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

Joan T. Merrill, Daniel J. Wallace, Michelle Petri, Kyriakos A. Kirou, Yihong Yao, Wendy I. White, Gabriel Robbie, Robert Levin, Seth M. Berney, Vishala Chindalore, Nancy Olsen, Laura Richman, Chenxiong Le, Bahija Jallal, Barbara White

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish (US)
Pages (from-to)1905-1913
Number of pages9
JournalAnnals of the Rheumatic Diseases
Volume70
Issue number11
DOIs
StatePublished - Nov 1 2011

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Double-Blind Method
Systemic Lupus Erythematosus
Interferons
Monoclonal Antibodies
Interferon Type I
Safety
Placebos
Labels
Pharmacodynamics
Pharmacokinetics
Virus Diseases
Immunosuppressive Agents
sifalimumab
Skin
Blood
Messenger RNA
Therapeutics
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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. / 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. In: Annals of the Rheumatic Diseases. 2011 ; Vol. 70, No. 11. pp. 1905-1913.
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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. 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.",
author = "Merrill, {Joan T.} and Wallace, {Daniel J.} and Michelle Petri and Kirou, {Kyriakos A.} and Yihong Yao and White, {Wendy I.} and Gabriel Robbie and Robert Levin and Berney, {Seth M.} and Vishala Chindalore and Nancy Olsen and Laura Richman and Chenxiong Le and Bahija Jallal and Barbara White",
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Merrill, JT, Wallace, DJ, Petri, M, Kirou, KA, Yao, Y, White, WI, Robbie, G, Levin, R, Berney, SM, Chindalore, V, Olsen, N, Richman, L, Le, C, Jallal, B & White, B 2011, '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', Annals of the Rheumatic Diseases, vol. 70, no. 11, pp. 1905-1913. https://doi.org/10.1136/ard.2010.144485

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. / 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.

In: Annals of the Rheumatic Diseases, Vol. 70, No. 11, 01.11.2011, p. 1905-1913.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Safety profile and clinical activity of sifalimumab, a fully human anti-interferon α monoclonal antibody, in systemic lupus erythematosus

T2 - A phase I, multicentre, double-blind randomised study

AU - Merrill, Joan T.

AU - Wallace, Daniel J.

AU - Petri, Michelle

AU - Kirou, Kyriakos A.

AU - Yao, Yihong

AU - White, Wendy I.

AU - Robbie, Gabriel

AU - Levin, Robert

AU - Berney, Seth M.

AU - Chindalore, Vishala

AU - Olsen, Nancy

AU - Richman, Laura

AU - Le, Chenxiong

AU - Jallal, Bahija

AU - White, Barbara

PY - 2011/11/1

Y1 - 2011/11/1

N2 - 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.

AB - 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.

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DO - 10.1136/ard.2010.144485

M3 - Article

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SP - 1905

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JF - Annals of the Rheumatic Diseases

SN - 0003-4967

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