title: Safety profile and clinical activity of sifalimumab, a fully human anti-interferon α monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study.
abstract: BACKGROUND
  Type I interferons (IFNs) appear to play a central role in disease pathogenesis in systemic lupus erythematosus (SLE), making them potential therapeutic targets.
  
  
  METHODS
  Safety profile, pharmacokinetics, immunogenicity, pharmacodynamics and clinical activity of sifalimumab, an anti-IFNα monoclonal antibody, were assessed in a phase I, multicentre, randomised, double-blind, dose-escalation study with an open-label extension in adults with moderately active SLE.
  
  
  METHODS
  received one intravenous dose of sifalimumab (n=33 blinded phase, 0.3, 1, 3, 10 or 30 mg/kg; n=17 open-label, 1, 3, 10 or 30 mg/kg) or placebo (n=17). Each phase lasted 84 days.
  
  
  RESULTS
  Adverse events (AEs) were similar between groups; about 97% of AEs were grade 1 or 2. All grade 3 and 4 AEs and all serious AEs (2 placebo, 1 sifalimumab) were deemed unrelated to the study drug. No increase in viral infections or reactivation was observed. Sifalimumab caused dose-dependent inhibition of type I IFN-induced mRNAs (type I IFN signature) in whole blood and corresponding changes in related proteins in affected skin. Exploratory analyses showed consistent trends toward improvement in disease activity in sifalimumab-treated versus placebo-treated subjects. A lower proportion of sifalimumab-treated subjects required new or increased immunosuppressive treatments (12% vs 41%; p=0.03) and had fewer Systemic Lupus Erythematosus Disease Activity Index flares (3% vs 29%; p=0.014).
  
  
  CONCLUSIONS
  Sifalimumab had a safety profile that supports further clinical development. This trial demonstrated that overexpression of type I IFN signature in SLE is at least partly driven by IFNα, and exploratory analyses suggest that IFNα inhibition may be associated with clinical benefit in SLE. Trial registration number NCT00299819.
authors.affiliation: Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA. jtmmail@aol.com
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wallace
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: Kyriakos A
authors.initials: KA
authors.lastname: Kirou
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.forename: Wendy I
authors.initials: WI
authors.lastname: White
authors.forename: Gabriel
authors.initials: G
authors.lastname: Robbie
authors.forename: Robert
authors.initials: R
authors.lastname: Levin
authors.forename: Seth M
authors.initials: SM
authors.lastname: Berney
authors.forename: Vishala
authors.initials: V
authors.lastname: Chindalore
authors.forename: Nancy
authors.initials: N
authors.lastname: Olsen
authors.forename: Laura
authors.initials: L
authors.lastname: Richman
authors.forename: Chenxiong
authors.initials: C
authors.lastname: Le
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.forename: Barbara
authors.initials: B
authors.lastname: White
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D007275:Injections, Intravenous; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D007370:Interferon Type I; D016898:Interferon-alpha; D012333:RNA, Messenger; C568334:sifalimumab