Safety and Tolerability of Ponesimod Compared to Teriflunomide in Patients with Relapsing Multiple Sclerosis: Results of the Randomized, Active-Controlled, Double-Blind, Parallel-Group Phase 3 OPTIMUM Study (1770)

Objective: To assess safety and tolerability of oral ponesimod and teriflunomide in patients with relapsing multiple sclerosis (RMS) in phase 3 OPTIMUM study. Background: Ponesimod, an orally active, second-generation, rapidly reversible, highly selective sphingosine-1-phosphate receptor 1 (S1P1) modulator causes sequestration of lymphocytes in lymphoid organs, leading to reduced blood lymphocyte counts. Design/Methods: Patients (18–55 years) with RMS were randomized (1:1) to ponesimod 20 mg or teriflunomide 14 mg for 108 weeks. For ponesimod, a 14-day gradual up-titration, starting with 2-mg, was implemented to mitigate potential first-dose cardiac effects associated with S1P-receptor modulators. Safety was assessed based on incidence of treatment-emergent adverse events (TEAEs), AEs of special interest (AESIs), cardiac monitoring and laboratory results. Results: Of 1131 patients treated (ponesimod: n=565, teriflunomide: n=566), 83.1% and 83.6% patients completed treatment, respectively. Incidence of TEAEs (88.8% vs 88.2%) and serious AEs (8.7% vs 8.1%) were similar. Most common TEAEs in ponesimod vs. teriflunomide groups were increased alanine aminotransferase (ALT) levels (19.5% vs 9.4%), nasopharyngitis (19.3% vs 16.8%), headache (11.5% vs 12.7%), and upper respiratory tract infection (10.6% vs 10.4%). Two deaths were reported in the teriflunomide group. TEAEs leading to treatment discontinuation were 8.7% and 6.0% in ponesimod and teriflunomide groups. Most common AESIs up to end-of-treatment (EOT)+15 days, unless otherwise specified, were hepatobiliary disorders/liver enzyme abnormalities (EOT+1 day) (22.7% vs 12.2%), hypertension (10.1% vs 9.0%), and pulmonary events (8.0% vs 2.7%). ALT increase ≥3×upper limit of normal (ULN) was higher with ponesimod (17.3% vs 8.3%), while ALT increase ≥8×ULN was more frequent with teriflunomide (0.7% vs 2.1%) treatment. Events related to heart rate and rhythm (including hypotension) on Day 1 occurred in 2.1% of ponesimod patients and were neither serious nor led to permanent discontinuation. Conclusions: Ponesimod’s safety profile was consistent with previous safety observations of ponesimod and the known profile of other S1P receptor modulators. Disclosure: Dr. Sprenger has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with I did not receive any personal compensation. My employer received compensation for speaking, advisory board/consulting activities from: Actelion, Lilly, Roche, Novartis, Sanofi Genzyme and Teva.. 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. 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. Fox has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Robert Fox has received compensation for serving as a consultant or speaker from Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis, and Teva. He, or the institution he works for, has received research support from Novartis.. Dr. Fox has received research support from He, or the institution he works for, has received research support from Novartis..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.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. Hohlfeld has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Biogen, Genzyme-Sanofi, Novartis, and Roche. Dr. Hohlfeld has received research support from Biogen, Genzyme-Sanofi, Novartis, and Roche. Dr. Lublin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen; EMD Serono; Novartis; Teva; Actelion; Sanofi/Genzyme; Acorda; Roche/Genentech; MedImmune; Receptos/Celgene; Forward Pharma; TG Therapeutics; Abbvie; Regeneron; Medday; Atara Biotherapeutics; Polpharma; Mapi Pharma; Innate Immunotherapeutics; Apito. Dr. Lublin has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Disorders- Co-Chief Editor. Dr. Lublin has received research support from Acorda Therapeutics, Biogen Idec, Genzyme, National MS Society, Novartis, Sanofi, Teva Neuroscience. Dr. Montalban has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Alexion, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Hoffmann-La Roche, Immunic AG, Medday, Medscape, Merck, Mylan, Nervgen, Novartis, Sanofi-Genzyme, Teva Pharmaceutical and TG Therapeutics. Dr. Montalban has received research support from Abbvie, Biogen, Hoffmann-La Roche, Medday, Merck, Novartis, Sanofi-Genzyme and Teva Pharmaceutical.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. 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. 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. Linscheid 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.. Dr. Pirozek-Lawniczek has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with are employee of Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson.. Dr. Kracker 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. Dr. Kappos has received research support from Bayer, Biogen, Innosuisse, Novartis, the Swiss MS Society, the Swiss National Research Foundation, and the European Union.