SAN DIEGO – Compared with placebo, the investigative tyrosine kinase inhibitor nintedanib helped preserve forced vital capacity in patients with idiopathic pulmonary fibrosis, according to phase III results published online May 18 in the New England Journal of Medicine and presented at an international conference of the American Thoracic Society.
Across two trials, a total of 1,066 patients were randomized 3:2 to receive 150 mg of nintedanib twice daily or placebo for 52 weeks. In the first trial, dubbed INPULSIS-1, the adjusted annual rate of change in forced vital capacity (FVC) was –114.7 mL with nintedanib versus –239.9 mL with placebo (difference 125.3 mL; 95% confidence interval, 77.7-172.8; P less than .001). In INPULSIS-2, the second trial, the rate of change was –113.6 mL with nintedanib versus –207.3 mL with placebo (difference 93.7 mL; 95% CI, 44.8 to 142.7; P less than 0.001).
"The curves for changes from baseline in FVC over time in the nintedanib and placebo groups separated early in the two studies and continued to diverge over time," said the investigators (N. Engl. J. Med. 2014 May 18 [doi:10.1056/NEJMoa1402584]). Myocardial infarctions were reported in five (1.6%) nintedanib patients and one (0.5%) placebo patient in the first trial and five (1.5%) nintedanib patients and one (0.5%) placebo patient in the second. Two infarctions in the nintedanib groups and one in the placebo groups were fatal. "The clinical significance of this finding is unknown, and further observation in larger cohorts is needed," the investigators said.
University of Southampton
Dr. Luca Richeldi
Idiopathic pulmonary fibrosis (IPF) "is a very serious disease with a high unmet medical need for which there are currently no FDA-approved treatments. We are all very excited by these data because they suggest evidence of nintedanib’s impact on lung function loss in patients with IPF. Overall, [it’s] a positive message that we are making progress," said lead investigator Dr. Luca Richeldi, chair of interstitial lung disease at the University of Southampton (England).
Results were mixed on secondary endpoints. There was no significant between-group difference in death from any cause or respiratory causes; 5.5% of nintedanib patients and 7.8% of placebo patients died.
Likewise, the time to first acute exacerbation and progression on the St. George’s Respiratory Questionnaire (SGRQ) were significantly delayed only in INPULSIS-2, not INPULSIS-1. On pooled analysis, nintedanib offered no advantage over placebo in time to first exacerbation (Hazard Ratio, 0.64; 95% CI, 0.39-1.05; P = .08) or mean 52-week change from baseline SGRO.
The "difference in the key secondary endpoint between [the trials] was not explained by the differences in baseline characteristics." Regarding exacerbations, they "are relatively rare events in patients with idiopathic pulmonary fibrosis who are in clinical trials and are difficult to assess and categorize, which may explain some of the heterogeneity in our findings," the investigators said.
About 62% of nintedanib patients versus about 18% of placebo patients reported diarrhea, which was usually mild to moderate. Less than 5% of nintedanib patients left the trials because of it. Liver enzyme levels three times above normal were found in about 5% of nintedanib patients versus less than 1% of placebo patients.
The study groups were well matched; about 80% of subjects were men, about 67 years old on average. Baseline FVC was about 80% of predicted value in all study arms.
Boehringer Ingelheim – the maker of nintedanib – funded the work, along with the British National Health Service. Six of the 23 authors are employed by Boehringer Ingelheim. Most of the other authors reported consulting fees and other payments from pharmaceutical companies, including Boehringer Ingelheim in some cases. Dr. Richeldi reported advisory or consulting fees from InterMune, MedImmune, Roche, Takeda, Biogen Idec, Sanofi-Aventis, and ImmuneWorks, plus lecture fees from Shionogi and grant support from InterMune.