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

• Published in: Annals of the rheumatic diseases Vol. 76; no. Suppl 2; p. 838
• Main Authors: Damask, A, Boyapati, A, Hamilton, JD, Hamon, S, Paccard, C, Parrino, J, Adelsberg, J van, Graham, NM, Penn, J, Lopez, A, Reid, J, Overton, J, Baras, A, Shuldiner, AR, Paulding, C
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01.06.2017
• Subjects: Genotype & phenotype; Genotypes; Monoclonal antibodies; Pharmaceuticals; Rheumatoid arthritis; Stockholders
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2017-eular.4983

BackgroundSarilumab 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.2ObjectivesTo determine the impact of the Asp358Ala variant on sIL-6R concentrations and response of RA patients to sarilumab.MethodsDNA 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).ResultsConcentrations 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).Table 1.Efficacy Endpoints1 and sIL-6R Levels by Asp358Ala Genotypes in Sarilumab-Treated Patients2GenotypesIL-6RmTSS3ACR20ACR50ACR70MCR4SJC5TJC6 AA (n=129)317.7 (21.0)1.4 (0.5)59402213-10.9 (0.8)-16.5 (1.2)AC (n=190)362.3 (16.4)0.7 (0.3)65432212-11.1 (0.6)-18.3 (1.0)CC (n=77)470.8 (22.8)0.9 (0.5)75483117-11.6 (1.0)-19.1 (1.5) p value7.8×10-120.890.060.670.570.710.250.201sIL-6R, mTSS, SJC, TJC show LS mean (SE). Wk 24 ACR20, ACR50, ACR70, and MCR show % achieving endpoint. 2150 or 200 mg q2w doses combined. 3van der Heijde modified total Sharp score at wk 52. 4Major clinical response is defined as achieving and maintaining ACR70 for ≥24 consecutive weeks during the 52-wk period. 5Swollen joint count. 6Tender joint count.ConclusionsThe 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. AcknowledgementsThis 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 InterestA. 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