Deborah Bauer

Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis. METHODS In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18-55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700. FINDINGS Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379-0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416-0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515-0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540-0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]). INTERPRETATION TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect. FUNDING Genzyme, a Sanofi company.

Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis

Objective: To investigate the effect of teriflunomide on the efficacy and safety of seasonal influenza vaccine. Methods: The 2011/2012 seasonal influenza vaccine (containing H1N1, H3N2, and B strains) was administered to patients with relapsing forms of multiple sclerosis (RMS) treated for ≥6 months with teriflunomide 7 mg (n = 41) or 14 mg (n = 41), or interferon-β-1 (IFN-β-1; n = 46). The primary endpoint was the proportion of patients with influenza strain–specific antibody titers ≥40, 28 days postvaccination. Results: More than 90% of patients achieved postvaccination antibody titers ≥40 for H1N1 and B in all groups. For H3N2, titers ≥40 were achieved in ≥90% of patients in the 7 mg and IFN-β-1 groups, and in 77% of the 14-mg group, respectively. A high proportion of patients already had detectable antibodies for each influenza strain at baseline. Geometric mean titer ratios (post/prevaccination) were ≥2.5 for all groups and strains, except for H1N1 in the 14-mg group (2.3). The proportion of patients with a prevaccination titer <40 achieving seroprotection was ≥61% across the 3 treatment groups and 3 influenza strains. However, fewer patients in the 14-mg than the 7-mg or IFN-β-1 groups exhibited seroprotection to H3N2 (61% vs 78% and 82%, respectively). Conclusion: Teriflunomide-treated patients generally mounted effective immune responses to seasonal influenza vaccination, consistent with preservation of protective immune responses. Classification of evidence: This study provides Class II evidence that teriflunomide generally does not adversely impact the ability of patients with RMS to mount immune responses to influenza vaccination.

Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial

Objectives To compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response. Methods MONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24. Results Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (−3.28 vs −2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences. Conclusions Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects. Trial registration number NCT02332590.

Sarilumab and Nonbiologic Disease‐Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors

To evaluate the efficacy and safety of sarilumab plus conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) in patients with active moderate‐to‐severe rheumatoid arthritis (RA) who had an inadequate response or intolerance to anti–tumor necrosis factor (anti‐TNF) therapy.

Sarilumab and Non‐Biologic Disease‐Modifying Antirheumatic Drugs in Patients With Active RA and Inadequate Response or Intolerance to TNF Inhibitors

To evaluate the efficacy and safety of sarilumab plus conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) in patients with active moderate‐to‐severe rheumatoid arthritis (RA) who had an inadequate response or intolerance to anti–tumor necrosis factor (anti‐TNF) therapy.

SAT0180 Onset of Action of Sarilumab in Patients with Rheumatoid Arthritis in 2 Phase 3 Studies

Background The investigational human anti–interleukin 6 receptor monoclonal antibody sarilumab plus methotrexate (MTX) has demonstrated efficacy in patients with rheumatoid arthritis (RA) and inadequate response to MTX (MOBILITY; NCT01061736),1 while sarilumab plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) demonstrated efficacy in patients with RA and inadequate response or intolerance to tumor necrosis factor (TNF) inhibitors (TARGET; NCT01709578).2 Among the most common treatment-emergent adverse events in both studies were infections, neutropenia, injection site reactions, and increased transaminases. Objectives This analysis of MOBILITY and TARGET study data assessed the time to onset of clinical efficacy of sarilumab and the durability of response over 24 weeks. Methods Adults with active, moderate-to-severe RA were randomized to 1 of 3 groups receiving subcutaneous sarilumab 150 or 200 mg or placebo every 2 weeks (q2w) plus background MTX (MOBILITY) or csDMARDs (TARGET). Clinical efficacy was evaluated in these patients at weeks 2, 4, 8, 12, and 24 in a post hoc analysis. ACR20/50/70 response rates were analyzed using the 2-sided Cochran-Mantel-Haenszel test stratified by prior biologic use and region (MOBILITY) or by region and number of prior TNF inhibitors (TARGET); nonresponder imputation was applied for patients who started rescue medication or discontinued the study. Changes from baseline in Health Assessment Questionnaire–Disability Index (HAQ-DI), 28-joint disease activity score by C-reactive protein (DAS28-CRP), and clinical disease activity index (CDAI) were analyzed with a mixed model for repeated measures; no data were imputed. Results Baseline demographic and disease characteristics were similar between treatment groups in both studies.1,2 Improvements in ACR20 responses were observed as early as week 2 in both studies, with nominal P<0.05 observed at week 8 for all sarilumab-treated groups in both studies. Similar trends were observed for ACR50 and ACR70 responses. Greater reductions in DAS28-CRP mean change from baseline vs placebo were observed with both doses of sarilumab by week 2 in both studies (nominal P<0.05). Similarly, numerical improvements in HAQ-DI and CDAI were observed with both doses of sarilumab vs placebo by week 4 in both studies (nominal P<0.05; Table). Improvements in all efficacy parameters were sustained through the end of each study (ie, week 52 for MOBILITY and week 24 for TARGET). The most common treatment-emergent adverse events at week 12 were infection and neutropenia, consistent with the safety profile previously reported for the entire study periods. Conclusions Sarilumab rapidly improved signs and symptoms of RA in patients with inadequate response to MTX (MOBILITY) or TNF inhibitors (TARGET), and improvements were sustained through the end of treatment. References Genovese et al. Arthritis Rheumatol. 2015;67:1424–1437 Fleischmann et al. Presented at: ACR; Nov. 7–11, 2015; San Francisco, CA Acknowledgement This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Editorial assistance was provided by Kristi Porter, PhD, MedThink SciCom, and funded by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Amgen, Ardea Biosciences, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Eli Lilly, Pfizer, Roche, Sanofi, and UCB, Consultant for: AbbVie, Akros Pharma, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, Eli Lilly, Pfizer, Roche, and UCB, 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, J. Fay Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, H. van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, D. Bauer Shareholder of: Sanofi, Employee of: Sanofi, D. Thompson Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Kivitz Shareholder of: Sanofi and Regeneron Pharmaceuticals, Inc., Consultant for: Sanofi, Pfizer, Roche, and UCB, G. Burmester: None declared

