The oral S1P1 modulator joins a number of other agents in its class, and has also been submitted to the European Medicines Agency for approval in the treatment of MS.
Robert J. Fox, MD
The FDA has approved ponesimod (Ponvory; Janssen Pharmaceutical), an oral selective sphingosine-1-phosphate receptor 1 (S1P1) modulator that functionally inhibits S1P activity and reduces circulating lymphocytes, for the treatment of adults with relapsing multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.1
"In the pivotal study, ponesimod demonstrated superior clinical efficacy in reducing annual relapses and MRI activity compared against teriflunomide, another oral MS therapy. Those results, combined with a favorable side effect profile, make ponesimod a useful treatment option for people with relapsing MS," said Robert J. Fox, MD, staff neurologist, Mellen Center for MS Treatment and Research, and Vice-Chair for Research, Neurological Institute, Cleveland Clinic, in a statement. Fox has served as a paid consultant to Actelion Pharmaceuticals Ltd and Janssen as a member of the ponesimod Advisory Board.
The drug was previously submitted to the European Medicines Agency for approval, as well, in the first quarter of 2020. It is currently under review. The FDA decision was made after assessing supporting data from the phase 3 OPTIMUM study (NCT02425644), a head-to-head evaluation that examined the safety and efficacy of 20-mg ponesimod against 14-mg teriflunomide (Aubagio; Sanofi) in adults with relapsing MS.
Those data were previously presented at the 2019 ECTRIMS annual meeting and showed a 30.5% greater reduction in annualized relapse rate (ARR) with treatment with ponesimod compared with teriflunomide at week 108, with respective rates of 0.202 and 0.290, respectively (P = .003). The secondary end points—which consisted of fatigue-related symptoms as assessed with the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS), an MS-specific, 20-item patient-reported outcome measure—were also positive in OPTIMUM. At week 108, scores suggested statistically significant effects on symptoms of fatigue with ponesimod treatment compared with teriflunomide, with a mean difference of –3.57 (P = .0019).2
In addition, treatment with ponesimod was associated with a 56% reduction in the cumulative number of combined unique active lesions (P <.001). The most common adverse events (AEs) recorded in OPTIMUM were nasopharyngitis, headache, upper respiratory tract infections, and an increase in alanine aminotransferase.
Additional data from OPTIMUM was presented last fall at MS Virtual 2020, the 8th Joint ECTIMS-ACTRIMS meeting, by Till Sprenger, MD, neurologist, DKD Helios Klinik Wiesbaden, which evaluated the cardiac safety profile of ponesimod. The results suggested that treatment was not associated with an increased risk for major cardiovascular (CV) events such as myocardial infarction (MI), stroke, or CV death when compared to teriflunomide.3
No major CV events (MACE)—defined as CV death, non-fatal MI, and non-fatal stroke—in patients who were treated with ponesimod. In comparison, 3 instances of MACE occurred in the teriflunomide group. The cohort of 1131 patients who received treatment with either ponesimod (n = 565) or teriflunomide (566), experienced cardiac treatment-emergent adverse events (TEAEs) that led to discontinuation for 1 patient (0.2%) on ponesimod (cardiomyopathy) and 2 patients (0.4%) on teriflunomide (1 atrial fibrillation, 1 coronary artery insufficiency).
Hazard risks (HRs) and rhythm TEAEs of special interest were reported in 29 patients (5.1%) on ponesimod compared to 24 patients (4.2%) in the teriflunomide group. On Day 1, the incidence of heart rate and rhythm TAES of special interest was 2.1% in the ponesimod group and included bradycardia (<50 bpm) in 0.7% and first-degree atrioventricular block in 0.5%. First-degree atrioventricular block was observed in 0.4% of teriflunomide patients.
Another trial of the ponesimod, which was set to compare 20-mg doses to placebo in those who are treated with dimethyl fumarate (Tecfidera; Biogen), called POINT (NCT02907177) was recently terminated due to low recruitment. The study was planned to be conducted under a Special Protocol Assessment (SPA) with the FDA.4
In a statement accompanying the approval, Mathai Mammen, MD, PhD, Global Head of Janssen Research & Development, Johnson & Johnson, emphasized the varying effect of MS as both an underlying disease and a symptom-laden condition.1
"Continued innovation in this space is critical, and we're committed to meeting patients' evolving healthcare needs," Mammen said. "We are proud to offer PONVORY as a valuable new option for people with MS that may help them gain better control of their disease."