google Patents

Abstract

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.

Description

A medicament for reducing the incidence and / or severity of a new outbreak of a new COPD disease process

Technical field

The present invention relates to a medicament for reducing the incidence and / or severity of a new outbreak of a new COPD disease process.

BACKGROUND OF THE INVENTION

Chronic obstructive pulmonary disease (COPD) is characterized by a decrease in expiratory flow rate and slow forcible emptying of the lungs that do not change significantly within a few months (1). The disease is primarily caused by smoking, has a high incidence of emerging diseases with high mortality, and is very difficult to treat with existing therapies. In England, COPD accounts for approximately 6% of deaths in men and 4% of deaths in women and is the third leading cause of death (2). The World Health Organization (WHO) study on global disease burden puts COPD in the 6th most common cause of death in 1990 and predicts 3rd in 2020. COPD is associated with the highest cost of health care, most often due to long-term costly treatment, such as long-term oxygen therapy and hospitalization, as well as indirect costs including loss of work capacity. Recent epidemiological data show that the incidence of the disease is underestimated. From data from NHANES III (1988-1994) for US subjects, it was estimated that 4.6% of men and 3.7% of women had COPD and another 24.2% of men and 16.7% of women had flow problems air that was not diagnosed • tt tttt tttttt • tt tttt tt. tttt tt «· · ·. * • tttttt tttt ·· ·· tttt tttt forged (4). Patients with COPD often show acute relapse, which is an important cause of morbidity and mortality and there is a significant economic impact. On average, patients experience one or two outbreaks per year, the frequency increases with disease progression (Anthonisen NR, Manfreda J., Warran CPW et al., Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease, Ann. Intern. Med., 106, 196). Fletcher C., Peto R., The Natural History of Chronic Airflow Obstruction, BMJ 1, 1977, 1645-1648 (1977)).

Cyclic nucleotide phosphodiesterases (PDEs) are a group of enzymes that hydrolyze the ubiquitous intracellular second transporter, adenosine 3 ', 5'-monophosphate (cAMP) and guanosine 3', 5'-monophosphate (cGMP) to their corresponding inactive 5'-monophosphate metabolites. It is believed that there are at least seven distinct classes of PDE isoenzymes, each exhibiting unique physical and kinetic properties and each representing a product of a different gene family. These are distinguished using the Arabic numerals 1 to 7.

The target enzyme for administration of the compositions of the invention is the PDE4 isoenzyme in all its forms and in the entire domain of its distribution in all cells. It is an enzyme with low sensitivity of cAMP to K _m (K _m = 1 to 5 μΜ), which shows low activity for cGMP (K _m > 10Q μΜ). Members of this group have interesting properties, exist in two or more non-transferable or slow transferable forms, which differ in the order of binding of rolipram and other PDE IV inhibitors. Thus, a product of the same gene may exist in more than one catalytically active conformational state.

Importantly, the relative relationships of the different binding forms may vary greatly depending on the type of tissue of the cells. For example, inflammatory cells may contain relatively high A3 A3 **3 **3 ** ** ** ** *. * Amount of low affinity rolipram binding form, while brain and parietal cells may contain relatively high amounts of high affinity rolipram binding form. PDE inhibitors currently used to treat inflammation and as bronchodilators, drugs such as theophylline and pentoxyphylin, inhibit PDE isoenzymes in all tissues without discrimination. These compounds exhibit side effects, presumably because they non-selectively inhibit all classes of PDE isoenzymes in all tissues. With such compounds, the target disease state can be effectively, treated, but unwanted secondary effects can occur that, if reduced or eliminated, could enhance the general therapeutic effect of this concept of treating certain disease states. Although the theory of PDE isoenzyme selective inhibitors should be an improvement over non-selective inhibitors, the selective inhibitors investigated to this date are not deprived of the side effects resulting from the broadening of inhibition of the isoenzyme of interest in inappropriate or untargeted tissue. For example, clinical studies with the selective PDE4 inhibitor rolipram, which was developed as an antidepressant, have shown to have psychotropic effects and have gastrointestinal effects such as heartburn, nausea and vomiting. The side effects of denbufylin, another PDE 4 inhibitor aimed at the treatment of multi-infarct dementia, have also been shown to include heartburn, nausea and vomiting. These side effects are interpreted as the results of PDE4 inhibition in certain regions of the CNS and gastrointestinal system.

