Exposure-safety analyses of nintedanib in patients with chronic fibrosing interstitial lung disease.

Nintedanib reduces the rate of decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib is 150 mg twice daily (BID). Data from Phase II and III trials in IPF and Phase III trials in SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and safety (liver enzyme elevations [defined as transaminase elevations equal or greater than 3 times the upper limit of normal] and diarrhea). Using data from 1403 subjects with IPF treated with 50-150 mg nintedanib BID, a parametric time-to-first-event model for liver enzyme elevations was established. Besides exposure, gender was a significant covariate, with a three-fourfold higher exposure-adjusted risk in females than males. Subsequent analysis of combined data from IPF, SSc-ILD (n = 576) and progressive fibrosing ILD (n = 663) studies suggested a consistent exposure-liver enzyme elevation relationship across studies. No exposure-diarrhea relationship was found using data from the various fibrosing ILDs, but diarrhea risk was dependent on dose administered. The positive correlation between exposure and risk of liver enzyme elevations was consistent across nintedanib studies in IPF, SSc-ILD and progressing fibrosing ILDs other than IPF. The effect size does not warrant a priori dose adjustment in patients with altered plasma exposure (excluding hepatic impairment patients, where there are specific labelling recommendations). For diarrhea, dose administered was a better predictor than exposure.

Schmid U ，Weber B ，Sarr C ，Freiwald M ... -  《BMC Pulmonary Medicine》

Exposure-efficacy analyses of nintedanib in patients with chronic fibrosing interstitial lung disease.

The tyrosine kinase inhibitor nintedanib reduces the rate of decline in forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib is 150 mg twice daily (BID). Data from Phase II and III trials in IPF, SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and efficacy. Using data from 1403 patients with IPF treated with 50-150 mg nintedanib BID in Phase II and III studies, a linear disease progression model with a maximum drug effect on the rate of decline in FVC was established. Age, height and gender were pre-specified covariates on baseline FVC. Stepwise analysis revealed no other covariates with a distinct effect on the exposure-efficacy relationship. The estimated plasma concentration producing 80% of the maximum drug effect was 10-13 ng/mL, close to the median exposure at 150 mg BID (10 ng/mL). The model in IPF was adapted using Phase III data from 575 patients with SSc-ILD and 663 patients with progressive fibrosing ILDs other than IPF. Besides differences in the natural decline in FVC without treatment, data were consistent with the exposure-efficacy relationship in IPF. For most patients with chronic fibrosing ILDs, the 150 mg nintedanib BID dose provides exposure levels associated with a therapeutic effect close to the maximum nintedanib effect independent of disease condition or baseline demographics.

Schmid U ，Weber B ，Magnusson MO ，Freiwald M ... -  《-》

Nintedanib: A Review in Fibrotic Interstitial Lung Diseases.

Lamb YN 《-》

Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial.

The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI -8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [-31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. Boehringer Ingelheim.

Wells AU ，Flaherty KR ，Brown KK ，Inoue Y ，Devaraj A ，Richeldi L ，Moua T ，Crestani B ，Wuyts WA ，Stowasser S ，Quaresma M ，Goeldner RG ，Schlenker-Herceg R ，Kolb M ，INBUILD trial investigators ... -  《-》

Progressive fibrosing interstitial lung diseases: A new concept and indication of nintedanib.

Makino S 《-》