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Abstract Number: 1737

Association Of HLA-DRB1 Alleles With Clinical Responses To The Anti-Interleukin−17A Monoclonal Antibody Secukinumab In a Cohort Of Patients With Active Rheumatoid Arthritis:  An Exploratory Phase 2 Biomarker Study

Gerd Burmester1, Patrick Durez2, Galina Shestakova3, Yue Li4, Amanda Wang5, Steve Lewitzky5, Irina Koroleva5, David Lee6 and Wolfgang Hueber7, 1Department of Rheumatology & Clinical Immunology, Charité-Universitätsmedizin Berlin, Free University and Humboldt University of Berlin, Berlin, Germany, 2Université Catholique de Louvain, Brussels, Belgium, 3Kaluga State Pedagogical Tsiolkovsky University, Kaluga, Russia, 4IIS, Novartis Pharma AG, Basel, Switzerland, 5Novartis Pharma AG, Cambridge, MA, 6Novartis Pharma AG, Basel, Switzerland, 7Translational Medicine Autoimmunity, Novartis Pharma AG, Basel, Switzerland

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Biologic agents, biomarkers and rheumatoid arthritis (RA)

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Session Information

Title: Rheumatoid Arthritis Treatment - Small Molecules, Biologics and Gene Therapy: Efficacy and Safety of Novel Entities

Session Type: Abstract Submissions (ACR)

Background/Purpose: The shared epitope (SE) may play a functional role in RA via Th17/interleukin (IL)-17 polarization (Holoshitz et al. FEBS Lett 2011;585:3619-26). Two phase 2 studies of secukinumab in RA suggested that HLA-DRB1*04 allelic group and the SE could be candidate biomarkers for treatment with secukinumab. In this study, validation in an independent cohort was sought for candidate markers of response.

Methods: In a randomized, double-blind, placebo-controlled trial, patients with RA (2010 criteria),  TJC ≥ 6, SJC ≥ 6, CRP > 10 mg/L, who were biologic-naive and DMARD incomplete responders or DMARD naive, were randomized 2:1 to secukinumab 6×10 mg/kg i.v. or placebo every other week (wk). Associations of treatment effect of secukinumab vs. placebo with HLA-DRB1*04 (primary endpoint), HLA-DRB1*SE and protein markers RF and anti-CCP were assessed at wk 12 in 96 evaluable patients, using change from baseline in DAS28-CRP by ANCOVA, or ACR20 response by logistic regression.

Results: At baseline, 46 (72%) on secukinumab and 23 (72%) on placebo were taking concomitant DMARDs; 16% were RF/anti-CCP negative. Frequency of HLA-DRB1*SE and *04 was 72% and 47%, respectively. ACR20 responses at wk 12 were 87.9% for secukinumab compared to 25.0% for placebo. Change from baseline in DAS28-CRP differed significantly as early as wk 2 and continued through wk 12 (Fig 1). For change from baseline in DAS28-CRP, HLA-DRB1*SE status demonstrated a significant association with response to secukinumab vs. placebo (p=0.007), but the HLA-DRB1*04 allelic group and HLA-DRB1*0401 did not (Fig 2). Among protein markers, RF but not anti-CCP was significantly associated with both DAS28-CRP (RF p=0.022, anti-CCP p=0.124) and ACR20 response (RF p=0.013, anti-CCP p=0.228). The small number of HLA-DRB1*SE non-carriers within the CCP/RF-positive subcohort precluded assessment of associations in this subgroup. Two SAEs were reported, necrotizing vasculitis and ovarian adenoma, both leading to early secukinumab discontinuation.

Conclusion:  Secukinumab was associated with improvements in efficacy outcomes compared with placebo. HLA-DRB1*SE was associated with response to secukinumab vs. placebo. However, these associations are driven by lack of placebo response in carriers vs. non-carriers. Notable differences in genetic ancestry and disease activity suggest potential confounder effects. Additional studies with enhanced power are needed to confirm contributions of SE and other markers to anti-IL-17A responsiveness.

Description: Znycfp2ny deptNY BioscienceNOVARTISAIN457PROGRAM (CROSS INDICATION)PublicationsAbstracts2013ACRF2208Figure image filesFig1.png

Description: Znycfp2ny deptNY BioscienceNOVARTISAIN457PROGRAM (CROSS INDICATION)PublicationsAbstracts2013ACRF2208Fig2.png                        


Disclosure:

G. Burmester,

Novartis Pharma AG,

5;

P. Durez,

Pfizer, BMS,

8;

G. Shestakova,
None;

Y. Li,

Novartis Pharma AG,

1,

Novartis Pharma AG,

3;

A. Wang,

Novartis Pharma AG,

1,

Novartis Pharma AG,

3;

S. Lewitzky,

NIBR,

1,

NIBR,

3;

I. Koroleva,

Novartis Pharma AG; NIBR,

1,

Novartis Pharma AG; NIBR,

3;

D. Lee,

Novartis Pharma AG,

1,

Novartis Pharma AG,

3;

W. Hueber,

Novartis Pharma AG,

1,

Novartis Pharma AG,

3.

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