Investigational TKI nintedanib slowed lung function loss in idiopathic pulmonary fibrosis

Nintedanib, an investigational small molecule tyrosine kinase inhibitor (TKI), slowed lung function loss in patients with idiopathic pulmonary fibrosis (IPF), according to the results of 2 pivotal phase 3 trials presented at the American Thoracic Society International Conference in San Diego.

IPF is a chronic, progressive, severely debilitating, and ultimately fatal lung disease for which there are no FDA-approved drugs.  The disease 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,” according to Tunde Otulana, MD, senior vice president, clinical development and medical affairs at Boehringer Ingelheim.

“As a result, individuals with IPF experience shortness of breath, cough and often have difficulty participating in everyday physical activities,” Dr Otulana said.

The double-blind, randomized, and placebo-controlled INPULSIS trials (INPULSIS-1 and -2; NCT01335464 and NCT01335477), which were published May 18^th online in the New England Journal of Medicine, evaluated the effect of oral nintedanib, 150 mg twice daily, on annual rate of decline in forced vital capacity (FVC), in patients with IPF who were followed for 52 weeks. The trials were sponsored by the manufacturer, Boehringer Ingelheim.

INPULSIS-1 and -2, which involved more than 1,000 patients with IPF, met the primary end point: reduction in the annual rate of decline in FVC over 52 weeks.

"We believe these data help bring us closer to our goal of delivering an effective treatment option for people in the United States with this progressive and fatal lung disease,” said Dr Otulana.

A total of 1,061 (n=638, nintedanib vs 423, placebo) patients with IPF were enrolled in the 2 trials, including 513 people in INPULSIS-1 (n=309, nintedanib vs n=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 end points.

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]).

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 nausea was the second most common adverse event. However, less than 5% of patients dropped out of the trials because of diarrhea.

Diagnosing IPF can be difficult because it requires specific diagnostic testing, such as lung imaging using a high-resolution CAT scan and pulmonary function tests, according to Dr Otulana.

“Misdiagnosis often occurs because symptoms are similar to other respiratory diseases such as COPD and asthma, and to congestive heart failure,” he said.

Early and accurate diagnosis of IPF is important because management options such as supplemental oxygen treatment, cough management, and pulmonary rehabilitation (which can include special exercises or breathing strategies) may help patients manage their condition and maintain their quality of life.

IPF is the most common reason for lung transplant in the United States. “The procedure is infrequent because of the limited availability of lungs for transplantation or patients are either too ill or don’t survive long enough to undergo the transplant,” Dr Otulana said.