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

Therapeutic targeting of sphingosine-1-phosphate receptor 1 (S1PR1) in angioimmunoblastic T-cell lymphoma. (ASH 2025) - "The molecular landscape of AITL is characterized by frequent genomic alterationsin epigenetic regulators, including TET2, DNMT3A, and IDH2, as well as components of the T-cell receptor(TCR) signaling pathway...This, together with our observation of increased S1PR1 expression in humanRHOA G17V⁺ AITL tumor samples, identifies S1PR1 deregulation as a potentially relevant effector of theoncogenic effects of RHOA G17V in TFH cells.S1P receptor inhibitors, such as fingolimod (FTY720) and next-generation, more selective modulatorssuch as ozanimod, siponimod, and ponesimod, are FDA-approved for the treatment of multiple sclerosisand other autoimmune diseases...These findings definean S1PR1–STAT3 inflammatory loop that promotes survival and dissemination in RHOA G17V-driven AITLand identify this axis as a therapeutically actionable vulnerability.In summary, our preliminary data establish a mechanistic link between oncogenic RHOA signaling andS1PR1-mediated membrane receptor..."

IO biomarker • CNS Disorders • Hematological Malignancies • Immunology • Lymphoma • Multiple Sclerosis • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CD4 • DNMT3A • IDH2 • IL6 • RHOA • S1PR1 • S1PR5 • TET2 • TNFA

Selected aspects of epidemiology of multiple sclerosis in Poland: a multicenter pilot study. (PubMed, Neurol Neurochir Pol) - "This study highlights substantial progress in the diagnostic and therapeutic management of MS in Poland over the past 15 years. The widespread implementation of MRI and CSF analysis, alongside significantly improved access to DMTs, has contributed to notably better clinical outcomes. These improvements are reflected in reduced relapse rates, slower disability progression, and a decreased prevalence of secondary progressive MS."

Journal • CNS Disorders • Multiple Sclerosis

Recent Advances in Interventions Targeting Remyelination and a Systematic Review of Remyelinating Effects of Approved Disease-Modifying Treatments for Multiple Sclerosis. (PubMed, Eur J Neurol) - "Future 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."

Journal • Review • CNS Disorders • Multiple Sclerosis • Solid Tumor

Comparative Effectiveness of Cladribine and S1P Receptor Modulators in Treatment-Naive Relapsing-Remitting MS. (PubMed, JAMA Netw Open) - "All treatment-naive patients with RRMS who initiated cladribine or an S1PRM (fingolimod, ozanimod, or ponesimod) between January 2011 and October 2021 and had at least 12 months of follow-up were included. These findings suggest cladribine was associated with superior effectiveness in reducing disability progression over 25 months, likely due to reduced PIRA, despite comparable short-term NEDA-3 outcomes. However, relapse prevention declined after 36 months, suggesting retreatment or therapy modification within 3 years may be needed to maintain long-term disease control."

Clinical • HEOR • Journal • CNS Disorders • Multiple Sclerosis

Gastrointestinal Adverse Effects of Sphingosine-1-Phosphate (S1P) Receptor Modulators: A Real-World Pharmacovigilance Study (ACG 2025) - "Out of 26,928 S1P-related reports, 3,535 (13.1%) involved GI AEs. The proportion of GI AEs was highest for ozanimod (17.78%), followed by siponimod (13.02%), fingolimod (10.84%), and ponesimod (9.06%). Serious GI AEs accounted for 58% of cases."

Adverse events • Clinical • Real-world • Real-world evidence • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammatory Bowel Disease • Multiple Sclerosis • Ulcerative Colitis

Financial Highlights (PRNewswire) - "PONVORY net product sales were $7.0 million in the third quarter of 2025, a 20% increase compared to $5.9 million in the third quarter of 2024."

Sales • Multiple Sclerosis

The effect of disease-modifying therapies on brain volume loss and disability accumulation in multiple sclerosis: a systematic review and network meta-analysis. (PubMed, Lancet Reg Health Eur) - "Eight DMTs significantly reduced BVL compared to placebo, including ponesimod (ROM = 0.52; 95%-CI: 0.35-0.77), ofatumumab (ROM = 0.58; 95%-CI: 0.40-0.83), alemtuzumab (ROM = 0.63; 95%-CI: 0.49-0.83), teriflunomide (ROM = 0.71; 95%-CI: 0.52-0.97), ozanimod (ROM = 0.74; 95%-CI: 0.56-0.98), natalizumab (ROM = 0.77; 95%-CI: 0.61-0.96), siponimod (ROM = 0.77; 95%-CI: 0.60-0.98), and fingolimod (ROM = 0.83; 95%-CI: 0.71-0.96)...These findings support BVL as a meaningful treatment target in MS. None."

Journal • Retrospective data • CNS Disorders • Multiple Sclerosis

REAL-WORLD EXPERIENCE WITH SECOND-GENERATION S1P RECEPTOR MODULATORS IN MULTIPLE SCLEROSIS (WCN 2025) - "Ponesimod and Ozanimod induce expected lymphopenia while maintaining clinical-radiological stability. Patient-reported outcomes remained stable except for mild fatigue worsening in a sample of cases."

