Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis

Abstract

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)

Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study

“…Superiority of ponesimod was also shown on the exploratory end points of brain volume loss and NEDA status. Ponesimod was well tolerated, and the safety results were in line with previous observations in its phase 2 dose-finding study and findings on other S1P receptor modulators in controlled studies, including their extensions and postmarketing observations.…”

Ponesimod: An Oral Second-Generation Selective Sphingosine 1-Phosphate Receptor Modulator for the Treatment of Multiple Sclerosis

“…During the phase II extension study, the most common adverse events reported were as follows: nasopharyngitis (30%), headache (24%), and upper respiratory tract infection (21%). 15 No serious adverse events with an incidence greater than 1% were reported. Evaluation of clinical efficacy and tolerability of the 40 mg dose of ponesimod after 96 weeks suggested reduced tolerability and no additional efficacy.…”

“…After completing the phase IIb core study of 24 weeks, 435 patients were transitioned into an extension study to assess the long-term safety and efficacy of ponesimod. 15 The study was divided into 3 treatment periods: TP1, TP2, and TP3 (Table 2). The primary efficacy endpoints of the study were time to first confirmed relapse, the mean ARR, and time to 6-month confirmed disability accumulation (CDA).…”

Ponesimod to treat multiple sclerosis

“…Patients who participated in the phase II study rolled over into its extension, in which they were all treated with ponesimod 20 mg. After a median exposure of more than 8 years, between core and extension studies, the drug confirmed its substantial safety. No SAEs with an incidence greater than 1% were reported and the most common adverse events were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%) (33).…”

“…Patients who had completed the core study were offered enrollment in the extension of the phase II trial (NCT01093326), in which all 353 participants were treated with ponesimod (33). In an early part of the study, patients were still given the three different doses of ponesimod.…”