title: A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients.
abstract: OBJECTIVE
  To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure.
  
  
  METHODS
  A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab.
  
  
  RESULTS
  The IFNGS was suppressed by a median of 53-66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle.
  
  
  CONCLUSIONS
  Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.
authors: MedImmune, LLC, , Gaithersburg, Maryland, USA.
authors: Brandon W
authors: BW
authors: Higgs
authors: Wei
authors: W
authors: Zhu
authors: Chris
authors: C
authors: Morehouse
authors: Wendy I
authors: WI
authors: White
authors: Philip
authors: P
authors: Brohawn
authors: Xiang
authors: X
authors: Guo
authors: Marlon
authors: M
authors: Rebelatto
authors: Chenxiong
authors: C
authors: Le
authors: Anthony
authors: A
authors: Amato
authors: David
authors: D
authors: Fiorentino
authors: Steven A
authors: SA
authors: Greenberg
authors: Jorn
authors: J
authors: Drappa
authors: Laura
authors: L
authors: Richman
authors: Warren
authors: W
authors: Greth
authors: Bahija
authors: B
authors: Jallal
authors: Yihong
authors: Y
authors: Yao
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D003882:Dermatomyositis / Q000188:drug therapy* / Q000276:immunology*; D004311:Double-Blind Method; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007370:Interferon Type I / Q000097:blood / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000097:blood / Q000235:genetics / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000276:immunology; D010919:Placebos; D017285:Polymyositis / Q000188:drug therapy* / Q000276:immunology*; 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; D010919:Placebos; C568334:sifalimumab
keywords: Cytokines; Dermatomyositis; Polymyositis