Ridgefield, Connecticut based Boehringer Ingelheim Pharmaceuticals, Inc. reports that an interim analysis of the open-label, single arm INPULSIS-ON extension trial of its drug OFEV (nintedanib) for treatment of the rare and serious lung disease idiopathic pulmonary fibrosis (IPF) shows efficacy and safety data consistent to that in two previous identically-designed Phase III INPULSIS trials in patients with IPF.
Boehringer Ingelheim was granted Breakthrough Therapy designation by the FDA on October 15, 2014 for OFEV capsules for oral use, taken twice daily. OFEV is one of the first FDA-approved drug treatments for IPF and the only kinase inhibitor approved to treat this disease.
The FDA’s approval of OFEV was based on findings from a robust clinical trial program involving more than 1,200 patients with IPF worldwide, and included the Phase II TOMORROW trial (NCT00514683) and the Phase III INPULSIS trials (INPULSIS-1 and INPULSIS-2; NCT01335464 and NCT01335477). All these studies were randomized, double-blind, placebo-controlled trials comparing OFEV 150 mg twice daily to placebo for 52 weeks. Both INPULSIS trials were identically designed while the TOMORROW study design was similar.
Results in the latest clinical trials reportedly show no relevant changes in the safety and tolerability of OFEV, with trial results also suggesting that treatment with the drug has a long-term effect (approximately two years) on slowing disease progression across both pivotal and open-label trials (as measured by annual rate of forced vital capacity [FVC] decline). These new data are particularly important because people with IPF may be on therapy for an extended period. The results were presented at the European Respiratory Society (ERS) International Congress 2015.
The INPULSIS-ON interim analysis showed that the decline in FVC at 48 weeks in patients continuing treatment with OFEV in the extension trial was comparable to what was observed in the 52 week INPULSIS trials. These data support the beneficial effect of OFEV on slowing disease progression long-term in people with IPF.
“These data are significant because they provide additional evidence that OFEV maintains its safety profile and efficacy at slowing IPF disease progression over approximately two years, reinforcing the previously-reported one-year Phase III data,” says Eric White, M.D., Associate Professor of Medicine, Pulmonary and Critical Care, University of Michigan Health System. “Studies like INPULSIS-ON are important because they inform us about the longer-term safety and efficacy of OFEV. Evidence that OFEV maintains its clinical effect in the absence of any new safety signals provides me with more information to discuss with my patients considering treatment with OFEV.”
Dr. White’s clinical interests include interstitial lung diseases and lung cancer. His current research focus is on the role of connective tissue in lung cancer and interstitial lung diseases.
Idiopathic Pulmonary Fibrosis (IPF) is a rare, progressive, irreversible, unpredictable and ultimately fatal disease characterized by progressive scarring (fibrosis) in the lung. It is a specific type of interstitial lung disease in which the small air sacs of the lung, known as alveoli, gradually become replaced by fibrotic (scar) tissue. The abnormal fibrosis and scar formation typically begins in the terminal areas of the pulmonary tree lining the air sacs where gas exchange occurs. Normally, this tissue is a thin layer consisting of a few, easily permeable cells. With IPF, progressive scarring causes the normally thin and pliable tissue to thicken and become stiff, making it more difficult for the lungs to expand, preventing oxygen from readily getting into the bloodstream.
IPF inevitably leads to worsening lung function and exercise tolerance, and shortness of breath. There is a corresponding increase in respiratory symptoms with dyspnea, air hunger and a non-productive cough. Every IPF patient follows a different and unpredictable course and it is not possible to predict if a patient will progress slowly or rapidly, or when the rate of decline may change. Periods of transient clinical stability in IPF, should they occur, inevitably give way to continued disease progression. IPF is a uniformly fatal disease, with the median estimated survival time from diagnosis two to five years, with a five-year survival rate of approximately 20-40 percent, which makes IPF more rapidly lethal than many cancers, including breast, ovarian, colorectal, pancreatic, lung, and liver cancers. IPF typically occurs in patients over the age of 50, and is more common in men than in women.
The incidence of IPF is greater than that of ovarian cancer, similar to those of pancreatic cancer and of all leukemias combined, and nearly 30 times that of cystic fibrosis, and is estimated to affect as many as 132,000 Americans, typically men over the age of 65.
No new safety signals were identified following long-term treatment with OFEV in INPULSIS-ON. Adverse events (AEs) were reported in 92.8 percent and 96.7 percent of patients continuing with OFEV and initiating OFEV, respectively. Serious adverse events (SAEs) were reported in 41.9 percent and 39.5 percent of these same patients. The most frequent AEs were gastrointestinal in nature with diarrhea affecting 64 percent of patients and leading to drug discontinuation in 5 percent (2.3 percent and 9.5 percent of patients continuing or initiating therapy, respectively).
“These long-term data provide evidence that the effect of OFEV persists for close to two years,” says Danny McBryan, M.D., vice president, Clinical Development and Medical Affairs, Respiratory, Boehringer Ingelheim Pharmaceuticals, Inc. “At Boehringer Ingelheim, we are committed to advancing the science of this devastating disease through our robust clinical trial program and ongoing research of OFEV in IPF patients. This continued research, and the inclusion of OFEV in the international IPF treatment guidelines, demonstrate the value of OFEV in providing important patient outcomes, particularly in slowing disease progression in IPF.”
Consistent effect of OFEV in analyses of treatment interactions
New pooled subgroup analyses from the Phase III INPULSIS studies presented at the ERS conference examined whether OFEV had a consistent effect on patients with IPF who were also taking commonly used medications, including anti-acids (abstract OA4502) and corticosteroids (abstract OA4498), when they were enrolled in the study.
Anti-acid medications are often given to patients with IPF to manage gastroesophageal reflux disease (GERD), which is commonly coexistant in patients with IPF and is considered a risk factor for IPF disease progression. IPF patients are also sometimes treated with corticosteroid medications (e.g., prednisone) and therefore participants receiving low doses of corticosteroids were allowed in the INPULSIS trials.
Abstracts presented at the ERS congress can be downloaded here:
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Boehringer Ingelheim Inc.
Canadian Pulmonary Fibrosis Foundation
Toronto General Hospital University Health Network