Researchers concluded that uptitration of ponesimod was not associated with clinically significant bradyarrhythmia events; none were serious or lead to discontinuation.
An evaluation of the cardiac safety profile of ponesimod (Janssen Pharmaceutical) showed that treatment with the agent 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 (Aubagio; Sanofi).1
The dataset was from the phase 3 OPTIMUM study (NCT02425644) and was presented at MS Virtual 2020, the 8th Joint ECTIMS-ACTRIMS meeting, September 11–13, 2020, by Till Sprenger, MD, neurologist, DKD Helios Klinik Wiesbaden.
Researchers found 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.
Among a cohort of 1131 patients who received treatment with either ponesimod (n = 565) or teriflunomide (566), cardiac treatment-emergent adverse events (TEAEs) that led to discontinuation occurred in 1 patient (0.2%) on ponesimod (cardiomyopathy) and 2 patients (0.4%) on teriflunomide (1 atrial fibrillation, 1 coronary artery insufficiency).
Patients within the study were between the ages of 18 and 55 years were randomized 1:1 to ponesimod 20 mg or teriflunomide 14 mg for 108 weeks. Those on ponesimod underwent a gradual 14-day titration starting with 2 mg implemented to address first-dose cardia effects. Blood pressure (BP) and 12-lead electrocardiogram (ECG) measurements were used to assess cardiac safety.
Sprenger and colleagues noted that there was no association between clinically significant bradyarrhythmia events and patients who had dosage uptitrated. Additionally, none of those evens were serious or led to discontinuation. No 2nd degree or higher atrioventricular (AV) blocks were reported.
Hazard risks (HRs) and rhythm TEAEs of special interest (AESIs) 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 HR and rhythm AESIs was 2.1% in the ponesimod group and included bradycardia (HR, <50 bpm) in 0.7% and 1st degree AV block in 0.5%. First degree AV block was found in 0.4% of teriflunomide patients.
On Day 1, the max mean reduction in HR from pre- to post-dose at 2 hours was –8.7 bpm for ponesimod and –1.7 bpm for teriflunomide.
A total of 3 patients in the ponesimod group had post-dose asymptomatic HR ≤40 bpm on Day 1, and all had pre-treatment HR <55 bpm. Furthermore, new electrocardiogram (ECG) findings of sinus bradycardia was 20% in patients at risk for symptomatic bradyarrhythmia, compared to 3.0%, all of which were asymptomatic, in patients who were not at-risk.
Janssen presented the original data from OPTIMUM at ECTRIMS 2019. Results showed that ponesimod, an orally active, selective modulator of the sphingosine-1-phosphate receptor 1 (S1P) had a statistically significant 30.5% greater reduction in annualized relapse rate (ARR) compared to teriflunomide. At week 108, the respective ARRs for the ponesimod and teriflunomide groups were 0.202 and 0.290 (P = .003).2
Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS)
—an MS-specific, 20-item patient-reported outcome measure—scores at week 108 suggested statistically significant effects on fatigue symptoms with ponesimod in comparison to teriflunomide, with a mean difference of —3.57 (P = .0019).
Additionally, the cumulative number of combined unique active lesions (CUALs), measured with MRI, showed a 56% reduction (P <.0001) with ponesimod. Although 12-week confirmed disability accumulation was observed in 10.1% and 12.4% of patients in the ponesimod and teriflunomide arms, respectively, the results were not statistically significant.
The results from this study led Janssen to submit its new drug application (NDA) for ponesimod for the treatment of adults with relapsing MS in March. The company did not announce a prescription user drug fee act (PDUFA) date or when they would hear back from the FDA on the NDA.3