Long-term Efficacy and Safety of Ponesimod, an oral S1P1 Receptor Modulator: Results from Randomized Phase II Core and Extension Studies in Relapsing-Remitting Multiple Sclerosis (1752)

Objective: Evaluate the long-term efficacy and safety of ponesimod in patients with relapsing-remitting multiple sclerosis (RRMS). Background: Ponesimod, an orally active, selective sphingosine 1-phosphate receptor-1 (S1P1) modulator, showed benefits in clinical and MRI outcomes in a double-blind, placebo-controlled, phase 2b Core Study (NCT01006265). Patients rolled-over into an ongoing Extension Study (NCT01093326). Design/Methods: A total of 435 patients with RRMS received ≥1 dose of ponesimod (10, 20, or 40-mg/day) during the Core and/or Extension Study. The 40 and 10-mg doses were subsequently discontinued during Treatment Period 1 (TP1) and TP2 of the Extension Study. All patients received 10 or 20-mg during TP2, followed by open-label 20-mg in TP3. Key efficacy parameters: annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), and MRI outcomes. Safety parameters: frequencies of adverse events (AEs) and serious AEs (SAEs). Results of combined analyses of Core and Extension studies are presented. Results: As of 31 March 2019, 214 patients were still on ponesimod treatment; median exposure in 20-mg group was 8.02 years; Cumulative exposure across all doses was 2372.47 patients-years. In 20-mg group, ARR (95% CI) for confirmed relapses was 0.154 (0.111–0.214); 64.1% patients remained free of confirmed relapse; Kaplan-Meier estimate of 6-month CDA at Week 432 was 20.4% (13.7–29.7); Mean number of T1 gadolinium enhancing lesions per patient per scan was 0.448 (0.305–0.657); Mean number of new or enlarging T2 lesions per year was 0.718 (0.523–0.985). In ponesimod-treated patients, the most common treatment-emergent AEs were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%). Most SAEs were reported in a single patient, no SAE was reported at an incidence of >1%. Conclusions: Long-term treatment with ponesimod 20 mg showed consistently low levels of disease activity across relevant clinical and MRI outcomes in patients with RRMS. No new safety signals were identified. Disclosure: Dr. Freedman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Bayer Healthcare, Biogen Idec, Chugai, Clene Nanomedicine, EMD Serono Canada, Genzyme, Merck Serono, Novartis, F. Hoffmann-La Roche Ltd, Sanofi-Aventis and Teva Canada Innovation. Dr. Freedman has received compensation for serving on the Board of Directors of Actelion, Bayer Healthcare, Biogen Idec, Clene Nanomedicine, F. Hoffmann-La Roche Ltd, Merck Serono, MedDay Pharmaceuticals, Novartis and Sanofi-Aventis. Dr. Freedman has received research support from Genzyme Canada. Dr. Pozzilli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Served on scientific advisory boards for Novartis, Merck, Biogen, Sanofi, Genzyme, Teva, Actelion and funding for travel and speaker honoraria from Biogen, Teva, Sanofi Genzyme, Actelion and Novartis. Dr. Pozzilli has received research support from Biogen, Teva, Novartis and Genzyme. Dr. Havrdova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Biogen, Celgene Corporation, Merck, Novartis, Roche, Sanofi, and Teva. Dr. Havrdova has received research support from Czech Ministry of Education, project PROGRES Q27/LF1.Yes; Accordant, Alexion, Bayer, Biogen MA, Inc., Celgene Corporation, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Serono, TG Therapeutics Yes; Actelion, Alkermes, Corrona LLD, Genentech/Roche, MedDay, NINDS, Novartis Pharmaceuticals Corporation, PCORIDr. Lemle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Part of Janssen Pharmaceutical company of Johnson & Johnson. Dr. Lemle has received compensation for serving on the Board of Directors of Johnson & Johnson. Dr. Burcklen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson. Dr. Burcklen has received compensation for serving on the Board of Directors of Johnson & Johnson. Dr. Larbalestier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Part of Janssen Pharmaceutical Companies. Dr. Larbalestier has received compensation for serving on the Board of Directors of Johnson & Johnson. Dr. Hennessy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson. Dr. Hennessy has received compensation for serving on the Board of Directors of Johnson & Johnson, Novo Nordisk, Arena Pharmaceuticals, and Galapagos. Dr. Scherz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson and a former employee of Novartis Pharma AG. Dr. Scherz has received compensation for serving on the Board of Directors of Johnson & Johnson. Dr. Vaclavkova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Part of Janssen Pharmaceutical company of Johnson & Johnson. Dr. Vaclavkova has received compensation for serving on the Board of Directors of Johnson & Johnson. Dr. Olsson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Genzyme, Allmiral, AstraZeneca and Roche.