Clinical • Real-world • Real-world evidence • CNS Disorders

Suboptimal dose of approved disease modifying therapies in management of patients with multiple sclerosis: A systematic review. (PubMed, Mult Scler Relat Disord) - "Suboptimal dosing of DMTs in MS is a growing treatment strategy to enhance patient adherence and reduce adverse events. Future prospective studies are necessary to establish the safety and efficacy of suboptimal dosing protocols for different classes of DMTs in MS management."

Journal • Review • CNS Disorders • Infectious Disease • Multiple Sclerosis • Rare Diseases

Use of disease-modifying therapies in France from 2017 to 2023 (ECTRIMS 2025) - "DMTs were identified using specific codes and classified as: very-high-efficacy (natalizumab, rituximab, ocrelizumab, ofatumumab), high-efficacy (fingolimod, ponesimod, cladribine), moderate efficacy (beta interferon, glatiramer acetate, dimethyl fumarate, diroximel fumarate, teriflunomide), and an off-label category (methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide)... From 2017 to 2023, DMT use among PwMS in France increased, with a marked rise in very high-efficacy therapies, including as first treatment. While proportions were similar across sexes and socioeconomic levels, geographic disparities, especially in anti-CD20 use, persisted, highlighting the need to ensure equitable access to care."

Real-World Comparison of Cladribine and S1P-Receptor Modulators in Treatment-Naive Relapsing MS: A Propensity Score-Matched Study (ECTRIMS 2025) - " This retrospective analysis included treatment-naïve RRMS individuals who were first treated with cladribine or S1PRMs (fingolimod, ozanimod, ponesimod) across 108 Italian specialist centres between 2011 and 2021. Cladribine was more effective in reducing disability progression despite comparable short-term NEDA-3 outcomes. However, its effectiveness in preventing relapses declined after 36 months of follow-up, suggesting a potential need for re-treatment or a therapy switch within three years to sustain long-term disease control."

Clinical • Real-world • Real-world evidence • Multiple Sclerosis

Real-world experience with second-generation S1P receptor modulators in relapsing multiple sclerosis: a prospective observational study (ECTRIMS 2025) - "Ponesimod and Ozanimod showed expected lymphopenia while maintaining clinical-radiological stability. Patient-reported outcomes were generally stable, with fatigue and SDMT worsening observed in a number of cases."

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

Long Term Extension of Ponesimod Phase III Study in Relapsing Multiple Sclerosis: Final Efficacy Results of over 7 years Treatment with Ponesimod (ECTRIMS 2025) - "In the 2-year Phase 3 OPTIMUM study (core), ponesimod demonstrated superiority over teriflunomide in reducing relapses and MRI measures of disease activity. These final data of up to 7.9 years of ponesimod treatment in the now-closed Phase 3 OLE study support the long-term, sustained efficacy of ponesimod 20 mg with the majority of patients remaining relapse-free and without significant disability progression. Together with the safety analysis these data continue to support ponesimod as a viable long-term treatment option for patients with relapsing MS."

Clinical • P3 data • CNS Disorders • Multiple Sclerosis • S1PR1

Long-Term Safety of Ponesimod in Relapsing Multiple Sclerosis: Final Results of over 7 Years Exposure to Ponesimod in OPTIMUM Open-Label Extension Trial (ECTRIMS 2025) - "Introduction: The safety profile of ponesimod (20 mg), a selective sphingosine 1-phosphate receptor 1 modulator, was evaluated in comparison to teriflunomide (14 mg) in a 2-year core study, followed by over 5-year open-label extension (OLE) study. The safety profile of ponesimod in the OLE study was consistent with that described in the core study, with no unexpected safety findings over up to 7 years on treatment. Long-term exposure to ponesimod did not result in an increased incidence of SAEs."

Clinical • Back Pain • Cardiovascular • CNS Disorders • Gastrointestinal Disorder • Herpes Zoster • Hypertension • Infectious Disease • Multiple Sclerosis • Musculoskeletal Pain • Nephrology • Novel Coronavirus Disease • Ophthalmology • Rare Diseases • Respiratory Diseases • Varicella Zoster • S1PR1

Insights from Ponesimod long term efficacy and safety data (ECTRIMS 2025) - No abstract available

Clinical • Rhabdomyosarcoma

Role of Age in the Austrian Multiple Sclerosis Treatment Registry (ECTRIMS 2025) - "Objectives/Aims: To evaluate the efficacy and safety of Alemtuzumab (AZM), Cladribine (CLAD), Dimethyl fumarate (DMF), Fingolimod (FTY), Natalizumab (NTZ), Ocrelizumab (OCR), Ofatumumab (OFA), Ozanimod (OZA), Ponesimod (PONE), Siponimod (SIPO), and Teriflunomide (TERI) in MS patients across different age groups... 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 within the treated MS cohort. Furthermore, efficacy outcomes (ARR and EDSS progression) were comparable between younger and older patients. These findings should be integrated into treatment strategies for older MS patients, considering the impact of immunosenescence and the increasing prevalence of comorbidities with advancing age."

