KR20030019620A - Method for Reducing Exacerbations Associated with COPD - Google Patents

Abstract

The present invention relates to a method of reducing the incidence and / or extent of chronic obstructive pulmonary disease (COPD) exacerbation by administering a phosphodiesterase 4 (PDE 4) inhibitor.

Description

How to reduce the worsening of symptoms associated with COPD {Method for Reducing Exacerbations Associated with COPD}

Chronic obstructive pulmonary disease (COPD) is characterized by a decrease in aerobic volume and gradually emptying the lungs without changing rapidly over several months (1). The primary cause of the disease is smoking, which has high mortality and morbidity and is not well treated with current therapies. In the UK, mortality from COPD accounts for about 6% of male mortality, 4% of female mortality, and the third most common cause of death (2). The World Health Organization's Global Burden of Disease study found that COPD was the sixth leading cause of death worldwide in 1990 and is expected to reach third by 2020. COPD is primarily associated with most health care costs due to indirect costs, including loss of capacity, as well as expensive treatments such as long-term oxygen therapy and hospital admissions. Recent epidemiologic data suggest that the prevalence of the disease is underestimated. Based on data from NHANES III (1988-1994) on subjects in the United States, 4.6% of men and 3.7% of women were diagnosed with COPD, with 24.2% of other men and 16.7% of women not diagnosed It is presumed to suffer from atresia (4). Patients suffering from COPD quickly develop acute exacerbation of the disease, which is an important cause of morbidity and mortality, and are subject to significant economic impact. On average, patients experience 1-2 deteriorations a year, the frequency of which rapidly increases with disease progression [Anthonisen NR, Manfreda J, Warran CPW et al, Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern. Med 1987, 106: 196-204; Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ, 1977; 1: 1645-1648.

Cyclic nucleotide phosphodiesterase (PDE) corresponds to interspersed intracellular secondary messengers, namely adenosine 3 ', 5'-monophosphate (cAMP) and guanosine 3', 5'-monophosphate (cGMP) Is a group of enzymes that hydrolyze to an inactive 5'-monophosphate metabolite. PDE isozymes are believed to have at least seven distinct species, each with its own physical and dynamic properties and each representing the product of a different gene family. These were distinguished using the Arabic numerals 1-7.

Target enzymes for use in the formulations of the invention are PDE4 isozymes of all domains and all domains distributed in all cells. PDE4 isozyme is a low-K _m (cAMP K _m = 1-5 μM) cAMP selective enzyme with little activity against cGMP (K _m > 100 μM). This class of isozymes has the interesting characteristic that there are two or more non-interchangeable forms, or slowly interconverting forms, that bind to rolipram and other PDE4 inhibitors in potency, respectively. Thus, the same gene product may exist in more than one catalytically active configuration. It is important that the relative proportions of the different binding forms can vary depending on the tissue cell type. For example, inflammatory cells have a relatively high proportion of low-affinity forms of binding to rolipram, while brain and parietal cells have a relatively high proportion of forms that bind to rolipram. high. Drugs such as theophylline and pentoxifylline, conventional PDE inhibitors used to treat inflammation and as bronchodilators, indiscriminately inhibit PDE isozymes in all tissues. These compounds cause side effects because they nonselectively inhibit all of the PDE isozyme species in all tissues. Target disease states can be effectively treated by the compound, but undesirable secondary effects may occur, and if attempts to prevent or reduce these secondary effects, such attempts to treat certain disease states increase the overall therapeutic effect. I will. Theoretically, the isozyme selective PDE inhibitor should be improved over the non-selective inhibitor, but the selective inhibitors tested to date have no side effects resulting from inhibition of the isozyme in inappropriate or non-target tissues. For example, clinical studies of the selective PDE4 inhibitor rolipram, which has been developed as an antidepressant, have revealed that the drug has psychotropic activity and also exhibits gastrointestinal effects such as heartburn, nausea and vomiting. Side effects of denbuphylline (another PDE4 inhibitor aimed at the treatment of multi-infarct dementia) also include heartburn, nausea and vomiting. These side effects are thought to be caused by the inhibition of PDE4 in certain areas of the CNS and gastrointestinal tract.

However, certain compounds that compete strongly against the rolipram high affinity binding form (HPDE4) have more side effects or are more severe than compounds competing more strongly against the rolipram low affinity binding form (LPDE4). Found. From the current data, it can be seen that the compounds can target the low affinity binding form of PDE4 and this low affinity binding form is distinguished from the rolipram high affinity binding form. Inhibitors that act on both the high and low affinity binding forms of salifram have been found to have different SARs. In addition, these two forms appear to play different functional roles. As a result, compounds interacting with a low-lipofram affinity binding form exhibit anti-inflammatory activity, while compounds interacting with a high-affinity binding form of rolipram cause side effects or more severe side effects.

