title: Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Gilead Sciences Inc.
authors.affiliation: Center for Interstitial Lung Diseases, Department of Medicine, University of Washington, Seattle, WA, USA. Electronic address: graghu@u.washington.edu.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Raghu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, National Jewish Medical Center, Denver, CO, USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.affiliation: Department of Medicine, University of California San Francisco at San Francisco, CA, USA.
authors.forename: Harold R
authors.initials: HR
authors.lastname: Collard
authors.affiliation: University of Lyon, Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cottin
authors.affiliation: University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gibson
authors.affiliation: Department of Clinical Medicine and Genetic Medicine, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kaner
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, NY, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lederer
authors.affiliation: Department of Medicine, Cornell University, New York, NY, USA.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.affiliation: Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
authors.affiliation: Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, Seoul, South Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Song
authors.affiliation: Department of Medicine, National Heart & Lung Institute, Royal Brompton Hospital, Imperial College, London, UK.
authors.forename: Athol U
authors.initials: AU
authors.lastname: Wells
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Timothy P M
authors.initials: TP
authors.lastname: Whelan
authors.affiliation: Unit for Interstitial Lung Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.affiliation: Research and Development, bioMerieux, Lyon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moreau
authors.affiliation: Clinical Research, Gilead Sciences, Seattle, WA, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Patterson
authors.affiliation: Clinical Research, Gilead Sciences, Seattle, WA, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
authors.affiliation: Clinical Research, Gilead Sciences, Seattle, WA, USA.
authors.forename: Selina
authors.initials: S
authors.lastname: Bayly
authors.affiliation: Clinical Research, Gilead Sciences, Seattle, WA, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Chien
authors.affiliation: Clinical Research, Gilead Sciences, Seattle, WA, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Clinical Research, Gilead Sciences, Seattle, WA, USA.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Clinical Research, Gilead Sciences, Seattle, WA, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: O'Riordan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000594:Amino Acid Oxidoreductases / Q000097:blood; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000097:blood / Q000188:drug therapy*; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011728:Pyridones / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D004791:Enzyme Inhibitors; D007211:Indoles; D011728:Pyridones; C000613471:simtuzumab; C093844:pirfenidone; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; C530716:nintedanib