Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial

Background Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fi brosis (IPF). The aim of this study was to investigate the effi cacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF. Methods In this randomised, double-blind, phase 2 trial, we recruited patients aged 45-85 years with defi nite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratifi ed by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The primary endpoints were progression-free survival, defi ned as time to all-cause death or a categorical decrease from baseline in FVC % predicted, in the intention-to-treat population, in patients with sLOXL2 concentrations in the 50th percentile or higher, and in patients with sLOXL2 concentrations in the 75th percentile or higher. Treatment duration was event-driven, and interim analyses were planned and conducted after approximately 120 and 200 progression-free survival events, respectively, occurred. We compared treatment groups with the stratifi ed log-rank test. This study is registered with ClinicalTrials. gov, number NCT01769196. Findings Patients with IPF were recruited between Jan 31, 2013, and June 1, 2015. The intention-to-treat population included 544 randomly assigned patients (272 patients in both groups), and the safety population included 543 randomly assigned patients who received at least one dose of study medication. The study was terminated when the second interim analysis met the prespecifi ed futility stopping criteria in the intention-to-treat population. We noted no diff erence in progression-free survival between simtuzumab and placebo in the intention-to-treat population (median progression free survival times of 12.6 months and 15.4 months for simtuzumab and placebo, respectively; stratifi ed HR 1.13, 95% CI 0.88-1.45; p=0.329) and in patients with baseline sLOXL2 in the 50th percentile or higher (median progression-free survival 11.7 months and 14.3 months for simtuzumab and placebo, respectively; stratifi ed HR 1.03, 95% CI 0.74-1.43; p=0.851), or in the 75th percentile or higher (median progression-free survival 11.6 months and 16.(months for simtuzumab and placebo, respectively; stratifi ed HR 1.20, 95% CI 0.72-2.00; p=0.475). The incidence of adverse events and serious adverse events was similar between treatment groups. The most common adverse events in both the simtuzumab and placebo groups were dyspnoea, cough, upper respiratory tract infection, and worsening of IPF; and the most common grade 3 or 4 adverse events were worsening of IPF, dyspnoea, and pneumonia. Interpretation Simtuzumab did not improve progression-free survival in a well-defi ned population of patients with IPF. Our data do not support the use of simtuzumab for patients with IPF.