The usefulness of these findings can identify compounds that preferentially inhibit cAMP catalytic activity in the form of enzyme binding to low-affinity to rolipram, resulting in inhibition of the form of high-affinity binding to rolipram. It can reduce the side effects that seem to be. This provides a better therapeutic index regarding anti-inflammatory and / or bronchodilator activity and side effects. Occurrence of disease exacerbation, which is prevalent in patients with COPD even when these specific inhibitors are administered at the same or lower doses that do not induce unacceptable adverse adverse effects when administered at a dose that treats COPD itself, and Or) it has been found to decrease the degree.

<Overview of invention>

In a first aspect, the present invention relates to a method for reducing the incidence and / or extent of COPD exacerbation in a mammal suffering from COPD, comprising administering an effective amount of a PDE4 inhibitor to a patient suffering from COPD.

In another aspect, the present invention relates to the use of a PDE4 inhibitor in the manufacture of a medicament for reducing the incidence and / or extent of COPD exacerbations.

The present invention relates to a method of reducing the incidence and / or extent of chronic obstructive pulmonary disease (COPD) exacerbation by administering a phosphodiesterase 4 (PDE4) inhibitor.

1: Kaplan-Meier estimate of the percentage of ITT patients who did not worsen in Clinical Study A.

Figure 2: Kaplan-Meier estimates of the percentage of ITT patients not worsened in Clinical Study B.

Figure 3: Kaplan-Meier estimates of the percentage of ITT patients not worsened in Clinical Study C.

Figure 4: Relative risk of COPD exacerbation in the main study (95% CI).

Acute COPD exacerbation is defined as exacerbation of COPD symptoms that require a change in treatment, including antibacterial therapy, short-term oral corticosteroids or other bronchodilator therapy. Deterioration is divided into three stages:

Step 1: patient self care at home by increasing conventional dosing for COPD,

Step 2: Additional treatment prescribed by the family or initial physician or as a result of an outpatient hospital visit, including an emergency room visit, is required.

Step 3: A patient's hospitalization is required for treatment.

In certain clinical studies A and B, Ariflo, a rapid release tablet, cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1- Patients receiving 15 mg of carboxylic acid) with BID developed lower all categories of worsening than patients receiving placebo as well as more severe exacerbations (stages 2 and 3) requiring treatment by a physician or hospitalization.

Clinical trials were performed in COPD patients to investigate the efficacy of Ariflo 15 mg (BID), an immediate release tablet. These were a double-blind study of the same group of placebo-regulated 6-month periods designed to explain the efficacy and stability of Ariflo 15 mg (BID) in COPD treatment.

In the first clinical study, A, treatment with Ariflo (rapid release 15 mg, BID) reduced the risk of exacerbation by 39% (P = 0.002) compared to placebo, based on Kaplan Meier estimates, The risk of exacerbation requiring treatment was reduced by 45% (P = 0.001) (FIG. 1). Similarly, in study B, treatment with Ariflo over 26 weeks reduced the risk of exacerbation by 30% (P = 0.005) compared to placebo and the risk of exacerbation (stages 2 and 3) requiring treatment by a doctor or hospitalization. This was reduced by 32% (P = 0.004) (FIG. 2). In the third clinical trial C with Ariflo 15 mg BID over 6 months, ambiguous results in efficacy of treating COPD were obtained. In this study, the effect of Ariflo on exacerbation was not very significant (FIG. 3).

Survival rates of undeteriorated patients based on Kaplan-Meier estimates of the time they began to deteriorate again are summarized in Table 1 below.

Summary of Survival of Uncompromised Patients at Week 24 Treatment group Total number of patients Number of patients not worsened Survival Rate of Patients Not Exacerbated * Estimated Percentage of Patients Not Aggravated 95% CI down (%) 95% CI top (%) P-value Study A All worse Placebo 216 141 62.4 55.5 69.3 SB207499 431 336 74.0 69.3 78.6 0.008 Deterioration of stages 2 and 3 Placebo 157 69.7 63.1 76.3 SB207499 364 81.7 77.5 85.8 0.003 Study C All worse Placebo 226 143 56.0 47.8 64.2 SB207499 474 299 58.3 53.5 63.1 0.662 Deterioration of stages 2 and 3 Placebo 164 71.0 64.7 77.3 SB207499 354 70.9 66.5 75.3 0.793 Study B All worse Placebo 242 135 51.1 44.4 57.8 SB207499 469 318 63.9 59.1 68.6 0.004 Deterioration of stages 2 and 3 Placebo 165 64.3 57.9 70.8 SB207499 367 75.5 71.2 79.7 0.009 Results are shown for the population to be treated. * Survival rates of patients who did not worsen are estimated using Kaplan-Meier estimates of the time they began to worsen again. P-values are based on a log rating test.

