Phase 3 INPULSIS™ Trials Published in the New England Journal of Medicine Show Investigational Nintedanib Slowed Lung Function Loss in People with Idiopathic Pulmonary Fibrosis

RIDGEFIELD, Conn., May 18, 2014 /PRNewswire/ -- Boehringer Ingelheim announced the results of its two pivotal Phase 3 INPULSIS™ trials (INPULSIS™-1 and -2; NCT01335464 and NCT01335477), which were published online today in the New England Journal of Medicine (NEJM). The INPULSIS™ trials evaluated the efficacy and safety of nintedanib, an investigational therapy being studied in people with idiopathic pulmonary fibrosis (IPF). The INPULSIS™ data will also be presented at the 2014 American Thoracic Society (ATS) International Conference in a joint NEJM/Journal of American Medical Association (JAMA) session on May 18 and as a late-breaking oral presentation on May 20.

IPF is a rare, progressive and fatal lung disease that causes permanent scarring of the lungs, difficulty breathing and decreases the amount of oxygen the lungs can supply to the body. IPF affects as many as 132,000 Americans. There are currently no FDA-approved treatments.

INPULSIS™-1 and -2, which involved a total of 1,061 people with IPF, met the primary endpoint: reduction in the annual rate of decline in forced vital capacity (FVC) over 52 weeks. In these trials, nintedanib reduced the annual rate of FVC decline compared to placebo by 48% in INPULSIS™-1 (-114.7 vs. -239.9 mL/year, respectively [95% CI: 77.7, 172.8]) and by 55% in INPULSIS™-2 (-113.6 vs. -207.3 mL/year, respectively [95% CI: 44.8, 142.7]).

"IPF is a very serious disease with a high unmet medical need for which there are currently no FDA-approved treatments," said study investigator, Luca Richeldi, M.D., Ph.D., Professor of Respiratory Medicine, Chair of Interstitial Lung Disease, University of Southampton, Honorary Consultant Physician, University Hospital Southampton. "We are excited by these data because the INPULSIS™ trials suggest evidence of nintedanib's impact on lung function loss in patients with IPF."

In both trials, the most prevalent adverse events (AE) were gastrointestinal. Diarrhea was the most frequent AE in the nintedanib groups compared to the placebo groups, and was reported in 61.5% vs. 18.6% of participants in INPULSIS™-1 and 63.2% vs. 18.3% of participants in INPULSIS™-2. Most cases were mild to moderate in intensity (93.7% in INPULSIS™-1 and 95.2% in INPULSIS™-2). In both trials, about 4.5% of people who used nintedanib discontinued treatment due to diarrhea (n=28 of 638). In these clinical trials, investigators had the option of dose reduction or dose interruption to help manage diarrhea.

Nausea was the second most common adverse event among patients treated with nintedanib versus placebo, occurring in 22.7% vs. 5.9% of participants in INPULSIS™-1 and 26.1% vs. 7.3% of participants in INPULSIS™-2.

The absolute change from baseline in FVC at 52 weeks, a pre-specified secondary endpoint, for nintedanib versus placebo was 109.9 mL in INPULSIS™-1 (-95.1 mL, nintedanib vs. -205.0 mL, placebo [95% CI: 71.3, 148.6]) and 109.8 mL in INPULSIS™-2 (-95.3 mL, nintedanib vs. -205.0 mL, placebo [95% CI: 70.9, 148.6]).

The proportion of FVC responders (i.e., categorical change), a pre-specified secondary endpoint, was also measured based on the number of patients who had an absolute decline in FVC of less than 5%, as well as an absolute decline in FVC of less than 10% at 52 weeks.

• In both trials, more patients treated with nintedanib versus placebo had an absolute decline in FVC of less than 5%:
  • INPULSIS™-1: 52.8% vs. 38.2%, respectively; OR 1.85 [95% CI: 1.28, 2.66]
  • INPULSIS™-2: 53.2% vs. 39.3%, respectively; OR 1.79 [95% CI: 1.26, 2.55]
• More nintedanib versus placebo patients had an absolute decline in FVC of less than 10% in the INPULSIS™-1 trial (70.6% vs. 56.9%, respectively; OR 1.91 [95% CI: 1.32, 2.79])
• This difference did not reach statistical significance in the INPULSIS™-2 trial (69.6% vs. 63.9%, respectively; OR 1.29 [95% CI: 0.89, 1.86])

Key secondary endpoints included time to first acute exacerbation over 52 weeks and change from baseline in health-related quality of life at 52 weeks, as assessed by St. George's Respiratory Questionnaire (SGRQ).    

In INPULSIS™-2, there was a significant increase in time to first acute exacerbation in the nintedanib group compared with placebo (HR 0.38 [95% CI: 0.19, 0.77]). In addition, the proportion of patients with at least one investigator-reported acute exacerbation was lower in the nintedanib group (3.6%) compared with placebo (9.6%).

In INPULSIS™1, there was no difference between the nintedanib and placebo groups in time to first acute exacerbation (HR 1.15 [95% CI: 0.54, 2.42]), and the proportion of patients with at least one investigator-reported acute exacerbation was comparable between the nintedanib and placebo groups (6.1% vs. 5.4%, respectively).

