Pamufetinib (TAS-115) for Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype: A double-blind, multicenter, phase 2b Clinical Trial

Abstract Rationale No recommended therapy exists for chronic fibrosing interstitial lung diseases (CF-ILD) with disease progression despite ongoing treatment with nintedanib or pirfenidone. Pamufetinib (also known as TAS-115) is a novel oral antifibrotic tyrosine kinase inhibitor in development for CF-ILD with a progressive phenotype. Objective We sought to evaluate the dose-response of pamufetinib monotherapy in patients with CF-ILD including idiopathic pulmonary fibrosis (IPF) with a progressive phenotype despite an antifibrotic treatment. Methods In this double-blind, multicenter, active-controlled phase 2 b study, patients with CF-ILD with a progressive phenotype (defined as ≥ 5% decline in the annual percent predicted forced vital capacity [%FVC] despite treatment with nintedanib or pirfenidone and an %FVC ≥ 50%) were randomized 1:1:1 to pamufetinib 50 mg, 100 mg, or control (nintedanib or pirfenidone) for ≥ 26 weeks. The primary endpoint was the 26-week rate of decline in FVC. Measurements and Main Results Of the 243 patients randomized, approximately 70% had IPF. The 26-week rate of change in FVC was −157.8 mL, −95.9 mL, and −63.6 mL in patients receiving pamufetinib 100 mg, pamufetinib 50 mg, and control, respectively; as such, no clear dose-response relationship was observed. The most frequent adverse event in the pamufetinib groups was rash, which was mostly mild or moderate in severity. Conclusions While the safety profile was acceptable, pamufetinib failed to decelerate FVC decline in patients with CF-ILD with a progressive phenotype who had previously been treated with nintedanib or pirfenidone. No benefits were demonstrated by switching from standard antifibrotic treatment to pamufetinib monotherapy. Clinical trial registered with the Japan Registry of Clinical Trials (https://jrct.mhlw.go.jp/en-top; jRCT2051210050).