title: Sifalimumab, a human anti-interferon-α monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study.
abstract: OBJECTIVE
  To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE).
  
  
  METHODS
  In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.
  
  
  RESULTS
  Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n=4) versus 2.5% (n=1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.
  
  
  CONCLUSIONS
  The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.
authors: Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. mpetri@jhmi.edu
authors: Michelle
authors: M
authors: Petri
authors: Daniel J
authors: DJ
authors: Wallace
authors: Alberto
authors: A
authors: Spindler
authors: Vishala
authors: V
authors: Chindalore
authors: Kenneth
authors: K
authors: Kalunian
authors: Eduardo
authors: E
authors: Mysler
authors: C Michael
authors: CM
authors: Neuwelt
authors: Gabriel
authors: G
authors: Robbie
authors: Wendy I
authors: WI
authors: White
authors: Brandon W
authors: BW
authors: Higgs
authors: Yihong
authors: Y
authors: Yao
authors: Liangwei
authors: L
authors: Wang
authors: Dominique
authors: D
authors: Ethgen
authors: Warren
authors: W
authors: Greth
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; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016898:Interferon-alpha / Q000037:antagonists & inhibitors; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D016898:Interferon-alpha; C568334:sifalimumab
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