Chunpeng Fan

Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study

To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).

Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes

Abstract Objectives To examine 2-year safety, efficacy and radiographic outcomes of sarilumab in adults with RA and inadequate response to MTX (MTX-IR). Methods In the randomized, placebo-controlled MOBILITY trial, MTX-IR patients received subcutaneous sarilumab (150 or 200 mg) or placebo every 2 weeks (q2w) plus MTX for up to 1 year. Upon study completion, patients could enrol in the open-label, long-term extension study (EXTEND, NCT011046652), in which all patients received sarilumab 200 mg q2w plus MTX. Dose reduction to 150 mg q2w was allowed for abnormal laboratory findings and per investigator’s discretion. Results Of 1197 patients participating in MOBILITY, 901 entered EXTEND. Over the 2-year period, treatment-emergent adverse events (TEAEs) and serious AEs occurred at rates of 279.6 events per 100 patient-years and 16.6 events per 100 patient-years, respectively. The most common TEAEs were neutropenia, injection site erythema, increased alanine aminotransferase and upper respiratory tract infections. After 1 year in the open-label, long-term extension, disease activity reached similar levels regardless of initial treatment. Modified total Sharp scores at year 1 were maintained through year 2. Best radiographic outcomes were observed in patients initially randomized to sarilumab 200 mg q2w. After dose reduction, 89.4% of patients continued the study through 2 years. Conclusion Sarilumab safety through year 2 was consistent with IL-6 receptor blockade. Clinical response was similar irrespective of initial treatment, and radiographic progression stabilized. Patients initiated on sarilumab 200 mg q2w had the best radiographic outcomes. Dose reduction allowed most patients to continue with the study.

SAT0058 Consistency of Radiographic Responses with Sarilumab plus Methotrexate across Subpopulations of Patients with Rheumatoid Arthritis in A Phase 3 Study

Background The investigational drug sarilumab is a human monoclonal antibody directed against the interleukin 6 receptor.1 The phase 3 MOBILITY study (NCT01061736) examined sarilumab + methotrexate (MTX) vs placebo + MTX in a double-blind, 52-week, randomized trial of patients with active, moderate-to-severe rheumatoid arthritis (RA) with inadequate response to MTX.1 Both sarilumab doses (150 and 200 mg subcutaneously every 2 weeks [q2w]) demonstrated statistically significant improvements in signs and symptoms of RA, in physical function, and inhibition of radiographic progression. The most common treatment-emergent adverse events were infections, neutropenia, injection site reactions, and increased transaminases. Objectives In the present study, radiographic efficacy of sarilumab across subpopulations from MOBILITY was assessed. Methods To explore the consistency of radiographic response, treatment-by-subgroup interactions were assessed by rank ANCOVA for change in van der Heijde modified total Sharp score (mTSS) at week 52. A total of 19 subgroups were investigated (listed in Table footnote); those with P≤0.2 for interaction are presented. Radiographic progression was defined as mean change from baseline mTSS. Results Both doses of sarilumab showed less progression relative to placebo across all subgroups. Change in mTSS across subgroups based on rheumatoid factor and anti–cyclic citrullinated peptide status and demographic characteristics such as age, sex, and ethnicity appeared to be consistent with overall study findings. Subgroups with interaction P≤0.2 were prior use of biologics and baseline C-reactive protein (CRP), body mass index (BMI), RA disease duration, median mTSS, and smoking history (Table). In some groups (lower BMI, no prior biologic use, higher baseline CRP, no history of smoking, and high mTSS), the treatment effect increased, because there was greater progression in the placebo group relative to the sarilumab groups. The progression with sarilumab 200 mg q2w was consistently lower compared with sarilumab 150 mg q2w. Progression was substantially greater in placebo patients with baseline mTSS >25 compared with those with baseline mTSS ≤25. These differences were not observed in sarilumab-treated patients. Joint space narrowing and erosion score showed patterns similar to the total score. Overall, sample sizes were limited in some subgroups. Conclusions Sarilumab generally inhibited radiographic progression to a similar extent across a wide spectrum of subgroups. Nonetheless, the treatment effect appeared to be greater in subgroups with poor prognostic markers such as high levels of CRP and more structural damage at baseline, as well as in nonsmokers and patients with low BMI. References Genovese et al. Arthritis Rheumatol. 2015;67:1424–1437. Acknowledgement This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Editorial assistance was provided by Rebecca Slager, PhD, MS, MedThink SciCom, and funded by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest D. van der Heijde Consultant for: Sanofi, C. Fan Shareholder of: Sanofi, Employee of: Sanofi, H. van Hoogstraten Shareholder of: Sanofi, Consultant for: Sanofi, E. Mangan Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. van Adelsberg Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, P. Miranda Grant/research support from: Sanofi, M. Genovese Grant/research support from: Roche, Sanofi, GSK, R-Pharma, RuiYi, and BMS, Consultant for: Roche, Sanofi, GSK, R-Pharma, RuiYi, and BMS

