Ponesimod (Ponvory)
Ponesimod (Ponvory) is an oral DMT approved to treat adults with relapsing forms of MS (RMS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. It joins the currently available sphingosine 1-phosphate receptor (S1PR) modulator inhibitors: fingolimod, siponimod, and ozanimod.
The OPTIMUM trial was a multicenter, double-blind, active-comparator, superiority randomized clinical trial testing the efficacy, safety, and tolerability of 20 mg of ponesimod against 14 mg of teriflunomide for 108 weeks in people with RMS. Ponesimod was up-titrated from a 2 mg starting dose for the first 14 days to reduce first-dose cardiac effects of S1P1 modulators. In this randomized clinical trial, ponesimod was significantly superior to teriflunomide in reducing the annualized relapse rate (−30.5%), fatigue based on the Fatigue Symptom and Impact Questionnaire–Relapsing MS symptom score (−3.57), and combined unique active lesions on magnetic resonance imaging (−56%).
Prior to initiation of ponesimod, patients should have a CBC, LFT, Varicella titer, ophthalmologic exam, and electrocardiogram at baseline. Cardiac consultation should be considered if cardiac disease is present or concomitant medications that slow heart rate. Subsequently, patients should be monitored for development of infection, cutaneous malignancies, and cardiac changes.
While most patients do not require monitoring during the up-titration, first dose blood pressure and heart rate monitoring is still recommended for: Patients with sinus bradycardia (HR <55 beats per minute [bpm]), first- or second-degree (Mobitz type I) AV block, or a history of myocardial infarction (MI) or heart failure (HF) occurring >6 months before initiating treatment and in stable condition. With a half-life of 33 hours, if four or more missed consecutive doses during titration or maintenance requires a new titration starting at day one. Contraception should be used for 1 week after stopping ponesimod to avoid fetal harm.
Ponesimod is contraindicated for patients who in the past 6 months have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated HF requiring hospitalization, or Class III/IV HF. Presence of Mobitz second-degree, third degree, or sick sinus syndrome is also a contraindication unless a pacemaker is present.
Ponesimod has potential drug interactions with strong CYP3A4 and UGT1A1 inducers (e.g. rifampin, phenytoin, carbamazepine); concurrent administration is not recommended.
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