However, it has been found that certain compounds that effectively compete with the high affinity form of rolipram (HPDE 4) have a higher intensity of side effects than those that more effectively compete with LDPE 4 (a form of rolipram with low binding activity).

Data is now available showing that the compounds can be targeted to the low affinity binding form of PDE 4 and this form is different from the form for which rolipram is a high affinity binding agent. Different SARs were found

for inhibitors acting in a high affinity binding form to rolipram against a low affinity binding form rolipram.

Moreover, these two forms have different functional roles. Compounds which act with a low affinity binding form to rolipram exhibit anti-inflammatory effects, while active compounds with a high affinity binding form to rolipram show side effects or exhibit a more intense form of these side effects.

A useful consequence of these findings is that it is now possible to identify compounds that preferentially inhibit the catalytic activity of cAMP, wherein the enzyme is in a form that binds to low-affinity rolipram and thus reduces the side effects that appear to be associated with inhibiting the form binds rolipram with high affinity. This provides an excellent therapeutic indicator for the distribution of anti-inflammatory and / or bronchodilator effects versus side effects. It has now been found that some of these inhibitors, which do not give rise to unacceptable adverse adverse events when administered at doses that themselves treat COPD, when administered at equal or lower doses may also reduce the onset and / or difficulty of relapsing the disease. a process that often affects COPD sufferers.

SUMMARY OF THE INVENTION

It is an object of the present invention to use a selective PDE4 inhibitor for the manufacture of a medicament for limiting the incidence and / or severity of a new outbreak of a new COPD disease process.

An expedient embodiment of the invention consists in the use wherein the PDE4 inhibitor has an IC 50 ratio of about 0.1 or higher, said ratio being an IC ₅₀ ratio for competition with »9 ·

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9999 9 binding of 1nM [ ³ H] R-rolipram to form PDE4, which binds rolipram with high affinity over an IC ₅₀ value to inhibit the catalytic activity of PDE4 form, which binds rolipram with low affinity using 1 μΜ [ ³ Η] -οΑΜΡ as substrate .

A preferred embodiment of the invention consists in the use wherein the PDE4 inhibitor has an IC 50 ratio of about 0.5 or higher.

A particularly useful embodiment of the invention consists in the use wherein the PDE4 inhibitor has an IC 50 ratio of about 1.0 or higher.

Another useful form of the invention resides in the use wherein the PDE4 inhibitor is selected from the group disclosed in U.S. Pat.

552 438.

A preferred embodiment of the present invention resides in the use wherein the PDE4 inhibitor is cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] -cyclohexane-1-carboxylic acid or its salts, esters, prodrugs or physical forms.

Another useful form consists in the use wherein the PDE4 inhibitor is selected from the group consisting of AWD-12-281, NCS-613, D-4418, CI-1018 (PD-168787), a benzodioxole derivative disclosed in WO 99/16766, V -11294A, roflumilast, phthalazinone described in WO 99/47505 and T-440.

Description of the drawings

Giant. 1: Kaplan-Meier estimates of the percentage of patients without a new outbreak of the disease process - ITT in a clinical study

AND.

- 5a

Giant. 2: Kaplan-Meier estimates of the percentage of patients without a new outbreak of the disease process - ITT in a clinical study

B.

Giant. 3: Kaplan-Meier estimates of the percentage of patients without a new outbreak of the disease process - ITT in a clinical study

C.

Giant. 4: Relative risk (95% of Cl) of relapsing of COPD-associated disease process in baseline studies.

Detailed description of the invention

The present invention is related to finding a novel method for reducing the incidence and / or difficulty of relapsing the COPD disease process in COPD mammals, the method comprising administering an effective amount of a PDE4 inhibitor to a patient suffering from COPD.

Acute flare-up of the COPD disease process, described as worsening of COPD symptoms requiring changes in therapy including antimicrobial therapy, short-term corticosteroid administration, or other bronchodilator therapy. New outbreaks of the disease process were categorized into three levels:

Level 1: Managed by the patient himself at home, by increasing common medications against COPD.

Level 2: Requiring additional treatment prescribed by a family or general practitioner or treatment resulting from an outpatient visit, including an outpatient emergency service visit.

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Level 3: for healing.

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In clinical studies A and B, patients receiving Ariflo® (cis-4-cyano-4- [3- (icyclopenthyloxy) -4-methoxyphenyl] -cyclohexane-1-carboxylic acid) in 15 mg immediate-release tablets twice daily, a lower incidence in all categories of sudden outbreaks of the disease process, as well as a lesser severity of new outbreaks (levels 2 and 3) that required medical treatment or hospitalization compared to patients receiving placebo.

