Nintedanib In Idiopathic Pulmonary Fibrosis Research Articles

Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis, Cytisine versus Nicotine for Smoking Cessation, and FACED Score for Non-Cystic Fibrosis Bronchiectasis.

Idiopathic pulmonary fibrosis (IPF) is chronic, and ultimately fatal, lung scarring of unknown etiology characterized by dyspnea and progressive loss of lung function. Nintedanib is an intracellular inhibitor of various tyrosine kinases shown in a phase 2 trial to decrease the rate of decline of FVC in IPF (2). The INPULSIS study group conducted two replicate phase 3 trials (INPULSIS-1 and INPULSIS-2) to determine the efficacy and safety of nintedanib (150 mg twice daily) in patients with IPF. These trials were multinational, randomized, double-blind, placebo-controlled, parallel-group studies. Patients (1,066) were randomized in a 3:2 fashion (309 nintedanib and 204 placebo in INPULSIS-1; 329 nintedanib and 219 placebo in INPULSIS-2) to receive either nintedanib or placebo for 52 weeks. Inclusion criteria included the following: patient age, at least 40 years; high-resolution computed tomography (HRCT) within the previous 12 months; a diagnosis of IPF within the past 5 years, confirmed centrally by a single radiologist and single pathologist who reviewed the HRCT images (all patients) and lung biopsies (if available); FVC not exceeding 50% predicted, and diffusing capacity of the lung for carbon monoxide (DLCO) of 30–79% predicted. The primary end point was decline in FVC over 12 months, and secondary end points included time to first IPF exacerbation and change in the St. George’s Respiratory Questionnaire (SGRQ) score over 12 months. After 52 weeks, the annual rate of decline in FVC for INPULSIS-1 was 2114.7 ml with nintedanib versus 2239.9 ml with placebo (absolute difference, 125.3 ml; P , 0.001); for INPULSIS-2 it was 2113.6 ml with nintedanib versus 2207.3 ml with placebo (absolute difference, 93.7 ml; P , 0.001). In INPULSIS-1, there was no difference between groups in time to first IPF exacerbation (hazard ratio, 1.15; P = 0.67) or in the number of patients with an IPF exacerbation (6.1 vs. 5.4%). For INPULSIS-2, the nintedanib group had a significant increase in time to first IPF exacerbation (hazard ratio, 0.38; P = 0.005) and a smaller number of patients with at least one exacerbation (3.6 vs. 9.6%). In the pooled analysis there was no significant difference in exacerbations between INPULSIS and placebo groups (4.9 vs. 7.6%; P = 0.08). There was no difference in SGRQ scores in INPULSIS-1, but a significantly smaller increase in the SGRQ score in the nintedanib group (2.80 vs. 5.48 points; P = 0.02) was observed in INPULSIS-2. In the pooled analysis there was no significant difference in SGRQ scores between the INPULSIS and placebo groups (difference, 1.43; P = 0.09). The most frequent adverse event reported was diarrhea in both INPULSIS-1 (61.5%) and INPULSIS-2 (63.2%), leading to study drug discontinuation in 4.5% of INPULSIS-1 and 4.3% of INPULSIS-2 patients. This study was well designed, hit its primary end point, and supported the findings noted in the TOMORROW (To Improve Pulmonary Fibrosis with BIBF 1120) trial (2). There was, however, an inconsistent effect of nintedanib on exacerbation rates and SGRQ scores between INPULSIS-1 and INPULSIS-2, with the pooled analysis showing no significant difference between treatment and placebo groups. The differences in these secondary end points, unfortunately, cannot be explained by the patients’ baseline characteristics as they were similar. The variability in exacerbation rates can be explained by the paucity of exacerbations that occur in patients enrolled in clinical trials, as well as the difficulties with diagnosing and categorizing them; however, this reason does not account for the differences in SGRQ scores. Whereas almost two-thirds of patients receiving nintedanib had gastrointestinal side effects, less than 5% discontinued the drug. These data suggest that gastrointestinal side effects have little effect

Pre-specified subgroup analyses of pooled data from the INPULSIS™ trials of nintedanib in idiopathic pulmonary fibrosis

Background: The two replicate randomized, double-blind, placebo-controlled, 52-week Phase III INPULSIS™ trials assessed the efficacy and safety of nintedanib 150 mg twice daily in patients with IPF. Nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) in mL/year, the primary endpoint, in both trials (p < 0.001 for both), consistent with slowing disease progression. Statistically significant differences in favour of nintedanib on the key secondary endpoints (time to first acute exacerbation and change from baseline in St George's Respiratory Questionnaire [SGRQ] total score over 52 weeks) were observed in INPULSIS™-2, but not in INPULSIS™-1.

Pooled analysis of mortality data from the TOMORROW and INPULSIS™ trials of nintedanib in idiopathic pulmonary fibrosis (IPF)

Pooled analysis of mortality data from the TOMORROW and INPULSIS™ trials of nintedanib in idiopathic pulmonary fibrosis (IPF)

Nintedanib in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) conveys a median survival of 3 years and until recently has lacked effective therapies. Nintedanib, an orally available, small-molecule tyrosine kinase inhibitor with selectivity for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptors has recently been shown, in two pivotal phase III studies, to effectively slow IPF disease progression. Consequently, nintedanib was given accelerated approval by the FDA in October 2014 for the treatment of IPF. This monograph explores the preclinical rationale for the antifibrotic role of nintedanib and provides an overview of the available data on pharmacokinetics, efficacy and safety.

Nintedanib in idiopathic pulmonary fibrosis

Nintedanib in idiopathic pulmonary fibrosis

Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

BackgroundNintedanib (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.MethodsWe 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.ResultsA 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.ConclusionsIn 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.)