Ponvory (ponesimod) / Idorsia, J&J, Juvise Pharma, Vanda - LARVOL DELTA

Predictors of high- versus low-intensity first-line multiple sclerosis treatments. (PubMed, Mult Scler J Exp Transl Clin) - "The first DMT filled was classified as either high- (natalizumab, alemtuzumab, ocrelizumab, rituximab, ofatumumab, cladribine) or low-intensity (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, ponesimod, siponimod, ozanimod)...The minority of MS patients initiated high-intensity treatment although this proportion increased over time, and later years were predictive of high-intensity treatment. Providers had a significant role in the approach selected."

Journal • CNS Disorders • Multiple Sclerosis

Cardiac arrhythmias associated with S1PRMs: a pharmacovigilance study based on real-world data. (PubMed, Front Pharmacol) - "We identified 2,059 arrhythmia-related adverse events associated with S1PRMs, including 1,860 cases for fingolimod, 153 for siponimod, 38 for ozanimod, and 8 for ponesimod. As a disproportionality analysis of spontaneous reports, these results reflect statistical associations rather than causal relationships and should be regarded as hypothesis-generating; cross-drug comparisons are further influenced by differential reporting, market duration and cumulative exposure. These results may complement clinical trial data for informed risk-benefit assessment, particularly for newer S1PRMs with limited post-marketing surveillance data."

Adverse events • Journal • Real-world evidence • Cardiovascular • CNS Disorders • Multiple Sclerosis

Study to Evaluate the Efficacy and Safety of Ponesimod (VSP-128) in Patients With Moderately to Severely Active Ulcerative Colitis (clinicaltrials.gov) - P3 | N=150 | Recruiting | Sponsor: Vanda Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Long-term safety and efficacy of ponesimod, an oral S1P1 receptor modulator, in relapsing-remitting multiple sclerosis (RRMS): Results from randomized phase 2b core and extension studies spanning up to 13 years. (PubMed, Mult Scler Relat Disord) - P2 | "Ponesimod treatment for up to 13 years was not associated with new safety concerns. Participants continued to experience low levels of disease activity consistently across clinical and MRI outcomes."

Journal • P2b data • CNS Disorders • Multiple Sclerosis

Relapse activity after ponesimod discontinuation in the OPTIMUM long-term extension study. (EAN 2026) - "Background and aims: OPTIMUM was a 2-year phase 3 trial comparing ponesimod versus teriflunomide in relapsing multiple sclerosis. In this analysis, ARR and relapse EDSS did not suggest a clinically meaningful reactivation or rebound after ponesimod discontinuation within the available follow-up. Real-world data with longer follow-up are needed to confirm these findings."

CNS Disorders • Multiple Sclerosis

Effectiveness and safety of Ponesimod in Relapsing Multiple Sclerosis: results from an Italian multicenter real-world observational study (EAN 2026) - "Background and aims: In 2021, the phase III OPTIMUM trial demonstrated the efficacy of Ponesimod (PON) - a sphingosine-1-phosphate receptor modulator - over teriflunomide in treating Relapsing Multiple Sclerosis (RMS). In this Italian real-world study, PON showed high effectiveness in controlling clinical and radiological disease activity, with a favourable safety and tolerability profile."

Clinical • Observational data • Real-world • Real-world evidence • CNS Disorders • Infectious Disease • Multiple Sclerosis

Study to Evaluate the Efficacy and Safety of Ponesimod (VSP-128) in Patients With Moderately to Severely Active Ulcerative Colitis (clinicaltrials.gov) - P3 | N=150 | Not yet recruiting | Sponsor: Vanda Pharmaceuticals

New P3 trial • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Long-term efficacy and safety of ponesimod in females and males: post-hoc analysis of the ponesimod long-term extension trial (EAN 2026) - " After 108 weeks of double-blind treatment with ponesimod 20 mg (P) or teriflunomide 14 mg (T) in the core OPTIMUM study, participants were offered ponesimod 20 mg in the OLE for up to 5 years. Ponesimod demonstrated sustained long-term efficacy and safety with comparable outcomes in both sexes. These results support consistent use of ponesimod across both sub-populations."

Clinical • Retrospective data • CNS Disorders • Infectious Disease • Multiple Sclerosis • Nephrology

Ponesimod efficacy and safety in relapsing multiple sclerosis patients with mild to moderate disability: results from OPTIMUM and long-term extension (EAN 2026) - "Background and aims: OPTIMUM was a phase 3 trial comparing ponesimod with teriflunomide in relapsing multiple sclerosis (RMS). In patients with baseline EDSS ≤3.5, ponesimod showed sustained clinical and magnetic resonance imaging efficacy across OPTIMUM and the LTE with a favorable safety profile."

