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

Abstract

IMPORTANCE To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS).OBJECTIVE To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P 1 ) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. DESIGN, SETTING, AND PARTICIPANTSThis multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity.INTERVENTIONS Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P 1 modulators and a follow-up period of 30 days. MAIN OUTCOMES AND MEASURESThe primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status.RESULTS For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, −3.57 (−0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). CONCLUSIONS AND RELEVANCEIn this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, bu...

Ponesimod inhibits astrocyte‐mediated neuroinflammation and protects against cingulum demyelination via S1P 1 ‐selective modulation

“…As all approved S1PR modulators engage S1P 1 , including singly through ponesimod that exhibited unbiased functional antagonism in human astrocytes, it appears that major benefits accrue through functional antagonism of this receptor subtype. The novel reduction in MS fatigue accessed by ponesimod 16 underscores the benefits, particularly through CNS mechanisms that involve complex cell autonomous and non‐cell autonomous interactions, which may reveal novel therapeutic mechanisms.…”

“…Since ponesimod is only supposed to engage S1P 1 , it provided an opportunity to examine its mechanistic effects as a mono‐specific S1P 1 receptor modulator beyond the previously reported peripheral immunological effects 18 . Other effects included those relevant to ponesimod clinical trial data (OPTIMUM Phase 3 study) 16 that achieved a novel secondary endpoint of reduced MS fatigue. Independent examination of ponesimod was therefore pursued for receptor selectivity, human astrocyte signaling, single‐cell gene expression, and an animal model of cuprizone‐induced demyelination that might elucidate the mechanisms underlying ponesimod efficacy signals related to MS fatigue.…”

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis

“…In EAE models, ponesimod was found to be effective in both preventive and therapeutic settings in which the overall severity of MS was reduced; this effect was also observed through improved histological outcomes (Pouzol et al, 2019). Recently, a Phase III, active-comparator, randomized trial demonstrated that ponesimod was superior to teriflunomide on annualized relapse rate reduction (the primary study outcome), fatigue symptoms, and MRI activity (Kappos et al, 2021). However, a search of the literature did not identify any published studies on the effects of ponesimod on the integrity of the BBB, or the CNS penetration of the drug in patients with MS.…”

Reviewing the Significance of Blood–Brain Barrier Disruption in Multiple Sclerosis Pathology and Treatment

“…Compared with the previous two members of the same class, Ozanimod facilitates a quicker lymphocyte reconstitution after discontinuation. Ponesimod is a selective S1PR-1 modulator that has been evaluated by authorities and recently received approval for active RRMS treatment by the EMA [121][122][123].…”