Nintedanib is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of Nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis.
Researchers have conducted two replicate 52-week, randomized, double-blind, phase 3 trials ( INPULSIS-1 and INPULSIS-2 ) to evaluate the efficacy and safety of 150 mg of Nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis.
The primary end point was the annual rate of decline in forced vital capacity ( FVC ). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period.
A total of 1066 patients were randomly assigned in a 3:2 ratio to receive Nintedanib or placebo. The adjusted annual rate of change in forced vital capacity was −114.7 ml with Nintedanib versus −239.9 ml with placebo ( difference, 125.3 ml; P less than 0.001 ) in INPULSIS-1 and −113.6 ml with Nintedanib versus −207.3 ml with placebo ( difference, 93.7 ml; P less than 0.001) in INPULSIS-2.
In INPULSIS-1, there was no significant difference between the Nintedanib and placebo groups in the time to the first acute exacerbation ( hazard ratio with Nintedanib, 1.15; P=0.67 ); in INPULSIS-2, there was a significant benefit with Nintedanib versus placebo ( hazard ratio, 0.38; P=0.005 ).
The most frequent adverse event in the Nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the Nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.
In patients with idiopathic pulmonary fibrosis, Nintedanib has reduced the decline in forced vital capacity, which is consistent with a slowing of disease progression; Nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. ( Xagena )
Richeldi L et al, N Engl J Med 2014; 370:2071-2082