title: Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study.
abstract: BACKGROUND
  Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc.
  
  
  METHODS
  Subjects (≥18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes.
  
  
  RESULTS
  Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days.
  
  
  CONCLUSIONS
  The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00930683.
authors.forename: Avram
authors.initials: A
authors.lastname: Goldberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Geppert
authors.forename: Elena
authors.initials: E
authors.lastname: Schiopu
authors.forename: Tracy
authors.initials: T
authors.lastname: Frech
authors.forename: Vivien
authors.initials: V
authors.lastname: Hsu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Simms
authors.forename: Stanford L
authors.initials: SL
authors.lastname: Peng
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.forename: Nairouz
authors.initials: N
authors.lastname: Elgeioushi
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Stephen
authors.initials: S
authors.lastname: Yoo
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D053633:Receptor, Interferon alpha-beta / Q000276:immunology*; D012595:Scleroderma, Systemic / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053633:Receptor, Interferon alpha-beta; C582345:anifrolumab