CNS Disorders • Multiple Sclerosis

Clinical Status and CNS Adverse Drug Report of Sphingosine-1-Phosphate Receptor Modulators in Multiple Sclerosis. (PubMed, Drug Discov Today) - "The first accepted oral S1P modulator, Fingolimod has demonstrated significant efficacy in reducing relapse rates and MRI lesion activity in large-scale clinical trials. Subsequent development of more selective agents, such as siponimod, ozanimod, and ponesimod, has further enhanced therapeutic outcomes by minimizing off-target effects while preserving efficacy. In this review, the role of S1PR modulators in MS management, results from clinical trials, associated CNS adverse effects, and their expanding potential have been discussed and summarized."

Journal • Review • CNS Disorders • Multiple Sclerosis

Time Course of Efficacy of Ponesimod in Patients with Moderate-to-Severe Chronic Plaque Psoriasis (ESDR 2025) - "Within a week of ceasing ponesimod treatment, it is also demonstrated that peripheral lymphocyte counts are restored to normal. These two features of early onset of efficacy, coupled with rapid immune recovery, offer a best-in-class therapeutic profile that has the potential to be a versatile therapeutic option to treat flares on an as-needed basis, and may also be used to prevent flares of moderate-to-severe chronic plaque psoriasis."

Clinical • CNS Disorders • Dermatology • Immunology • Multiple Sclerosis • Psoriasis

A Randomized Trial on the Combined Effect of Ponesimod and Propranolol on Heart Rate, Cardiac Safety, and Pharmacokinetics in Healthy Adults. (PubMed, Clin Transl Sci) - "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."

Clinical • Journal • PK/PD data • Cardiovascular • CNS Disorders • Fatigue • Multiple Sclerosis

Therapeutic Potential of Compounds with High Affinity to BAG2 in Inhibiting Keloid Disease. (PubMed, Biologics) - "This study revealed the pathogenic role of BAG2 in keloid and identified compounds with high-affinity to BAG2, Bazedoxifene acetate and Ponesimod. The therapeutic capabilities of these compounds demonstrated their potential to improve therapeutic strategies for localized, targeted treatment to keloids."

IO biomarker • Journal • Fibrosis • BAG1 • BCL2

DELIVER-MS: Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (clinicaltrials.gov) - P4 | N=800 | Active, not recruiting | Sponsor: The Cleveland Clinic | Trial completion date: Sep 2030 ➔ Jul 2027

Trial completion date • CNS Disorders • Multiple Sclerosis

Comparative effectiveness of disease-modifying therapies for highly active relapsing-remitting multiple sclerosis despite previous treatment - a systematic review and network meta-analysis. (PubMed, BMC Neurol) - "Based on the largest possible evidence base, including previously unpublished data, our systematic review shows substantial evidence gaps for DMTs in highly active RRMS. This indicates a need for further research beyond regulatory requirements."

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

Real-world comparison of lymphopenia profiles in S1P receptor modulators for multiple sclerosis: a multicenter retrospective study. (PubMed, J Neurol) - "This is the first real-world, head-to-head observational study comparing lymphopenia among different S1P modulators. Our results might assist in therapy choice depending on patients baseline hematological characteristics."

Clinical • Journal • Real-world evidence • Retrospective data • CNS Disorders • Hematological Disorders • Multiple Sclerosis

Ponesimod as add-on treatment in patients with active relapsing multiple sclerosis under dimethyl fumarate (POINT): A phase 3, randomized, placebo-controlled clinical trial. (PubMed, Mult Scler Relat Disord) - P3 | "This terminated study did not demonstrate the superiority of ponesimod+DMF on clinical efficacy endpoints. In the exploratory analysis ponesimod+DMF versus DMF alone appeared associated with a lower disease activity as assessed by MRI. No new safety signals were reported for ponesimod+DMF."

Clinical • Journal • P3 data • CNS Disorders • Multiple Sclerosis

Screening of the FDA-approved drug library identifies CCL17 inhibitors that block arthritic pain. (PubMed, Sci Rep) - "In this study, we screened a panel of 1508 FDA-approved drugs and identified five drugs, namely fluoxetine, ractopamine, ponesimod, terbutaline and etravirine, which potently inhibited CCL17 production without adverse effects on cell viability and CCL22 formation in human monocytes and mouse macrophages. Significantly, therapeutic administration of these five drugs in an inflammatory arthritis model revealed that fluoxetine, ractopamine, ponesimod and terbutaline could inhibit arthritic pain, correlating with decreased CCL17 expression. Given the need for new and safe anti-inflammatory therapeutics to treat RA and the benefits of repurposing existing drugs for new indications, our findings reported here offer four new promising analgesics for treating inflammatory pain."

FDA event • IO biomarker • Journal • Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Pain • Rheumatoid Arthritis • Rheumatology • CCL2 • CCL22 • CCR4 • CSF2 • IRF4 • STAT5 • STAT5AWqe