ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 755

Sifalimumab, an Anti-IFN-Alpha Monoclonal Antibody Shows Target Suppression of a Type I IFN Signature in Blood and Muscle of Dermatomyositis and Polymyositis Patients

Brandon W. Higgs1, Wei Zhu2, Chris Morehouse1, Wendy White3, Philip Brohawn1, Charles Le4, Anthony A Amato5, David Fiorentino6, Steven A. Greenberg5, Laura Richman1, Warren Greth4, Bahija Jallal1 and Yihong Yao3, 1Translational Sciences, MedImmune, LLC, Gaithersburg, MD, 2Translational Science, MedImmune, LLC, Gaithersburg, MD, 3Translational Sciences, MedImmune, Gaithersburg, MD, 4Clinical Development, MedImmune, LLC, Gaithersburg, MD, 5Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 6Dermatology, Stanford University School of Medicine, Redwood City, CA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Muscle Biology, Myositis and Myopathies: Classification, Treatment and Outcome in Idiopathic Inflammatory Myopathies

Session Type: Abstract Submissions (ACR)

Background/Purpose: To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-alpha monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring the suppression of a type I IFN signature following sifalimumab administration. 

Methods:

A phase 1b randomized, double-blinded, placebo-controlled, dose-escalation, multicenter clinical trial was conducted in adult patients with dermatomyositis or polymyositis. Blood and muscle biopsies were procured before and after administration with sifalimumab. Samples were transcript-profiled using microarray and qRT-PCR. The target modulation in patients following administration with either sifalimumab or placebo was measured by a 13-gene type I IFN signature.

Results: The type I IFN signature was suppressed by a median of 53-66% across the three times points (day 28, 56, and 98) in blood and 47% at day 98 in muscle specimens post sifalimumab administration, with the latter exhibiting dose-dependent target modulation. Patients with ≥15% improvement from baseline manual muscle testing scores showed a greater suppression of the gene signature than those with <15% improvement as measured in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leukocyte infiltration, antigen presentation, and immunoglobulin categories were most suppressed following administration with sifalimumab and were highly correlated with suppression of the type I IFN signature (r=-0.93; p<0.001 and r=-0.84; p<0.001, and r=-0.64, p=0.001, respectively) in muscle tissue.

Conclusion:

Administration of sifalimumab resulted in suppression of the type I IFN signature in peripheral blood and muscle tissue in patients with myositis, consistent with this molecule’s mechanism of action and a positive trend of correlation between this target suppression and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.

Disclosure:

B. W. Higgs,

AstraZeneca,

1,

MedImmune,

3;

W. Zhu,

AstraZeneca,

1,

MedImmune,

3;

C. Morehouse,

AstraZeneca,

1,

MedImmune,

3;

W. White,

AstraZeneca,

1,

MedImmune,

3;

P. Brohawn,

AstraZeneca,

1,

MedImmune,

3;

C. Le,

AstraZeneca,

1,

MedImmune,

3;

A. A. Amato,

MedImmune,

5;

D. Fiorentino,
None;

S. A. Greenberg,

MedImmune,

6;

L. Richman,

AstraZeneca,

1,

MedImmune,

3;

W. Greth,

MedImmune LLC,

3;

B. Jallal,

AstraZeneca,

1,

MedImmune,

3;

Y. Yao,

AstraZeneca,

1,

MedImmune,

3.

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