Clinical • CNS Disorders • Multiple Sclerosis

Efficacy and safety of ponesimod in patients aged 50 years or older in OPTIMUM and its long-term extension (EAN 2026) - "Background and aims: OPTIMUM was a 2-year phase 3 trial comparing ponesimod with teriflunomide in relapsing multiple sclerosis. In this post-hoc analysis of patients aged 50 years or older, ponesimod demonstrated sustained clinical and imaging efficacy with a favorable safety profile. These findings require confirmation in larger real-world cohorts."

Clinical • CNS Disorders • Multiple Sclerosis

Unplanned Pregnancy During Ponesimod Therapy in RRMS: Clinical Course and Outcome (EAN 2026) - No abstract available

Clinical • Multiple Sclerosis

Post-hoc analysis ofthe OPTIMUM long-term extension study: Preservation of independent ambulation in patients treated with Ponesimod (EAN 2026) - " Following 108 weeks of double-blind treatment with ponesimod 20 mg or teriflunomide 14 mg in the core OPTIMUM study, participants could enter the long-term extension (LTE) and receive open-label ponesimod 20 mg. This post-hoc analysis of OPTIMUM-LTE shows a sustained preservation of mobility and functional independence with ponesimod over up to 7 years of follow-up, supporting its durable efficacy in patients with RMS."

Clinical • Retrospective data • CNS Disorders • Multiple Sclerosis

The Role of Sphingosine-1-Phosphate Signaling in Cerebral Ischemia/Reperfusion Injury and Alzheimer's Disease Pathology. (PubMed, Int J Mol Sci) - "Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood-brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I/R injury and AD."

Journal • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Inflammation • Multiple Sclerosis • Reperfusion Injury • S1PR1 • S1PR5

The impact of age on efficacy and safety of disease modifying treatment-insights from the Austrian Multiple Sclerosis Treatment Registry. (PubMed, J Neurol) - "Our findings indicate that approximately one-third of treated MS patients in our registry are aged 50 years or older, underscoring the substantial presence of older patients in contemporary MS treatment cohorts. Furthermore, efficacy outcomes, including ARR and EDSS progression, differed significantly between younger and older age groups. These results suggest that both disease activity and chronological age are primary determinants of treatment outcomes."

Journal • Observational data • CNS Disorders • Multiple Sclerosis

Open Label Study to Investigate the Safety and Efficacy of Ponesimod in Moderate-to-Severe Chronic Plaque Psoriasis (clinicaltrials.gov) - P3 | N=300 | Recruiting | Sponsor: Vanda Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Dermatology • Immunology • Psoriasis

A Study to Learn More About The Safety of Diroximel Fumarate (VUMERITY®) in Participants Who Took it During Pregnancy And About the Health of Their Babies (clinicaltrials.gov) - P=N/A | N=1178 | Active, not recruiting | Sponsor: Biogen | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Multiple Sclerosis

Indirect Treatment Comparison of Brain Volume Loss with Tolebrutinib Versus Other Therapies In Relapsing Multiple Sclerosis: A Network Meta-Analysis (CMSC 2026) - "For tolebrutinib, ublituximab, and cladribine, percent change in BVL from 6 months to end of study (EOS) was extracted, while change from baseline to EOS was used for all other comparators...Relative to other approved DMTs in RMS, tolebrutinib showed numerically lower change in BVL across most comparisons, except with ponesimod 20 mg and alemtuzumab 12 mg, where trends favored the comparator. Tolebrutinib 60 mg was associated with less BVL versus placebo, peginterferon 125 µg Q2W and glatiramer acetate 40 mg TIW and showed numerically favorable BVL outcomes compared with most established RMS therapies, suggesting a potential beneficial effect on BVL."

Retrospective data • CNS Disorders • Multiple Sclerosis

Effects of Sphingosine 1-phosphate Modulators on Central Remyelination: A Systematic Review of Animal Models. (PubMed, Cell Mol Neurobiol) - "While fingolimod showed limited evidence on remyelination, more promising effects were observed with selective S1PR1/5 modulators such as siponimod and ponesimod. 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."

