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Lung fibrosis is partially mediated by tyrosine kinase pathways. BIBF 1120 is a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) -- all receptors known to be involved in lung fibrosis.
Supported by Boehringer Ingelheim, Richeldi et al randomized 432 patients with idiopathic pulmonary fibrosis (265 with probable, 141 with definite, mostly with moderately severe disease) to receive oral BIBF 1120 in one of four doses (from 50 mg daily, up to 150 mg twice daily) or placebo for one year (the phase 2 TOMORROW study). The doses were then adjusted up and down according to their internal protocol -- a technique that introduces a daunting complexity into the statistical analysis, beyond your traditional randomized trial, and puts it beyond my ability to analyze their methodology. I suppose these newfangled and sophisticated study designs are wringing more information and statistical power out of the same number of patients. (The downside is, we regular docs can't understand it and need an independent arbiter to verify its legitimacy. But when there are potentially a few billion on the table, I don't imagine they're too concerned about my opinion.) Anyway:
At 12 months, the 150 mg b.i.d. dose reduced the decline in forced vital capacity by 0.12 liters more than placebo (the primary endpoint), with a p-value of 0.06 that just missed statistical significance.
96 of the 432 patients discontinued the drug due to adverse events, including 30% of patients at the high dose of 150 mg b.i.d.; however, 25% of placebo patients discontinued BIBF 1120 for adverse events, creating some confusion as to whether the adverse events were due to the drug or complications of underlying IPF.
Intriguingly, the 150 mg b.i.d. (high dose) of BIBF 1120 prevented exacerbations (a prespecified 2' endpoint), with 2.4 per 100 patient-years vs. 15.7 in the placebo group, p=0.02. That's a number needed to treat of 8 to prevent a possibly lethal exacerbation -- although there were no differences in reported mortality, which was not a prespecified endpoint. Expect results of a phase 3 trial that will provide more information within the next few years.
Richeldi L et al. Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis. N Engl J Med 2011; 365:1079-1087.