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Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis: Results from Randomized Phase 2b Core and Extension Studies.
Neurology 2022 June 7
OBJECTIVE: To evaluate the dose-response relationship of 10, 20 and 40-mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in relapsing-remitting multiple sclerosis (RRMS) patients.
METHODS: In the Core study, 464 patients were randomized (1:1:1:1): placebo (n=121), 10-mg (n=108), 20-mg (n=116), or 40-mg ponesimod (n=119) once-daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks), TP2 and TP3 (up to 432 weeks). The 40-mg dose was discontinued due to low tolerability at the end of TP1 and 10-mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated.
RESULTS: A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg=139, 20 mg=145, 40 mg=151) at any time during the Core and/or the Extension study. As of 31 March 2019, 214 patients were still on ponesimod treatment. Median (range) of ponesimod exposure was 7.95 (0-9.36) years. Ponesimod 20-mg, from Core up to end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9% and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%).
CONCLUSION: The effects on MS disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in individuals with relapsing-remitting multiple sclerosis, long-term treatment with ponesimod 20mg was associated with sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free.
TRIAL REGISTRATION INFORMATION: EudraCT Number 2008-006786-92 (Core study) and EudraCT Number 2009-011470-15 (Extension study).
METHODS: In the Core study, 464 patients were randomized (1:1:1:1): placebo (n=121), 10-mg (n=108), 20-mg (n=116), or 40-mg ponesimod (n=119) once-daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks), TP2 and TP3 (up to 432 weeks). The 40-mg dose was discontinued due to low tolerability at the end of TP1 and 10-mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated.
RESULTS: A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg=139, 20 mg=145, 40 mg=151) at any time during the Core and/or the Extension study. As of 31 March 2019, 214 patients were still on ponesimod treatment. Median (range) of ponesimod exposure was 7.95 (0-9.36) years. Ponesimod 20-mg, from Core up to end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9% and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%).
CONCLUSION: The effects on MS disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in individuals with relapsing-remitting multiple sclerosis, long-term treatment with ponesimod 20mg was associated with sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free.
TRIAL REGISTRATION INFORMATION: EudraCT Number 2008-006786-92 (Core study) and EudraCT Number 2009-011470-15 (Extension study).
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