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Background 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 IL6R gene, Asp358Ala (rs2228145), falls within a proteolytic cleavage site and individuals with an alanine at this position have increased sIL-6R in circulation. 1 In addition, this variant has been associated with several diseases including RA. 2 Objectives To determine the impact of the Asp358Ala variant on sIL-6R concentrations and response of RA patients to sarilumab. Methods 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). Results Concentrations of sIL-6R were strongly associated with the Asp358Ala genotypes at baseline ( p =4.2 × 10 -11 ). 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; p =7.8 × 10 -12 ). There was a modest association for change in sIL-6R in placebo + MTX–treated patients ( p =0.0052). Variation in Asp358Ala was not associated with sarilumab efficacy, including mTSS at week 52 and ACR scores (Table). Conclusions The Asp358Ala variant in the IL6R 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. References Garbers et al. Biochim Biophys Acta. 2014;1842:1485–1494. Okada et al. Nature. 2014;506:376–381. Acknowledgements 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. Disclosure of Interest 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&D, Employee of: Sanofi R&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

Background Sarilumab is a human mAb that blocks IL-6 from binding to both membrane-bound and soluble IL-6Rα. Variants in the UGT1A1 gene have been shown to be strongly associated with increased unconjugated bilirubin levels in patients treated with tocilizumab, another IL-6Rα inhibitor.1,2UGT1A1 encodes the enzyme responsible for the glucuronidation of bilirubin and variation in this gene is also responsible for Gilbert9s syndrome, a mild benign condition characterized by elevations in unconjugated bilirubin and jaundice. The underlying main genetic variation responsible for Gilbert9s syndrome has been identified as a TA repeat located in the promoter of UGT1A1 (UGT1A1*28 allele), which is in linkage disequilibrium with a single nucleotide polymorphism, rs6742078, previously associated with higher bilirubin levels after tocilizumab treatment.1 Objectives To test for an association between rs6742078 and bilirubin levels in RA patients treated with sarilumab. Methods DNA was collected from patients enrolled in MOBILITY (NCT01061736), which evaluated the efficacy and safety of sarilumab + methotrexate (MTX) in RA patients with inadequate response to MTX. The pharmacogenetic analysis was conducted in 599 Caucasian patients treated with MTX + sarilumab (150 or 200 mg q2w) or placebo. Log-transformed unconjugated and total bilirubin levels were analyzed at baseline and over the treatment period (using maximum bilirubin). Results There was a strong association between the rs6742078 TT genotype and higher unconjugated bilirubin levels. The least squares mean (SE) for patients at baseline with the TT genotype was 0.48 (0.02) mg/dL vs 0.25 (0.009) and 0.21 (0.009) mg/dL for those with GT and GG genotypes, respectively (p=1.02×10-21). After sarilumab treatment, the difference between genotype groups increased over the course of the study (p=4.3×10-10; Figure). In the binary analysis of maximum total bilirubin in sarilumab-treated patients, the TT genotype was significantly associated with mild bilirubin elevations (OR =34.7; p=1.2×10-8; Table). Conclusions The association observed between the rs6742078 TT genotype in UGT1A1 and unconjugated bilirubin elevations in sarilumab-treated patients is consistent with previous observations in tocilizumab-treated patients. These findings suggest that sarilumab-related increases in bilirubin levels are likely benign and caused by common genetic variation in UGT1A1 and are not due to underlying liver injury. References Mori et al. Mod Rheumatol. 2012;22:515–523. Lee et al. Pharmacogenet Genomics. 2011;21:365–374. Acknowledgements 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. Disclosure of Interest 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&D, Employee of: Sanofi R&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