Ponesimod 2mg tablets

Abstract Promoting remyelination is a key therapeutic goal in demyelinating diseases such as multiple sclerosis (MS), yet effective strategies remain limited. Sphingosine-1-phosphate (S1P), a ubiquitous bioactive lipid, has emerged as a key therapeutic target in MS due to its dual roles in immune regulation and neuroprotection; however, the therapeutic efficacy of current S1P-based therapies in remyelination remains unclear. This systematic review evaluated in vivo studies up to July 2025, in accordance with PRISMA guidelines, to assess the efficacy of S1P modulators on remyelination in mammalian models of demyelination. A comprehensive search across three databases identified 24 eligible studies that investigated S1P receptor (S1PR) modulation in both acute and chronic models of demyelination, with or without immune-mediated components. Fingolimod was the most extensively studied compound (16 studies). Of the 18 studies assessing demyelination outcomes, S1P modulation consistently attenuated myelin loss and oligodendrocyte depletion. In contrast, remyelination outcomes were inconsistent: among 15 studies assessing repair, most reported no significant enhancement. While fingolimod showed limited evidence on remyelination, more promising effects were observed with selective S1PR1/5 modulators such as siponimod and ponesimod. Overall, current evidence supports a model in which S1P modulators act primarily through S1PR1-mediated immunomodulation and S1PR5-associated oligodendroglial protection, preserving oligodendrocyte lineage cells rather than driving terminal differentiation or de novo remyelination. Several compounds displayed bell-shaped dose-response patterns, highlighting the importance of dosing and treatment paradigms. Collectively, these findings indicate S1PR-based therapies primarily limit demyelination, with limited evidence of remyelination, emphasising the need for more efficacious S1P modulators to improve MS outcomes.

Abstract licence: CC BY

BackgroundRegenerative strategies in progressive multiple sclerosis (MS) pose a significant unmet need. Combining immunomodulatory treatment with remyelinating interventions to target the complex underlying pathogenesis appeals as the next frontier in MS therapeutic developments. Therefore, it is important to identify which disease-modifying treatments (DMT) with proremyelinating properties are most promising for future use in combination treatments. This systematic review provides an overview of preclinical and clinical research on remyelination, focusing on the effects of currently available FDA and EMA-approved DMT.MethodsThe search was conducted in accordance with the "Synthesis without meta-analysis" (SWiM) reporting guideline. The protocol was registered at PROSPERO prior to the search.ResultsFifty-seven articles on preclinical research, three randomized controlled trials (RCTs), 29 non-randomized clinical studies, and eight reviews were included. Preclinical research suggested neuroprotective properties of various DMT. However, convincing evidence of true remyelination, either by influencing oligodendrocyte lineage cells in cell cultures or histological analysis in vivo, could only be found in studies investigating glatiramer acetate, teriflunomide, Fingolimod, Siponimod, Ponesimod, and alemtuzumab. Clinical trials using surrogate markers of myelin repair, such as advanced imaging and electrophysiological techniques, demonstrated promising results with glatiramer acetate, Fingolimod, Siponimod, natalizumab, alemtuzumab, and ocrelizumab. However, we found insufficient proof to claim that changes in these surrogate markers can be explained by remyelination alone.ConclusionsFuture proof-of-concept clinical trials investigating remyelinating agents in MS should consider combining outcome measures into composite endpoints. Furthermore, research efforts should be dedicated to novel biomarkers to assess repair mechanisms in MS.

Abstract licence: CC BY-NC-ND

ABSTRACT The objective of this phase 1 study was to evaluate the pharmacokinetics (PK), pharmacodynamics, and cardiac effect following administration of ponesimod (a selective sphingosine‐1‐phosphate receptor modulator) and propranolol in healthy adults. In treatment period (TP) 1, participants received ponesimod (2 mg). In TP2, if resting heart rate (HR) was ≥ 55 bpm, the ponesimod up‐titration regimen was initiated. Participants were randomized to TP2A (placebo plus ponesimod up‐titration) or TP2B (80 mg propranolol plus ponesimod up‐titration). Concomitant administration resulted in an increased bradyarrhythmic effect on HR versus ponesimod alone. The mean maximum difference in mean hourly HR from time‐matched baseline for TP2B compared with TP2A during the first 12 h post‐dose was −12.4 bpm. This was observed after the first dose of ponesimod, persisted for the first 4 doses, then decreased to −7.4 bpm post‐up‐titration. The lowest mean of the HR nadir in TP2B was 48.9 bpm (95% CI: 46.4–51.3). There was no significant difference in the occurrence of 1st degree AV block between groups and no occurrences of 2nd or higher degree AV block. No clinically relevant changes were observed in the PK of ponesimod or propranolol. Overall, 88.5% of participants experienced ≥ 1 AE during the study. In TP2, the most reported TEAEs (≥ 5%) considered related to ponesimod were fatigue (12 [25.5%]) and dizziness (10 [21.3%]). No deaths were reported. Co‐administration of ponesimod with propranolol resulted in a greater HR‐lowering effect compared to ponesimod alone, without significant changes in PK parameters or serious cardiac adverse events in healthy adults.

Abstract licence: CC BY-NC-ND 4.0