Ponesimod (ACT-128800) met most of its endpoints in the phase III OPTIMUM trial versus teriflunomide in patients with MS, according to a preliminary announcement. Ponesimod is the latest in a series of sphingosine-1-phosphate receptor drugs, a group that includes fingolimod, siponimod and ozanimod. Somewhat unique is that ponesimod is selective to S1PR-1 and acts as an agonist rather than an antagonist (or functional agonist). Ponesimod has a short half-life (30 hours) and is eliminated in about 1 week (Dash et al. Xenobiotica 2018;48:442-451). The drug was developed by Actelion and will be marketed by Janssen, both of which are owned by Johnson & Johnson.
The OPTIMUM trial enrolled 1133 patients with relapsing MS (RRMS and SPMS) and included four study sites in Canada. Subjects were randomized to oral ponesimod 20 mg/day or teriflunomide 14 mg/day for 108 weeks. The primary endpoint was annualized relapse rate (ARR). Secondary endpoints included the time to 12- and 24-week confirmed disability progression, and the cumulative number of combined unique lesions (T2 and Gd+ T1) on MRI. An additional endpoint was the change from baseline in fatigue-related symptoms as assessed by the Fatigue Symptoms and Impact Questionnaire-Relapsing MS. The primary endpoint was met but no additional data are available. Results are expected to be released at ECTRIMS 2019 in Stockholm.
A second phase III trial, POINT, is comparing ponesimod in combination with dimethyl fumarate (DMF) versus DMF monotherapy. That study is ongoing.
A 24-week phase II trial previously reported a significant reduction in the number of new Gd+ lesions in weeks 12-24 with ponesimod 20 mg/day versus placebo (Olsson et al. J Neurol Neurosurg Psychiatry 2014;85:1198-1208). Adverse effects included anxiety, dizziness, dyspnea, elevated liver enzymes and peripheral edema. A separate study on lymphocyte kinetics found that ponesimod sequesters T and B cells, with greater effects on naïve T cells versus memory T cells, and on CD4+ T cells versus CD8+ or regulatory T cells (D’Ambrosio et al. Immunopharmacol Immunotoxicol 2015;37:103-109).