Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: Subgroup analysis of the randomised, double-blind, placebo-controlled, phase 3 INBUILD trial

Yoshikazu Inoue,Takafumi Suda,Hideya Kitamura,Masaki Okamoto,Arata Azuma,Naohiko Inase,Masataka Kuwana,Shigeki Makino,Yasuhiko Nishioka,Takashi Ogura,Ayako Takizawa,Hiroyuki Ugai,Susanne Stowasser,Rozsa Schlenker-Herceg,Tsutomu Takeuchi

doi:10.1016/j.rmed.2021.106574

Abstract

BackgroundThe efficacy of nintedanib in progressive fibrosing interstitial lung diseases (ILDs) was demonstrated in the randomised, double-blind, placebo-controlled INBUILD trial. This subgroup analysis evaluated the efficacy and safety of nintedanib in the Japanese population. MethodsPatients with progressive fibrosing ILDs (evaluated by physicians within 24 months of screening) were randomised (1:1) to twice-daily 150-mg nintedanib or placebo; treatment continued until the last patient completed 52 weeks. The primary endpoint was the annual rate of decline in forced vital capacity (FVC) over 52 weeks. Time-to-first acute ILD exacerbation or death and time-to-death up until the last patient had completed the week 52 visit were evaluated. This subgroup analysis included 108 Japanese patients. ResultsThe adjusted annual rates of FVC decline (mL/year) over 52 weeks for Japanese patients were −148.31 (nintedanib) and −240.36 (placebo), adjusted difference: 92.05 (95% CI: −10.69–194.80) and for non-Japanese patients were −67.41 (nintedanib) and −177.65 (placebo), adjusted difference: 110.24 (95% CI: 64.97–155.52). No heterogeneity in treatment effect between Japanese and non-Japanese subgroups was observed (treatment-by-subgroup interaction, p = 0.75). The risks of “acute exacerbation or death” (hazard ratio, 0.30 [95% CI: 0.10–0.91]) and mortality (hazard ratio, 0.54 [95% CI: 0.14–2.11]) in Japanese patients were numerically lower for nintedanib than placebo. There were no new or unexpected safety findings. ConclusionsIn Japanese patients, nintedanib slowed ILD progression, evidenced by a reduction in the annual rate of decline in FVC vs placebo. The efficacy and safety of nintedanib in Japanese patients were consistent with the overall INBUILD population. Clinicaltrials.govNCT02999178 (21-Dec-2016).

Highlights

Interstitial lung diseases (ILDs) represent a spectrum of lung pa thologies of non-autoimmune and autoimmune background that commonly manifest with a progressive fibrosing phenotype [1,2,3,4,5]
Nintedanib, a small molecule inhibitor of selected tyrosine kinases [10,11], is approved for treatment of idiopathic pulmonary fibrosis (IPF) based on results of the INPULSIS and TOMORROW trials [12,13], for systemic sclerosis-associated ILD (SSc-ILD) based on the results of the SENSCIS trial [4,14,15], and for progressive fibrosing ILD based on the results of the INBUILD trial [16,17]
There was a numerical imbalance in baseline demographics and disease characteristics of Japanese patients (Table 1) between the treatment groups with respect to sex, smoking status, percentage of heavy smokers (≥40 pack-years), and some clinical ILD diagnoses

Summary

Introduction

Interstitial lung diseases (ILDs) represent a spectrum of lung pa thologies of non-autoimmune and autoimmune background that commonly manifest with a progressive fibrosing phenotype [1,2,3,4,5]. The INBUILD trial was not designed or powered to evaluate the potential benefit of nintedanib in specific ILD subgroups, recent subgroup analyses from the INBUILD trial suggest that nintedanib reduces the annual rate of decline in lung function irrespective of underlying ILD diagnoses [18]. This is supported by preclinical data showing that nintedanib inhibits important pathways involved in fibrosis progression [19,20] and has antifibrotic activity in various animal models of pulmonary fibrosis that replicate the different features and triggers of human pathology [21]. The risks of “acute exacerbation or death”

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Discussion

Conclusion