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

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Summary

Background

Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy 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 definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratified 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, defined 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 stratified 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 prespecified futility stopping criteria in the intention-to-treat population. We noted no difference 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; stratified 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; stratified 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 16·9 months for simtuzumab and placebo, respectively; stratified 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-defined population of patients with IPF. Our data do not support the use of simtuzumab for patients with IPF.

Funding

Gilead Sciences Inc.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease that affects middle-aged and elderly patients. It is characterised by replacement of normal lung tissue with fibrotic scarring, and the suggested median survival time in patients with IPF based on several retrospective longitudinal studies is 2–3 years from the time of diagnosis.1 Long term survival data subsequent to the 2011 and 2015 guidelines for treatment of IPF is lacking. Approved treatment options include pirfenidone and nintedanib; however, even with treatment, progression of disease occurs.2, 3, 4 There is an unmet need for novel, effective, safe, and well-tolerated drugs to prevent disease progression and improve survival in patients with IPF.

Lysyl oxidase-like 2 (LOXL2) is an enzyme that catalyses collagen cross-linking, a potentially important step in the pathogenesis of pulmonary fibrosis (figure 1).5, 6 LOXL2 exhibits increased expression in active disease interfaces of tumours and fibrosing tissues compared with healthy tissue.5, 7 Thus, LOXL2 might have a more prominent role in pathological scar formation and a less prominent role in normal wound healing or elastin metabolism.5

Research in context

Evidence before this study

We searched PubMed from Jan 1, 2000, to June 16, 2016, for “idiopathic pulmonary fibrosis treatment,” “LOX,” and “LOXL2” and found no other clinical studies.

Added value of this study

Simtuzumab, a specific inhibitor of LOXL2, failed to show efficacy in patients with idiopathic pulmonary fibrosis (IPF) in either the intention-to-treat population or in a subgroup of patients with elevated LOXL2. The study design is novel because it included a blood-based biomarker relevant to the mechanism of action of simtuzumab in the primary endpoints of the study.

Implications of all the available evidence

Further study is required to explain the failure of simtuzumab to show efficacy. Although the results of this clinical trial do not support the clinical use of simtuzumab for the treatment of IPF, future clinical trials should capture all pertinent clinical data that can be adjudicated to assess outcomes for patients with IPF. These include clinically meaningful measures such as validated patient reported respiratory symptoms and respiratory hospitalisations. Furthermore, the use of pre-specified criteria for consideration of hospitalisation for change or decline in respiratory status based on objective findings as a priori will need to be implemented in future well-designed clinical trials for IPF. This will reduce potential concerns regarding decisions for hospitalisations and management in patients based on subjective judgment by site investigators and other varying confounding factors such as differences in clinical practice and cultures across centres worldwide.

Simtuzumab is a monoclonal antibody that inhibits LOXL2. The murine equivalent (AB0023) showed efficacy in a murine model in preventing and reversing fibrosis following bleomycin instillation.5 Antifibrotic properties have also been shown in rodent models of fibrosis in liver and cancer models.5 Expression of LOXL2 in fibrotic foci in IPF has been confirmed by both immunohistochemistry and in situ hybridisation in human tissue,5 suggesting that simtuzumab might have similar efficacy for IPF in humans.

This study investigated the efficacy and safety of simtuzumab in patients with IPF. The rationale for the use of LOXL2 concentration as a stratification factor was based on the finding that high serum LOXL2 concentrations have been associated with increased risk of disease progression and mortality in patients with IPF.8 Thus, we hypothesised that increased serum LOXL2 concentrations at baseline would predict the likelihood of treatment benefit.

Section snippets

Study design

RAINIER was a phase 2, randomised, double-blind, placebo-controlled study undertaken at 183 hospitals and specialist respiratory clinics in 14 countries (Australia, Belgium, Canada, Czech Republic, France, Germany, Israel, Italy, Poland, South Korea, Spain, Switzerland, the UK, and the USA). Institutional review board or independent ethics committee approval was obtained at each site before study initiation.

Participants

The patient population comprised men and women aged 45 to 85 years with a definite

Results

Screening for the study began on Jan 31, 2013, and the last patient was randomly assigned on June 19, 2015; the final patient study visit was on Feb 23, 2016. Overall, 1250 patients were screened for eligibility, with 706 found to be ineligible (figure 2). The most common reasons for patient ineligibility were a lack of diagnosis of definite IPF (n=268), DLCO less than 25% of the predicted threshold (n=132), and evidence of concomitant airway obstruction (n=88). A patient might have failed

Discussion

In this large clinical trial, treatment with simtuzumab failed to show benefit over placebo as measured by the primary endpoints of progression-free survival in either the intention-to-treat population or the subgroups with serum LOXL2 concentrations in the 50th percentile or higher or in the 75th percentile or higher. There was no evidence of benefit as measured by slowing the rate of decline in FVC % predicted, DLCO% predicted, or 6-min walk distance, or as measured by reducing all-cause

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