In the pre-specified pooled analysis, there was no significant difference between nintedanib and placebo in time to first investigator-reported acute exacerbation (HR 0.64 [95% CI: 0.39, 1.05]). The proportion of patients with at least one investigator reported acute exacerbation was 4.9% in the nintedanib group versus 7.6% in the placebo group. A pre-specified sensitivity analysis based on adjudicated acute exacerbations (confirmed or suspected) in the pooled data was conducted and showed a benefit of nintedanib compared with placebo (HR 0.32 [95% CI: 0.16, 0.65]).

In INPULSIS™-2, there was a significantly smaller increase in SGRQ total score with nintedanib versus placebo at week 52, which is consistent with less deterioration in health-related quality of life (2.80 versus 5.48; difference of -2.69 [95% CI: -4.95, -0.43]). In INPULSIS™-1, there was no difference between the treatment groups in adjusted mean change from baseline at week 52 in SGRQ total score (4.34, nintedanib vs. 4.39, placebo [95% CI: -2.50, 2.40]).

"The results of the Phase 3 INPULSIS™ trials help bring us closer to our goal of delivering an effective treatment option for people in the U.S. with this progressive and fatal lung disease," said Tunde Otulana, M.D., senior vice president, Clinical Development and Medical Affairs at Boehringer Ingelheim. "Boehringer Ingelheim has a long-standing heritage in treating respiratory diseases, and we continue to conduct important research in the rapidly evolving respiratory space. These nintedanib data exemplify our commitment to researching therapies for a variety of chronic lung diseases such as IPF."

A higher proportion of patients in the nintedanib groups versus placebo experienced elevations in liver enzymes. In INPULSIS™-1, 15 patients (4.9%) in the nintedanib group and 1 patient (0.5%) on placebo experienced ALT and/or AST elevations of =3x ULN. In INPULSIS™-2, 17 patients (5.2%) in the nintedanib group and 2 patients (0.9%) on placebo experienced ALT and/or AST elevations of =3x ULN.

Overall, the proportions of people experiencing serious adverse events was similar in the nintedanib and placebo groups (31.1% vs. 27.0% in INPULSIS™-1; 29.8% vs. 32.9% in INPULSIS™-2, respectively). A total of 65 nintedanib patients (21.0%) and 22 (10.8%) placebo patients in INPULSIS-1 and 58 nintedanib patients (17.6%) and 33 placebo patients (15.1%) in INPULSIS-2 discontinued study medication due to adverse events.  

About the Phase 3 INPULSIS™ trials (INPULSIS™-1 and INPULSIS™-2)   
The double-blind, randomized and placebo-controlled trials evaluated the effect of oral nintedanib, 150 mg twice daily, on annual rate of decline in forced vital capacity FVC, in people with IPF over 52 weeks. A total of 1,061 (n=638, nintedanib vs. 423, placebo) people with IPF were enrolled in the two trials, including 513 people in INPULSIS™-1 (n=309, nintedanib vs. 204, placebo) and 548 in INPULSIS™-2 (n=329, nintedanib vs. n=219, placebo). The trials had an identical design, matched dosing, inclusion criteria, and endpoints.

The primary endpoint was the annual rate of decline in FVC (expressed in mL over 52 weeks). There were two key secondary endpoints: change from baseline in health-related quality of life, as assessed by the SGRQ total score, and time to first acute exacerbation (days). Other secondary endpoints were respiratory mortality, overall survival, on-treatment survival, and time to death or lung transplant.

Included were people over 40 years of age with a diagnosis of IPF within five years before enrollment based on the most recent American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT) IPF guideline for diagnosis and management.

Diagnosis required central review and confirmation of a combination of high resolution computerized tomography pattern and surgical lung biopsy if available.

About nintedanib 
Nintedanib is an investigational small molecule tyrosine kinase inhibitor (TKI) in development by Boehringer Ingelheim for idiopathic pulmonary fibrosis (IPF). It targets growth factors, which have been shown to be potentially involved in pulmonary fibrosis -- the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR).

About idiopathic pulmonary fibrosis  
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, severely debilitating and ultimately fatal lung disease for which there are no FDA-approved treatment options in the U.S. Although lung transplantation has been shown to improve survival, the procedure is uncommon because of the limited availability of lungs for transplantation or people are either too ill or don't survive long enough to undergo the transplant. The incidence of IPF can vary considerably and there is some evidence that the population is increasing. IPF is characterized by progressive scarring of lung tissue and loss of lung function over time. Development of scarred tissue is called fibrosis. Over time, as the tissue thickens and stiffens with scarring, the lungs lose their ability to take in and transfer oxygen into the bloodstream, and vital organs do not get enough oxygen. As a result, individuals with IPF experience shortness of breath, cough and often have difficulty participating in everyday physical activities.

About Boehringer Ingelheim Pharmaceuticals, Inc.  
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, Conn., is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates and more than 47,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

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In 2013, Boehringer Ingelheim achieved net sales of about $18.7 billion (14.1 billion euro). R&D expenditure in the Prescription Medicines business corresponds to 19.5% of its net sales.

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