Clinical trials in COPD patients were conducted to investigate the efficacy of Ariflo 15 mg immediate release tablets, administered twice daily. These were compared to the parallel placebo group using 6-month double-blind studies designed to demonstrate the efficacy and safety of Ariflo 15mg tablets for the treatment of COPD twice daily.

In Clinical Study A, treatment with Ariflo (15 mg immediate-release tablets twice daily) reduced the risk of relapsing of the disease by 39% relative to placebo (P = 0.002) and reduced the risk of relapsing of the disease requiring medical treatment or hospitalization by 45% (P 0,00 0.001) according to Kaplan-Meier estimates (Fig. 1). Similarly, in the second study, B treatment with Ariflo within 26 weeks reduced the risk of relapsing of the new disease process by 30% relative to placebo (P = 0.005) and reduced the risk of relapsing of the disease process requiring medical treatment or hospitalization (levels 2 and 3) by 32% (P = 0.004) (fig.

2). The third clinical trial C with Ariflo, 15 mg twice daily, within 6 months gave uncertain results as to the effectiveness of COPD treatment. In this study, the effect of Ariflo on the new outbreak of the disease process was unimportant (Fig. 3).

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Survival rates without disease outbreak based on Kaplan-Meier estimates of time relative to first outbreak are summarized in the table below.

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Table 1

Survey of survival without relapse of disease process for 24 weeks according to study

Disease-free survival rate *

Total Number without patients new flash- nuti Estimate percent without new flash- nuti Bottom 95% Upper 95% Nursing- number diseases- diseases- kont- kont- bathtub pacien- Joint Joint field field Value group here process process limit limit P

study

All new outbreaks of the disease process

Placebo 216 141 62.4 55.5 69.3

SB207499 431,336 74.0 69.3 78.6 0.008

Levels 2 and 3 of a new outbreak of the disease process

Placebo

157

69.7

63.1

76, 3 • · · 4

-8.SB207499

364 81.7

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77.5 85.8

0.003

Study C

All new outbreaks of the disease process

Placebo 226 143 56.0 47.8 64.2 SB207499 474 299 58.3 53, 5 63.1 0, 662 Levels 2 and 3 a new outbreak of the disease process Placebo 164 71.0 64.7 77.3 SB207499 354 70, 9 66.5 75.3 0.793 Study B All] new flare sick process Placebo 242 135 51.5 44.4 57.8 SB207499 469 318 63, 9 59.1 68, 6 0.004 Levels 2 and 3 new outbreaks of the disease process Placebo 165 64.3 57, 9 70.8 SB207499 367 75.5 71.2 79.7 0.009

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Results are presented for the population to be treated * Surge-free survival based on Kaplan-Meier estimates of time relative to the first new outbreak of the disease process. P values are based on the log-rank test.

In two clinical studies A and B, in which Ariflo (15mg, immediate release tablets and twice daily administration) showed efficacy in the treatment of COPD, the estimated percentages of patients without relapsing of the disease process were significantly higher in patients receiving 15mg, Ariflo tablets with immediate-release and twice-daily administration, as compared to patients who received placebo (P = 0.008 and P = 0.004) (Figure 4).

The benefit of Ariflo lies in reducing the risk of relapsing of the COPD disease process in two studies, a significant clinical finding, since new outbreaks of disease process are associated with insufficient long-term clinical outcomes and have significant consequences for health care costs.

A preferred class of inhibitors are those having an IC ₅₀ ratio of about 0.1 or greater, the determination of the IC ₅₀ ratio being described in U.S. Patent No. 5,998,428, which is incorporated herein by reference in its entirety as set forth herein. . A preferred standard for PDE 4-specific inhibitors which can be utilized according to this invention is one where the compound has an _IC50 ratio of about 0.1 or greater, where said ratio is the ratio of the ICs ₀ for competing with the binding nM ^[3 H] R -rolipram to form PDE4 that binds rolipram with high affinity over an IC 50 value for inhibiting the catalytic activity of PDE4 form which binds rolipram with low affinity using 1 μΜ [ ³ Η] -οΑΜΡ as substrate.