TERIFLUNOMIDE IN EARLY STAGE MS: RESULTS FROM TOPIC

Introduction Teriflunomide is a once-daily oral immunomodulator approved for relapsing–remitting multiple sclerosis (RRMS). Here we report the efficacy and safety outcomes from the TOPIC trial (NCT00622700). Methods TOPIC was a double-blind, placebo-controlled, parallel-group study in patients with a first clinical episode consistent with MS. Patients were randomised to teriflunomide 14 mg, 7 mg or placebo. The primary endpoint was occurrence of a new clinical relapse, and the key secondary endpoint was occurrence of a new clinical relapse or MRI lesion. Safety and tolerability were also assessed. Results Baseline characteristics were generally well balanced across groups. Teriflunomide 14mg significantly reduced the risk of a new clinical relapse by 42.6% (p=0.0087) and the risk of a new clinical relapse or MRI lesion by 34.9% (p=0.0003) versus placebo. Teriflunomide 14 mg significantly reduced total lesion volume increase from baseline at every time point and the number of gadolinium-enhancing T1 lesions per scan versus placebo. Safety observations were similar to those of TEMSO and TOWER. Conclusions Teriflunomide demonstrated efficacy in patients with early stage MS. Together with outcomes from TEMSO and TOWER, these findings support the beneficial effect of teriflunomide across a broad range of patients and disease activity.

SAT0168 Clinical Remission Outcomes with Sarilumab plus Csdmards in Active, Moderate-To-Severe RA Patients with Inadequate Response To Tumor Necrosis Factor Inhibitors

Background Clinical remission is an important treatment goal in rheumatoid arthritis (RA) and is associated with improved physical function and quality of life.1,2 In the phase 3 TARGET study (NCT01709578), sarilumab (150 or 200 mg subcutaneously every 2 weeks + conventional synthetic disease-modifying antirheumatic drugs [csDMARDs]) demonstrated efficacy in adults with active, moderate-to-severe RA and inadequate response to tumor necrosis factor (TNF) inhibitors.3 Infections, neutropenia, injection site reactions, and increased transaminases were among the most common treatment-emergent adverse events.3 Objectives This analysis assessed the proportions of patients achieving clinical remission measured by 4 different disease activity measures in a difficult-to-treat patient population with active RA and inadequate response or intolerance to ≥1 prior TNF inhibitor(s). Methods Four definitions of remission were used: 28-joint disease activity score by C-reactive protein (DAS28-CRP) <2.6, clinical disease activity index (CDAI) ≤2.8, simplified disease activity index (SDAI) ≤3.3, and Boolean-based ACR/EULAR remission (tender and swollen joint counts [28 joints] ≤1, CRP ≤10 mg/L, and patient global visual analog scale ≤10 mm/100 mm). Differences in incidence of these benchmarks between the active treatment groups and placebo were assessed using 2-sided Cochran-Mantel-Haenszel tests stratified by geographic region and number of prior TNF inhibitors. Patients who started rescue medication or discontinued the study were considered not to be in remission (nonresponder imputation). Results Baseline demographic and disease characteristics were balanced among the 3 treatment groups. At week (wk) 12 and wk 24, the proportion of patients achieving DAS28-CRP <2.6, CDAI, SDAI, and Boolean-based remission was higher in the sarilumab-treated groups than in the placebo group (Table). At wk 24, a significantly greater proportion of sarilumab patients achieved DAS28-CRP <2.6 compared with placebo. In comparison with placebo patients, a greater proportion of sarilumab patients who achieved DAS28-CRP <2.6 or Boolean-based remission also had clinically meaningful improvements in Health Assessment Questionnaire–Disability Index (HAQ-DI) and Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) at wk 24 (Table). Conclusions Sarilumab induced remission (using a broad range of definitions) as early as 12 weeks after initiation of therapy in patients with an inadequate response to TNF inhibitors. Patients with remission generally had improvements in physical function and fatigue as well. References Smolen et al. Ann Rheum Dis. 2014;73:492–509. Radner et al. Arthritis Res Ther. 2014;16:R56. Fleischmann et al. Presented at: ACR; November 7–11, 2015; San Francisco, CA. Acknowledgement This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Editorial assistance was provided by Kristi Porter, PhD, MedThink SciCom, and funded by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest G. Burmester Grant/research support from: AbbVie, Pfizer, Roche, and UCB, Consultant for: AbbVie, BMS, Pfizer, Merck, MedImmune, UCB, and Roche, Speakers bureau: AbbVie, BMS, Pfizer, Merck, UCB, and Roche, P. Hrycaj: None declared, C. Pacheco-Tena Consultant for: BMS, Janssen, Pfizer, Roche, and UCB, H. van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, E. Mangan Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, Y. Lin Shareholder of: Sanofi, Employee of: Sanofi, D. Bauer Shareholder of: Sanofi, Employee of: Sanofi, J. Fay Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Parrino Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Kivitz Shareholder of: Sanofi and Regeneron Pharmaceuticals, Inc., Consultant for: Sanofi, Pfizer, Roche, and UCB