Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.

BACKGROUND Nintedanib (formerly known as BIBF 1120) 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. METHODS We 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. RESULTS 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 FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<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; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; 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. CONCLUSIONS In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, 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. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).

[1]  B. Ryffel,et al.  Antifibrotic and Anti-inflammatory Activity of the Tyrosine Kinase Inhibitor Nintedanib in Experimental Models of Lung Fibrosis , 2014, The Journal of Pharmacology and Experimental Therapeutics.

[2]  S. Rosselot.  Idiopathic pulmonary fibrosis. , 2014, Nursing standard (Royal College of Nursing (Great Britain) : 1987).

[3]  A. Wells,et al.  Acute Exacerbations of Idiopathic Pulmonary Fibrosis , 2013, Respiration.

[4]  H. Collard,et al.  Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials , 2013, Respiratory Research.

[5]  M. L. R. D. Christenson,et al.  An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management , 2012 .

[6]  S. Sahn,et al.  Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference. , 2011, American journal of respiratory and critical care medicine.

[7]  Moisés Selman,et al.  Idiopathic pulmonary fibrosis , 2011, The Lancet.

[8]  Luca Richeldi,et al.  Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. , 2011, The New England journal of medicine.

[9]  W. Coward,et al.  The pathogenesis of idiopathic pulmonary fibrosis , 2010, Therapeutic advances in respiratory disease.

[10]  Jong-Min Song,et al.  Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome , 2010, European Respiratory Journal.

[11]  W. Sommergruber,et al.  BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. , 2008, Cancer research.

[12]  J. Egan,et al.  Idiopathic Pulmonary Fibrosis , 2007 .

[13]  G J Roth,et al.  Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis , 2007, European Respiratory Journal.

[14]  J. Hankinson,et al.  Standardisation of spirometry , 2005, European Respiratory Journal.

[15]  P. Jones.  St. George's Respiratory Questionnaire: MCID , 2005, COPD.

[16]  G. Raghu,et al.  Analyses of efficacy end points in a controlled trial of interferon-gamma1b for idiopathic pulmonary fibrosis. , 2005, Chest.

[17]  F. Martinez,et al.  Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. , 2003, American journal of respiratory and critical care medicine.

[18]  H. Collard,et al.  Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. , 2003, American journal of respiratory and critical care medicine.

[19]  A. Nicholson,et al.  Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. , 2003, American journal of respiratory and critical care medicine.

[20]  P. Jones,et al.  American translation, modification, and validation of the St. George's Respiratory Questionnaire. , 2000, Clinical therapeutics.

[21]  J. Roca,et al.  Standardization of the measurement of transfer factor (diffusing capacity) , 1993, European Respiratory Journal.

[22]  P. Jones,et al.  The St George's Respiratory Questionnaire. , 1991, Respiratory medicine.