Siponimod 250microgram tablets

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.

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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.

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BackgroundIn recent years a broader range of immunomodulatory and immunosuppressive treatment options have emerged for people with progressive forms of multiple sclerosis (PMS). While consensus supports these options as reducing relapses, their relative benefit and safety profiles remain unclear due to a lack of direct comparison trials.ObjectivesTo compare through network meta-analysis the efficacy and safety of alemtuzumab, azathioprine, cladribine, cyclophosphamide, daclizumab, dimethylfumarate, diroximel fumarate, fingolimod, fludarabine, glatiramer acetate, immunoglobulins, interferon beta 1-a and beta 1-b, interferon beta-1b (Betaferon), interferon beta-1a (Avonex, Rebif), laquinimod, leflunomide, methotrexate, minocycline, mitoxantrone, mycophenolate mofetil, natalizumab, ocrelizumab, ofatumumab, ozanimod, pegylated interferon beta-1a, ponesimod, rituximab, siponimod, corticosteroids, and teriflunomide for PMS.Search methodsWe searched CENTRAL, MEDLINE, and Embase up to August 2022, as well as ClinicalTrials.gov and the WHO ICTRP.Selection criteriaRandomised controlled trials (RCTs) that studied one or more treatments as monotherapy, compared to placebo or to another active agent, for use in adults with PMS.Data collection and analysisTwo review authors independently selected studies and extracted data. We performed data synthesis by pair-wise and network meta-analysis. We assessed the certainty of the body of evidence according to GRADE.Main resultsWe included 23 studies involving a total of 10,167 participants. The most frequent (39% of studies) reason for a rating of high risk of bias was sponsor role in study authorship and data management and analysis. Other concerns were performance, attrition, and selective reporting bias, with 8.7% of studies at high risk of bias for all three of these domains. The common comparator for network analysis was placebo. Relapses over 12 months: assessed in one study (318 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 24 months: assessed in six studies (1622 participants). The number of people with clinical relapses is probably trivially reduced with rituximab (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.19 to 1.95; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 36 months: assessed in four studies (2095 participants). The number of people with clinical relapses is probably trivially reduced with interferon beta-1b (RR 0.82, 95% CI 0.73 to 0.93; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 24 months: assessed in 11 studies (5284 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 36 months: assessed in five studies (2827 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Serious adverse events: assessed in 15 studies (8019 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Discontinuation due to adverse events: assessed in 21 studies (9981 participants). The number of people who discontinued treatment due to adverse events is trivially increased with interferon beta-1a (odds ratio (OR) 2.93, 95% CI 1.64 to 5.26; high certainty evidence). The number of people who discontinued treatment due to adverse events is probably trivially increased with rituximab (OR 4.00, 95% CI 0.84 to 19.12; moderate certainty evidence); interferon beta-1b (OR 2.98, 95% CI 1.92 to 4.61; moderate certainty evidence); immunoglobulins (OR 1.95, 95% CI 0.99 to 3.84; moderate certainty evidence); glatiramer acetate (OR 3.98, 95% CI 1.48 to 10.72; moderate certainty evidence); natalizumab (OR 1.02, 95% CI 0.55 to 1.90; moderate certainty evidence); siponimod (OR 1.53, 95% CI 0.98 to 2.38; moderate certainty evidence); fingolimod (OR 2.29, 95% CI 1.46 to 3.60; moderate certainty evidence), and ocrelizumab (OR 1.24, 95% CI 0.54 to 2.86; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo.Authors' conclusionsThe number of people with PMS with relapses is probably slightly reduced with rituximab at two years, and interferon beta-1b at three years, compared to placebo. Both drugs are also probably associated with a slightly higher proportion of withdrawals due to adverse events, as are immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab; we have high confidence that this is the case with interferon beta-1a. We found only low or very low certainty evidence relating to disability progression for the included disease-modifying treatments compared to placebo, largely due to imprecision. We are also uncertain about the effect of interventions on serious adverse events, also because of imprecision. These findings are due in part to the short follow-up of the included RCTs, which lacked detection of less common severe adverse events. Moreover, the funding source of many included studies may have introduced bias into the results. Future research on PMS should include head-to-head rather than placebo-controlled trials, with a longer follow-up of at least three years. Given the relative rarity of PMS, controlled, non-randomised studies on large samples may usefully integrate data from pivotal RCTs. Outcomes valuable and meaningful to people with PMS should be consistently adopted and measured to permit the evaluation of relative effectiveness among treatments.

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