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Certain PDE 4 inhibitors that may be included in these formulations include those disclosed in U.S. Patent No. 5,552,438 issued September 3, 1996. This patent and the compounds it discloses are incorporated herein by reference in their entirety. The compound of particular interest disclosed in U.S. Patent No. 5,552,438 is cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid, and salts, esters, prodrugs, or physical forms thereof. . This compound is described herein by the IUPAC nomenclature, its trademark Ariflo, the generic name targetomilast, and the code number SB207499. Other PDE 4 inhibitors that may be of interest are AWD-12-281 from Astra (Hofgen, N. et al., 15 ^th EFMC Int. Symp. Med. Chem. (6-10 September 1998, Edinburgh) , Abst. P98), a 9-benzyladenine derivative named NCS-613 (INSERM), D-4418 from Chiroscience and ScheringPlow, a benzodiazepine PDE4 inhibitor identified as Cl-1018 (PD-168787, Parke-Davis / Warner-Lambert), a benzodioxole derivative described by Kyowa Hakko in WO 99/16766, V11294A by Napp (Landells, LJ et al., Eur. Resp. J. [Annu Cong. Eur. Resp. Soc. (19-23 September 1998, Geneva) 1998,

12 (Supplement 28), Abst P2393), roflumilast (CAS ref. 162401-32-3) and phthalazinone (WO 99/47505) from Byk-Gulden and the compound identified as T-440 (Tanabe Seiyaku, Fujii, K. et al., J. Pharmacol. Exp. Ther., 284 (1), 162 (1998). Preferred compounds of the invention are those having an IC ₅₀ ratio greater than 0.5 and particularly preferably greater than 1.0. .

The most preferred compound is roflumilast and cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid.

Other drugs suitable for the treatment of diseases associated with PDE4 may also be included in this therapy. Examples of other categories of therapeutics are drugs that treat inflammatory diseases of the respiratory tract, such as bronchodilators, leukotriene receptor antagonists, and biosynthetic leukotriene inhibitors.

Inflammatory diseases other than the respiratory tract such as irritable bowel disease (IBD), immunomodulatory drugs, perception enhancers, drugs for the treatment of rheumatoid arthritis, rheumatoid vertebral inflammation, osteoarthritis ,. inflammatory arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, silicosis, lung benign lymphogranuloma, agents for treating bone resorption diseases, reperfusion injury, graft reaction and host, allograft rejection, fever and myalgia due to infection, such as influenza, secondary relapse after infection or malignancy, secondary relapse in a human with acquired immune deficiency syndrome (AIDS), AIDS, ARC (complex AIDS-related) keloid formation, formation scar tissue, Crohn's disease, ulcerative colitis, pyres, autoimmune diseases such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosus, drugs for the treatment of viral infections such as cytomegalovirus (CMV), influenza, adenovirus and herpes virus, and drugs for the treatment of diseases caused by yeast and fungal inf ekcích.

Examples of compounds for the treatment of respiratory diseases are leukotriene antagonists, mucolytics, antitussives and coughing agents, antibiotics, β-agonists for oral or inhalation administration, phosphodiesterase inhibitors other than PDE4 specific inhibitors, nasal congestion reducing agents, elastase inhibitors, protein agents such as IL4, IL5, IL8 and IL13 monoclonal antibodies, anti-IgE or corticosteroids for oral or inhalational administration. Particularly preferred for the treatment of secondary infections are combinations of therapies wherein a therapeutic amount of a corticosteroid, a β agonist, an anticholinergic, a cromone inhalation, a leukotriene antagonist or an antibiotic is used.

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The amount of inhibitor that is effective in this treatment method is between 100 µg and 100 mg per dose, administered one to four times daily as needed. A range of 1 to 60 mg per dose administered once or twice daily is preferred. A more preferred dosage is 5 to 30 mg per dose administered once or twice daily. Most preferred is a 10 to 20 or 10 to 15 mg dose administered once or twice daily, e.g., a 15 mg twice daily dose, or a 30 or 60 mg dose once daily. The dose to reduce the number of new flares of the disease process and / or reduce its severity may be less than that used to treat COPD as such.

The inhibitor may be administered by conventional means. For example, it will be administered orally or in the form of an inhaled powder or aerosol. It is possible to formulate some of these inhibitors in the form of a topical patch, a sustained release form for injection or a suppository, and the oral or inhalation formulation is believed to be the best route of administration.