In two clinical studies A and B in which ariflo (15 mg IR, BID) was efficacious in COPD treatment, the estimated percentage of patients that did not worsen was ariflo tablet 15 mg IR (BID) compared to patients receiving placebo. ) Were significantly higher (P = 0.008 and P = 0.004, respectively) (FIG. 4).

The benefit of Ariflo in reducing the risk of COPD exacerbation in both studies is an important clinical outcome because exacerbation is associated with poor long-term clinical outcomes and closely related to healthcare costs.

A preferred group of inhibitors are compounds in which the CI ₅₀ ratio is measured as described in US Pat. No. 5,998,428, wherein the IC ₅₀ ratio (high binding / low binding) is at least about 0.1. Such patents are incorporated herein by reference in their entirety. A preferred standard for PDE4-specific inhibitors that can be used in the present invention is that the IC ₅₀ ratio of the compound is at least about 0.1, wherein the IC ₅₀ ratio is [ ³ H] R-rolls for the PDE4 form that binds to high affinity to rolipram IC ₅₀ value when competing with the binding of rilam 1nM, and IC ₅₀ value when inhibiting PDE4 catalytic activity in the form of low affinity binding to rolipram using 1 μM [ ³ H] -cAMP as a substrate. to be.

Specific PDE4 inhibitors that may be included in such formulations include the compounds described in US Pat. No. 5,552,438, issued September 3, 1996. The patents and compounds described therein are all incorporated herein by reference. Compounds of particular interest described in US Pat. No. 5,552,438 are cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid and salts, esters thereof, In prodrug or physical form. The compound is considered herein the IUPAC name, the trademark Ariflo, the generic name cilomilast, and the combination of letters and numbers SB207499. Other PDE4 inhibitors that may be of interest include Astra's AWD-12-281 (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P. 98); 9-benzyladenin derivative (INSERM) named NCS-613; D-4418 from Chiroscience and Schering-Plough; Benzodiazepine PDE4 inhibitors identified as CI-1018 (PD-168787; Parke-Davis / Warner-Lambert); Benzodioxol derivatives of Kyowa Hakko described in WO 9916766; Napp's V-11294A (Landells, LJ et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998) 1998, 12 (Suppl. 28): Abst P2393); Roflumilast from Byk-Gulden (CAS reference No 162401-32-3) and phthalazinone (WO 9947505); And compounds identified as T-440 (Tanabe Seiyaku; Fujii, K. et al. J Pharmacol Exp Ther, 1998, 284 (1): 162). The compounds of the invention are preferably compounds having an IC ₅₀ ratio greater than 0.5, in particular compounds greater than 1.0. Most preferred compounds are roflumilast and cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid.

Other drugs useful for treating PED4-related diseases can also be included in the treatment. Examples of other therapeutic agents include drugs that treat inflammatory respiratory diseases such as bronchodilators, leukotriene receptor antagonists and leukotriene biosynthesis inhibitors; Drugs to treat non-respiratory inflammatory diseases such as irritable bowel disease (IBD); Immune control drugs such as recognition enhancers; Drugs to treat rheumatoid arthritis, rheumatoid myelitis, osteoporosis, gouty arthritis and other arthritis symptoms; blood poisoning; Septic shock; Endotoxin shock; Gram negative sepsis; Toxin shock syndrome; Adult respiratory distress syndrome; Brain malaria; Silicosis; Pulmonary sarcoidosis; Drugs for treating bone absorption disease; Reperfusion injury; Transplantation versus host response; Allograft rejection; Fever and myalgias due to infections such as influenza, secondary cachexia to infections or malignancies, secondary cachexia to human acquired immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS related syndrome); Keloid formation; Scar tissue formation; Crohn's disease; Ulcerative colitis; Heartburn; Autoimmune diseases such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosus; Drugs for treating viral infections such as cytomegalovirus (CMV), influenza virus, adenovirus and herpes virus; And drugs for treating yeast and fungal infections.

Examples of compounds for treating respiratory diseases include leukotriene antagonists; Mucolytic agents; Antitussives and expectorants; Antibiotic; Beta-agonists for oral or inhalation; PDE4-specific inhibitors and other phosphodiesterase inhibitors; Anti-colorants; Elastase inhibitors; Protein therapeutics such as IL4, IL5, IL8 and IL13 monoclonal anti-antibodies, anti-IgE; Or oral or inhaled corticosteroids. Particularly preferred combination therapy is the use of corticosteroids, beta agonists, anticholinergic agents, inhaled chromones, leukotriene antagonists or antibiotics for the treatment of secondary infections.

