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

• Published in: Annals of the rheumatic diseases Vol. 70; no. 11; pp. 1905 - 1913
• Main Authors: Merrill, Joan T, Wallace, Daniel J, Petri, Michelle, Kirou, Kyriakos A, Yao, Yihong, White, Wendy I, Robbie, Gabriel, Levin, Robert, Berney, Seth M, Chindalore, Vishala, Olsen, Nancy, Richman, Laura, Le, Chenxiong, Jallal, Bahija, White, Barbara
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.11.2011; BMJ Publishing Group
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - therapeutic use; Biological and medical sciences; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gene Expression Regulation - drug effects; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - blood; Immunosuppressive Agents - therapeutic use; Injections, Intravenous; Interferon Type I - biosynthesis; Interferon Type I - genetics; Interferon-alpha - antagonists & inhibitors; Interferon-alpha - immunology; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - immunology; Male; Medical sciences; Middle Aged; RNA, Messenger - genetics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Severity of Illness Index; Treatment Outcome; Young Adult; Human; Immunopathology; Connective tissue disease; Skin disease; Alpha interferon; Toxicity; Rheumatology; Autoimmune disease; Monoclonal antibody; Systemic lupus erythematosus; Systemic disease; Phase I trial; Double blind study
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard.2010.144485

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. Subjects 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.