SAT0179 The ASP358ALA variant in the IL6R gene is significantly associated with differences in soluble IL-6R protein levels but not with differences in sarilumab response in rheumatoid arthritis (RA) patients
Authors: A Damask, A Boyapati, JD Hamilton, S Hamon, C Paccard, J Parrino, J van Adelsberg, NM Graham, J Penn, A Lopez, J Reid, J Overton, A Baras, AR Shuldiner, C Paulding
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Sarilumab is a human mAb that blocks IL-6 from binding to both membrane-bound and soluble IL-6Rα (sIL-6R). A missense variant in the <i>IL6R</i> gene, Asp358Ala (rs2228145), falls within a proteolytic cleavage site and individuals with an alanine at this position have increased sIL-6R in circulation.<sup>1</sup> In addition, this variant has been associated with several diseases including RA.<sup>2</sup> <h3>Objectives</h3> To determine the impact of the Asp358Ala variant on sIL-6R concentrations and response of RA patients to sarilumab. <h3>Methods</h3> DNA was collected from patients enrolled in the MOBILITY study (NCT01061736) that evaluated the efficacy and safety of sarilumab + methotrexate (MTX) in RA patients with inadequate response to MTX. The pharmacogenetic analysis was conducted on 599 Caucasian patients (396 sarilumab 150 or 200 mg q2w + MTX, 203 placebo + MTX). <h3>Results</h3> Concentrations of sIL-6R were strongly associated with the Asp358Ala genotypes at baseline (<i>p</i>=4.2 × 10<sup>-11</sup>). The difference in sIL-6R concentrations between genotype groups continued to increase in sarilumab-treated patients through the end of treatment, particularly for the CC genotype (Figure; <i>p</i>=7.8 × 10<sup>-12</sup>). There was a modest association for change in sIL-6R in placebo + MTX–treated patients (<i>p</i>=0.0052). Variation in Asp358Ala was not associated with sarilumab efficacy, including mTSS at week 52 and ACR scores (Table). <h3>Conclusions</h3> The Asp358Ala variant in the <i>IL6R</i> gene is significantly associated with differences in sIL-6R levels at baseline and after sarilumab treatment. The differences across genotypes may be due to increases in sIL-6R production. Importantly, this variant was not associated with differences in sarilumab treatment response. These data suggest that the sarilumab doses used for this clinical study saturate both the membrane and soluble forms of IL-6R and effectively block IL-6 signaling. Sarilumab provides therapeutic benefit for RA patients irrespective of their Asp358Ala genotype status. <h3>References</h3> Garbers et al. Biochim Biophys Acta. 2014;1842:1485–1494. Okada et al. Nature. 2014;506:376–381. <h3>Acknowledgements</h3> This study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Editorial support was provided by MedThink SciCom and funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. <h3>Disclosure of Interest</h3> A. Damask Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Boyapati Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Hamilton Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, S. Hamon Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, C. Paccard Shareholder of: Sanofi R&amp;D, Employee of: Sanofi R&amp;D, J. Parrino Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. van Adelsberg Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, N. Graham Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Penn Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Lopez Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Reid Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Overton Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Baras Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Shuldiner Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, C. Paulding Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc