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Nintedanib Receives FDA ‘Breakthrough Therapy’ Designation

Treatment under review for patients with pulmonary fibrosis

The FDA has granted “breakthrough therapy” status to nintedanib (Boehringer Ingelheim), an investigational therapy currently under regulatory review for the treatment of patients with idiopathic pulmonary fibrosis (IPF). The drug’s efficacy and safety in the treatment of IPF have not been established.

The “breakthrough therapy” designation process was established by the FDA in 2012 and is intended to expedite the development and review of drugs for serious or life-threatening conditions if preliminary clinical evidence has indicated that the treatment may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

IPF is a serious, life-threatening lung disease that causes permanent scarring of the lungs and 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. Results from two pivotal phase III studies (INPULSIS-1 and INPULSIS-2) that evaluated the efficacy and safety of nintedanib in patients with IPF were published online May 18 in the New England Journal of Medicine.

In both studies, which involved a total of 1,061 patients, nintedanib met the primary endpoint: a reduction in the annual rate of decline in forced vital capacity (FVC) over 52 weeks. Nintedanib reduced the annual rate of FVC decline by 48% compared with placebo in the INPULSIS-1 study (–114.7 vs. –239.9 mL/year, respectively) and by 55% in the INPULSIS-2 study (–113.6 vs. –207.3 mL/year, respectively).

The absolute change from baseline in FVC at 52 weeks (a pre-specified secondary endpoint) for nintedanib compared with placebo was 109.9 mL in the INPULSIS-1 trial (–95.1 mL vs. –205.0 mL, respectively) and 109.8 mL in the INPULSIS-2 trial (–95.3 mL vs. –205.0 mL, respectively).

In a pre-specified pooled analysis, there was no significant difference between nintedanib and placebo in the time to first investigator-reported acute exacerbation (hazard ratio, 0.64). The proportion of patients with at least one investigator-reported acute exacerbation was 4.9% in the nintedanib group compared with 7.6% in the placebo group.

Overall, the proportions of patients experiencing serious adverse events were similar in the nintedanib and placebo groups — 31.1% vs. 27.0%, respectively, in the INPULSIS-1 study, and 29.8% vs. 32.9%, respectively, in the INPULSIS-2 study. A total of 65 nintedanib-treated patients (21.0%) and 22 placebo patients (10.8%) in the INPULSIS-1 trial and 58 nintedanib-treated patients (17.6%) and 33 placebo-treated patients (15.1%) in the INPULSIS-2 trial discontinued study medication because of adverse events.

Nintedanib is an investigational small-molecule tyrosine kinase inhibitor (TKI) in development for the treatment of IPF. It targets growth factors that are believed to be involved in pulmonary fibrosis: the vascular endothelial growth factor receptor (VEGFR), the fibroblast growth factor receptor (FGFR), and the platelet-derived growth factor receptor (PDGFR).

Sources: Boehringer Ingelheim; July 16, 2014; and Boehringer Ingelheim; May 18, 2014.

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