Journal • Preclinical • CNS Disorders • Immunology • Multiple Sclerosis • Solid Tumor • S1PR1 • S1PR5

Disease-modifying treatment for multiple sclerosis in Poland in a European context: current practices and therapeutic strategies. (PubMed, Neurol Neurochir Pol) - "Current treatment algorithms in Poland include both platform agents, such as interferon beta, glatiramer acetate, fumarates, and teriflunomide, as well as high-efficacy therapies, including monoclonal antibodies (e.g., ocrelizumab, ofatumumab, ublituximab, alemtuzumab, natalizumab) and oral agents (e.g., fingolimod, cladribine, ozanimod, ponesimod)...The future development of MS management in Poland will depend on expanding access to innovative therapies, advancing biomarker research, and implementing the latest diagnostic criteria for MS. European treatment recommendations will continue to provide an important framework supporting high-quality care and early intervention for people with MS."

Journal • CNS Disorders • Multiple Sclerosis

Uncoupling Relapse Reduction and Disability Progression: Evidence From Tolebrutinib Studies. (PubMed, Neurol Clin Pract) - "Tolebrutinib was the only therapy to show a benefit on CDW without a measurable effect on relapses, highlighting a dissociation between disability worsening and relapse suppression not observed with other DMTs."

Journal • CNS Disorders • Multiple Sclerosis

Comparative Efficacy of 35 Disease-modifying Therapies in Relapsing-remitting MS: A Network Meta-analysis Identifying Top Performers for Relapse, MRI Activity, and Disability Progression (AAN 2026) - "At 6 months, SC IFNbeta-1b (RR 0.14) and SC Ofatumumab (RR 0.33) were associated with the lowest disability progression...Conclusions Alemtuzumab and the Ocrelizumab formulations were highly effective for relapse prevention, while Ponesimod + DMF and Natalizumab formulations reduced MRI lesions. Mitoxantrone was associated with long-term prevention of disability progression."

Retrospective data • CNS Disorders • Multiple Sclerosis

Structural insights into subtype-specific agonist recognition by sphingosine-1-phosphate receptors. (PubMed, PLoS Biol) - "Through an integrated approach combining structural analysis, molecular dynamics simulations, and pharmacological assays, the molecular basis for the selectivity of CYM5442, HY-X-1011, Ponesimod, and SAR247799 toward S1PR1 over S1PR2-S1PR5 is uncovered. Besides, the relatively broad molecular width of the agonist sterically hinders its binding into S1PR2 and S1PR4 pocket by nonconserved residue pairs bearing bulky side chains. These findings establish a structural framework for the rational design of next-generation S1PR1 highly selective agonists with improved therapeutic potential."

Journal • S1PR1 • S1PR2 • S1PR5

The comparative efficacy of cladribine tablets versus alternative disease-modifying treatments for relapsing-remitting multiple sclerosis: Updated meta-regression estimates by patient subgroup. (PubMed, Mult Scler Relat Disord) - "Updated meta-regressions demonstrate that cladribine tablets have comparable relative efficacy to other high-efficacy therapies in HDA and SOT patient subgroups. For disability progression outcomes, cladribine tablets showed similar efficacy to ofatumumab; for relapse reduction, cladribine tablets were comparable to ocrelizumab. Cladribine tablets also consistently outperformed most platform therapies across all analyzed subgroups."

Journal • CNS Disorders • Multiple Sclerosis

Cost-effectiveness of treatment sequences following first-line rituximab in relapsing-remitting multiple sclerosis: a Norwegian microsimulation study. (PubMed, Front Neurol) - "The model allowed for three treatment lines after rituximab, with switches possible to fingolimod, ponesimod, cladribine tablets, or natalizumab. Patients on first line rituximab may require a treatment switch due to side-effect induced discontinuation or new disease activity. If a switch from rituximab to another DMT is the preferred clinical course of action, this study showed that it is most cost-effective to switch to cladribine tablets followed by ponesimod and natalizumab."

HEOR • Journal • CNS Disorders • Multiple Sclerosis

Efficacy and safety of disease-modifying oral drugs in treatment of relapsing-remitting multiple sclerosis: systematic review and network meta-analysis. (PubMed, Front Immunol) - "The NMA results demonstrated that Siponimod, Ponesimod, Laquinimod, Fingolimod, Cladribine, and Dimethyl Fumarate were all superior to placebo in reducing annualized relapse rates in patients with multiple sclerosis, with Siponimod (2 mg; SUCRA = 86.9%) and Laquinimod 0.3 mg (SUCRA = 10.1%) being the best and worst treatments, respectively...However, these findings still require further validation in subsequent studies. https://www.crd.york.ac.uk/prospero/, identifier CRD420250654500."

Clinical • Journal • Retrospective data • Review • CNS Disorders • Multiple Sclerosis