SAT0185 Clinical and Radiographic Efficacy of Sarilumab Plus Methotrexate in Biologic-Experienced and Biologic-Naïve Patients with Rheumatoid Arthritis in a Phase 3, Randomized, Double-Blind, Placebo-Controlled International Study

Background The efficacy and safety of sarilumab, a fully human monoclonal antibody directed against IL-6R, has been shown in patients with moderate-to-severe rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX) in the randomized, double-blind, placebo (Pbo)-controlled, phase 3 part of the MOBILITY study (NCT01061736).1 Approximately 20% of patients were exposed to biologic DMARDs (bDMARDs), defined as prior use of a non-investigational biologic DMARD for RA. Of these, 50% had received prior anti-TNF therapy and none had stopped bDMARD treatment due to lack of efficacy. The clinical efficacy and safety of sarilumab in bDMARD-experienced and -naïve MOBILITY patients was previously reported.2 Objectives To compare the clinical and radiographic efficacy and safety of sarilumab vs Pbo at 52 weeks in RA patients who were bDMARD-experienced (including prior anti-TNF therapy) and bDMARD-naïve in MOBILITY. Methods This post hoc analysis of MOBILITY evaluates sarilumab clinical and radiographic efficacy and safety over 52 weeks in the intention-to-treat population, categorized according to prior bDMARD exposure, including a subset of patients with prior anti-TNF therapy. Results Compared with placebo, smaller numerical mean increases in mTSS, including erosion (ES) and joint space narrowing (JSN), were observed with sarilumab (150 mg + MTX and 200 mg q2w + MTX), at Wks 24 and 52, irrespective of prior bDMARD use (including the prior anti-TNF therapy subgroup). For each group, a significantly greater percentage of patients receiving sarilumab had no radiographic progression at Wk 52 vs Pbo and, for patients with radiographic progression, the cumulative probability distribution plots for ΔTSS, ΔES and ΔJSN (from baseline) showed a frequency distribution favorable to sarilumab (both doses). In both bDMARD-experienced and -naïve RA patients, each of the sarilumab doses + MTX resulted in clinically meaningful and statistically significant ACR20, ACR50, ACR70, CDAI and DAS28-CRP responses vs Pbo at Wk 24; similar results were observed for the prior anti-TNF therapy subset. ACR20, 50 and 70 responses were maintained in bDMARD-experienced and -naïve subgroups up to Wk 52. The most common treatment-emergent adverse events with sarilumab + MTX included infections, neutropenia, injection site reactions and increased transaminases, irrespective of prior bDMARD experience. Conclusions These results suggest that, irrespective of prior bDMARD experience, sarilumab improved signs and symptoms of RA and inhibited progression of structural damage in patients with active RA and inadequate response to MTX. References Genovese M et al. Abstr. No. EULAR14-SCIE-3001 presented at EULAR 2014, Paris, France Fleischmann R et al. Arthritis Rheumatol 2014; 66(11) Abstr 2823:S1232–3 Acknowledgements The study was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. Editorial support was provided by Diane Davies of Envision Scientific Solutions and was funded by Sanofi and Regeneron Pharmaceuticals Inc. Disclosure of Interest D. van der Heijde: None declared, M. Genovese Grant/research support from: Sanofi, Regeneron, Eli Lilly, Consultant for: Sanofi, Regeneron, Eli Lilly, C. Fan Shareholder of: Sanofi, Employee of: Sanofi, S. Fiore Shareholder of: Sanofi, Employee of: Sanofi, D. Decktor Shareholder of: Johnson & Johnson, Employee of: Regeneron, R. Fleischmann Grant/research support from: AbbVie, Amgen, Ardea, AstraZeneca, BMS, Celgene, GSK, Janssen, Eli Lilly, Merck, Pfizer, Resolve, Roche, Sanofi, UCB, Consultant for: AbbVie, Akros, Amgen, Antares, Ardea, AstraZeneca, Augurex, BMS, Celgene, Covagen, Five Prime, GSK, Iroko, Janssen, Eli Lilly, McNeil, Merck, Pfizer, Plexxicon, Resolve, Roche, Sanofi, Teva, UCB, Vertex