The amount of inhibitor that is effective in this method of treatment is in the range of 100 μg to 100 mg per dose, administered 1 to 4 times daily as needed. Preferred ranges are administered 1-2 times per day at 1-60 mg per dose. More preferably, it is administered 1 to 2 times a day at a dosage of 5 to 30 mg. It is best to administer once or twice a day at a dose of 10 to 20, or 10 to 15 mg, for example twice a day at a dose of 15 mg or once a day at a dose of 30 or 60 mg. desirable. Dosages to reduce the exacerbation and / or extent of the disease may be less than the amount used to treat the COPD itself.

Inhibitors are administered by conventional means. For example, it may be administered orally or as an inhalable powder or aerosol. It may be possible to formulate some of these inhibitors in topical patch forms, sustained injectable forms or suppository forms, and administration as oral or inhalation agents is considered a better route of delivery.

Preferred formulations for the purposes of the present invention are immediate or sustained release oral formulations containing 1 mg to 200 mg, more preferably 5 to 100 mg, most preferably 5 or 10 to 60 mg of Ariflo as an active ingredient. Is a tablet. Further preferred dosages within these ranges are 10, 15, 20, 30, 40, 50, 60, 70, 80 or 90 mg per formulation.

Clinical study protocols were generally performed as follows:

Appropriate patients show a clinical diagnosis of COPD (according to international treatment guidelines), expected FEV ₁ above 30%, below 70%, FEV ₁ / FVC below 0.7, and beta2-agonist administration after bronchodilator use Post reversibility showed firm airflow obstruction, limited to 15% or less. In each study, patients with COPD were enrolled in the four-week placebo run-in period and then randomly divided (2: 1) or 15 mg twice daily or placebo. Patients were monitored 1, 2 and 4 weeks after treatment and subsequently 4 weeks apart. During the study, patients were given salbutamol (prn) and / or fast-acting anticholinergic treatment simultaneously at fixed doses.

The effect of discontinuous treatment was tested in Study B, which included a 2-week randomized double-blind run-out phase. Randomly divided (1: 1) ariflo 15 mg (BID) or placebo for patients who received ariflo for the first 24 weeks for the run-out cycle; Patients receiving placebo initially for 24 weeks continued to receive placebo during the run-out cycle.

Pulmonary function measurements were performed in each study (excluding 1 week). St. George's Respiratory Questionnaire (SGRQ) from St. George's Hospital was used at baseline and at weeks 12 and 24 (or at the time of discontinuation). Routine compliance, vital signs, and experimental evaluations were performed in each study. These studies include frequent ECG assessments and extensive monitoring of patients whose gastrointestinal side effects are reported, which is a possible clinical issue regarding the possible effects of SB 207499 in both cardiovascular and gastrointestinal tract. 12-lead ECG assessments were performed at screening, prior to dosing at baseline and prior to dosing in each study during the double blind treatment period. In addition, 12-lead ECG assessments were performed on the first day of administration and 3 hours after drug administration. In a subset of patients, 24-hour Holter ECG monitoring was performed during run-in and at 1 and 20 weeks. The orthogonal vital signs and fecal occult blood tests were measured for all patients to obtain a common incidence of abnormal assessments in this patient population. The orbital vital signs were measured at screening, at baseline, and at the end of the double blind treatment. Fecal occult blood test was performed between screening and baseline and between 20 weeks and the end (24 weeks) of double-blind treatment.

All efficacy measures were analyzed for the population to be treated (intent-to-treat (ITT)), which was randomly administered study drug and defined as all patients with baseline assessments and one or more therapeutic efficacy assessments during the double blind period. Efficacy analysis for the Protocol Population (PP) (defined as patients who do not significantly violate the protocol) includes: lowest FEV ₁ , total score on SGRQ, co-primary measures of efficacy, secondary parameters, exercise tolerance test, post-workout breathing Difficulty, overall symptom score, and trough FVC were limited.

Claims (2)

Reducing the incidence and / or extent of the disease exacerbation in a mammal with chronic obstructive pulmonary disease, comprising administering an effective amount of a phosphodiesterase 4 (PDE4) inhibitor to a patient with chronic obstructive pulmonary disease (COPD) Way. Use of a phosphodiesterase 4 (PDE4) inhibitor in the manufacture of a medicament for reducing the incidence and / or extent of chronic obstructive pulmonary disease (COPD) exacerbation.