Regulatory Decision Summary for Ponvory

Ponvory’s mechanism of action (MoA) for the treatment of multiple sclerosis (MS), is believed to relate mainly to down-modulation and functional antagonism of the Sphingosphine-1 phosphate subtype 1 receptor (S1P1), leading to retention of lymphocytes in the lymphoid tissues. In the phase three program, the safety and efficacy of Ponvory in the treatment of Relapsing Remitting Multiple Sclerosis (RRMS) were established on the results of one pivotal study, OPTIMUM (number of subjects (n) = 1,133 patients), and its long-term extension study (OPTIMUM-LT). OPTIMUM was a phase III confirmatory, multicenter, randomized, double-blind, parallel group, active-controlled, superiority study to compare the efficacy and safety of Ponvory (n = 566) to teriflunomide (n = 567) (teriflunomide is a MS treatment authorized in various jurisdictions, including Canada; teriflunomide’s MoA is different than that of ponesimod). OPTIMUM-LT is an ongoing study that had about 2 years of data available for interim analysis. It is a multicenter, non-comparative extension study, designed to investigate the long-term safety and tolerability of Ponvory. Subjects who completed the 108-week period in the OPTIMUM study were enrolled in OPTIMUM-LT (switched from teriflunomide or maintained on Ponvory). In OPTIMUM, a multiple testing strategy was conducted for four pre-planned efficacy endpoints. The four endpoints were assessed with hypotheses tested hierarchically from H1 to H4. H1: The primary endpoint was the Annualized Relapse Rate (ARR). Ponvory significantly reduced the relative ARR by 30.5% compared to teriflunomide (relative ARR: 0.695; p-value (p) = 0.0003). H2: the secondary endpoint was the fatigue-related symptoms measured by the symptom domain of the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ - RMS). Ponvory significantly lowered the mean difference of the FSIQ-RMS weekly Symptom (FSIQ-RMS-S) scores by 3.57 (on a scale of 0-100) compared to teriflunomide (p = 0.0019). H3: The third endpoint was the combined unique active lesions (CUALs) on brain MRIs. Ponvory significantly reduced the Relative Rate of CUALs by 56% compared to teriflunomide (Relative Rate: 0.444; p<0.0001). H4: The fourth endpoint was the difference in the time to first confirmed disability accumulation at 12 weeks (12-week CDA). This endpoint was not found to be statistically significant when comparing Ponvory to teriflunomide. No deaths were reported in the Ponvory groups.

In OPTIMUM, the most commonly reported treatment emergent adverse event (TEAE) was increased alanine aminotransferase, reported more frequently (19.5%) in the Ponvory group than in the teriflunomide group (9.4%). Increased aspartate aminotransferase was also among the most commonly reported TEAEs (6.4% and 3.5% in the Ponvory and teriflunomide groups, respectively). A single 10 milligram (mg) oral dose of ponesimod in non-MS subjects with mild, moderate and severe hepatic impairment, showed a 1.3-, 2.0- and 3.1-fold increase in total ponesimod exposure (AUC) compared to healthy subjects. The t_1/2 also increased by 1.4-, 1.8- and 2.5-fold, respectively, but the C_max remained unchanged. MS patients with mild hepatic impairment were included in OPTIMUM and OPTIMUM-LT. However, MS patients with moderate and severe hepatic impairment were excluded of these studies. Considering all these results, a contraindication of Ponvory in moderate and severe hepatic impairment was deemed necessary.

In decreasing order, TEAE of nasopharyngitis, respiratory tract infection, urinary tract infection, dyspnea, bronchitis, and cough were all reported with higher incidences in the Ponvory group in OPTIMUM (from 19.3% to 3.5%).

Similar to the other drugs of the class, Ponvory is associated with QTc interval prolongation, PR interval prolongation and decreased heart rate. Main cardiovascular adverse event (AE) were sinus bradycardia and delays in atrioventricular (AV) conduction. A titration scheme was put in place to minimise these risks upon initiation of treatment.

Risk mitigation measures have been outlined in the Product Monograph (PM) for management of the aforementioned risks and TEAEs. The measures include appropriate contraindications, warnings, description of drug interactions, guidance, dosage considerations with focus on titration, screening and monitoring. Uncertainties surrounding the long-term risks associated with Ponvory, including the Pregnancy Outcomes Enhanced Monitoring (POEM) system, that monitors outcomes of pregnancy were mitigated in the Ponvory’s Risk Management Plan (RMP). Furthermore, contraindications, similar to that of all the drugs in this class, were added as a precautionary measure.

Considering the above benefits, the safety issues and/or uncertainties identified during the review and the appropriate management of the risks they represent, the benefit-harm-uncertainty profile for Ponvory in the treatment of RRMS is considered favourable when patients are treated with Ponvory according to the PM.