FRI0186 Impact of Concomitant Methotrexate Dose on the Efficacy and Safety of Sarilumab for Treatment of Moderate-to-Severe Rheumatoid Arthritis: The Mobility Study

Background Methotrexate (MTX) is the most commonly used conventional synthetic DMARD (csDMARD) for the treatment of rheumatoid arthritis (RA). In the phase 3 MOBILITY study (NCT01061736),1 of sarilumab in inadequate responders to MTX, MTX was continued at the dose prescribed at screening, which was assumed to be the maximally tolerated dose. This sub-analysis evaluates whether the different doses of MTX, in association with sarilumab, had an effect on efficacy or safety outcomes in MOBILITY. Objectives To explore the relationship of MTX dose on the efficacy or safety of sarilumab in the treatment of active RA in MTX-IR patients. Methods The MOBILITY study design and methods have been reported.2 Patients were required to be on a stable dose of MTX of 10–25 mg/wk for at least 6 weeks, except for Asian-Pacific region patients (6–25 mg/wk) prior to enrolment and to maintain this dose throughout the trial. A sufficient number of subjects with doses of 7.5-25 mg/wk were included: 11 (0.92%) patients were excluded from the analysis due to small numbers receiving doses of <7.5 and >25mg/wk. The relationship between efficacy and safety outcomes for sarilumab and MTX was assessed by appropriate regression models (logistic or generalized linear) in this post hoc analysis. Results 1186 patients were included. For each dose group in each treatment arm we computed proportions of ACR20 responders at Wk 24 and 52; no apparent difference in achieving an ACR20 response was observed with increasing MTX dose in any treatment group (Figure). A logistic regression assessment confirms this observation: for sarilumab 150 mg and 200 mg. Based on mean change from baseline in HAQ-DI at Wk 24, no apparent relationship with MTX dose was observed. A linear regression model assessment provides confirmation of the results. There was no statistical difference in mean HAQ-DI change from baseline based on MTX dose in the Pbo, sarilumab 150 mg or sarilumab 200 mg groups. Similar findings were observed for changes from baseline for DAS28-CRP, FACIT-Fatigue, and mTSS (change and progression). There was no association of the incidence of treatment-emergent adverse events (AE), serious AEs and changes in ALT, neutrophil counts and lipids with increasing MTX doses.Figure 1. ACR20 Response % (±SE) at Wk 24 by MTX dose. Conclusions In this post hoc analysis, within the sarilumab 150 mg or sarilumab 200 mg dose groups, efficacy or safety was similar across concomitant MTX doses. References Genovese M et al. Abstr. No. EULAR14-SCIE-3001 presented at EULAR 2014, Paris, France Kavanaugh A et al. Abstr. No. 2824 presented at ACR 2014, Boston, MA, USA Acknowledgements The study was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. Editorial support was provided by Diane Davies of Envision Scientific Solutions and was funded by Sanofi and Regeneron Pharmaceuticals Inc. Disclosure of Interest T. Huizinga Consultant for: Merck, UCB, BMS, Biotest AG, Pfizer, Novartis, Roche, Sanofi, Abbott, Crescendo Bioscience, Nycomed, Boeringher Ingelheim, Takeda, Zydus, and Eli Lilly, Y. Yazici Shareholder of: Samumed, Grant/research support from: BMS, Celgene, Genentech, Consultant for: BMS, Celgene, Employee of: Samumed, D. Thompson Shareholder of: Regeneron, Employee of: Regeneron, D. Decktor Shareholder of: Johnson & Johnson, Employee of: Regeneron, C. Fan Shareholder of: Sanofi, Employee of: Sanofi, R. Fleischmann Grant/research support from: AbbVie, Amgen, Ardea, AstraZeneca, BMS, Celgene, GSK, Janssen, Eli Lilly, Merck, Pfizer, Resolve, Roche, Sanofi, UCB, Consultant for: AbbVie, Akros, Amgen, Antares, Ardea, AstraZeneca, Augurex, BMS, Celgene, Covagen, Five Prime, GSK, Iroko, Janssen, Eli Lilly, McNeil, Merck, Pfizer, Plexxicon, Resolve, Roche, Sanofi, Teva, UCB, Vertex