For purposes of this invention, preferred formulations are immediate release or controlled release tablets containing between about 1 mg to about 200 mg of Ariflo, more preferably 5 to 100 mg, and most preferably between 5 or 10 to 60 mg of the active ingredient. Other preferred dosage levels within these ranges are 10, 15, 20, 30, 40, 50, 60, 70, 70, 80, or 90 mg per composition.

DETAILED DESCRIPTION OF THE INVENTION

The clinical trial protocol was generally as follows:

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Eligible patients had a clinical diagnosis of COPD (according to international treatment standards),% predicted FEVi> 30% and <70% post-bronchodilation, FEVi / FVC <0.7, and stable airway obstruction defined as <15% reversibility after p ₂ administration. -agonists. In each study, COPD patients underwent a 4-week course of placebo and were then randomized to receive Ariflo, 15 mg twice daily or placebo at a 2 to 1 ratio. Patients were followed for 1, 2 and 4 weeks of treatment followed by 4 weekly intervals.

Patients were allowed to use concomitant salbutamol (prn) and / or a short-acting anticholinergic at a constant dose during these studies.

Study B included a 2-week random double-blind run-out phase to verify the effects of treatment interruptions. Patients who received Ariflo during the original 24-week period were randomly assigned 1: 1 to groups receiving Ariflo 15mg twice daily or placebo during the run-up phase. Patients who received placebo during the original 24-week period also received placebo during the run-up phase.

Lung function measurements were performed at each visit (except week 1). The St.George Respiratory Questionnaire (SGRQ) was applied at baseline and at weeks 12 and 24 (or at the time of departure). Compliance with routines, vital signs evaluation and laboratory assessments were performed at each visit. These studies included repeated ECG and extensive monitoring of patients who reported adverse gastrointestinal experiences of potential clinical interest to determine the contribution of the effects of SB 207499 on both the cardiovascular system and the gastrointestinal system. 12-lead ECG measurements were taken during the survey, before baseline dosing, and before dosing at each visit during

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4444 44 44 44 44 44 double blind treatment period. 12-lead ECG measurements were further taken 3 hours after drug administration on the first and last day of administration. 24-hour Holter ECG monitoring was performed on a sub-sample of patients during the lead-in phase and at weeks 1 and 20. To determine the general incidence of abnormal estimates in such a patient population, orthostatic tests for vitality signs and faecal occult bleeding tests were performed in all patients. Orthostatic signs of vitality were detected at screening, baseline, and at the end of the double blind experiment. Faecal occult bleeding tests were performed between sorting, baseline and between 20 weeks and at the end of the double blind (24 weeks).

All efficacy measurements were tested on a population in need of treatment (ITT) that is defined as all patients who received a randomized study medication and had a baseline and at least one efficacy evaluation per therapy during a double blind period. Efficacy analysis for the population per protocol (PP) (defined as patients who did not significantly break the protocol) was limited to FEVi channel and total SGRQ scores, primary efficacy and secondary parameters measurements, exercise test tolerance, difficulty breathing after exercise, total score symptoms and

Claims (7)

PATENT CLAIMS Use of a selective PDE4 inhibitor for the manufacture of a medicament for reducing the incidence and / or severity of a new outbreak of a new COPD disease process. The use of claim 1, wherein the PDE4 inhibitor has an IC 50 ratio of about 0.1 or greater, wherein said ratio is an IC ₅₀ ratio for competition with 1nM [ ³ H] R-rolipram binding to produce PDE4 that binds rolipram with a high affinity over the IC 50 value for inhibiting the catalytic activity of the PDE4 form that binds rolipram with low affinity using 1 µM [ ³ H] -cAMP as a substrate. Use according to claim 1 or 2, wherein the PDE4 inhibitor has an IC 50 ratio of about 0.5 or higher. Use according to any one of claims 1 to 3, wherein the PDE4 inhibitor has an IC 50 ratio of about 1.0 or higher. The use according to any one of the preceding claims, wherein the PDE4 inhibitor is selected from the group set forth in US Patent No. 5,201,549. 5,552,438. Use according to claim 5, wherein the PDE4 inhibitor is cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid or salts, esters, prodrugs or physical forms thereof. Use according to any one of claims 1 to 4, wherein the PDE4 inhibitor is selected from the group consisting of AWD-12-281, NCS-613, D-4418, CI-1018 (PD-168787), a benzodioxole derivative described in WO 99 / 16766, V-11294A, roflumilast, phthalazinone described in WO 99/47505 and T-440.