siponimod / Generic mfg. - LARVOL DELTA

Effects of sphingosine-1-phosphate receptor modulators on remyelination in multiple sclerosis: evidence from in vitro experiments, animal models and human studies. (PubMed, Front Immunol) - "There are four S1P modulators currently approved by the Food and Drug Administration/European Medical Agency (FDA/EMA): fingolimod, siponimod, ponesimod, and ozanimod. Potential mechanisms underlying the observed effects involve selective modulation of S1P receptor subtypes (particularly S1PR1, S1PR3, and S1PR5). This comprehensive review summarizes available preclinical and clinical evidence on the role of S1P modulators in remyelination in the context of MS and shows that fingolimod, siponimod and ponesimod possess emerging promise in this field."

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

TREAT-MS: Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial (clinicaltrials.gov) - P=N/A | N=900 | Completed | Sponsor: Johns Hopkins University | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Multiple Sclerosis

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

Computational Identification of Potential HMG-CoA Reductase Modulators Through Drug Repurposing: Structural Insights and Therapeutic Implications. (PubMed, Curr Comput Aided Drug Des) - "The study identifies computationally prioritized candidate scaffolds for putative non-orthosteric HMGCR modulation and defines the biochemical, kinetic, and structural validation required before any therapeutic interpretation."

Journal • Dyslipidemia • Metabolic Disorders

Fungal Infections Associated with Sphingosine 1-Phosphate Receptor Modulators: Immunological Mechanisms, Clinical Patterns, and Management Considerations. (PubMed, Microorganisms) - "Fungal infections constitute a large portion of serious infections worldwide and are increasing, partially due to new immunomodulatory therapies, such as Sphingosine-1-Phosphate (S1P) receptor modulators, including fingolimod for the treatment of multiple sclerosis (MS)...Decisions regarding interruption or discontinuation of MS therapy should be individualized according to the clinical syndrome, infection severity, and risk of MS rebound. This narrative review synthesizes the available mechanistic and clinical evidence on invasive fungal infections in patients with multiple sclerosis receiving S1P receptor modulator therapy."

Journal • Review • CNS Disorders • Infectious Disease • Multiple Sclerosis • Respiratory Diseases • S1PR1 • S1PR5

Real-world siponimod use in secondary progressive multiple sclerosis: the RESYZE study. (PubMed, Ther Adv Neurol Disord) - "Prior to siponimod, 44.3% received highly effective therapies: fingolimod (20.5%), rituximab (9.5%), ocrelizumab (5.2%), natalizumab (4.8%), and alemtuzumab (2.4%). In the study cohort, pwSPMS had high disability scores and comorbidities; more than half were unable to work, and over 40% had previously received high-efficacy therapies. After 1 year of siponimod treatment, most pwSPMS showed no signs of disease activity, with stabilized EDSS scores and relapses and new T2 or gadolinium-T1 lesions, as well as a favorable safety profile."

Clinical • Journal • Real-world evidence • CNS Disorders • Dyslipidemia • Mental Retardation • Metabolic Disorders • Multiple Sclerosis • Psychiatry

Extracellular Vesicle-Associated miRNA in Multiple Sclerosis Subtypes: Differential Profiles in Secondary Progressive Disease and the Effect of One-Year Siponimod Treatment. (PubMed, Cells) - "Nevertheless, the selective downregulation of EV-miR-223-5p and EV-miR-155-5p may tentatively suggest candidate molecular signatures warranting further interrogation. Adequately powered studies incorporating cell-specific EV sorting and paired cerebrospinal fluid sampling will be required to substantiate these signals and clarify their potential utility in monitoring disease progression and therapeutic response in progressive MS."

Journal • CNS Disorders • Inflammation • Multiple Sclerosis • MIR146A • MIR155 • MIR16 • MIR223 • MIR30A

Myelin and Oligodendrocyte Dysfunction in Demyelinating and Neurodegenerative Disorders: Signaling Pathways and Therapeutic Targets. (PubMed, CNS Neurol Disord Drug Targets) - "Myelin integrity and oligodendrocyte function are central to the progression of demyelinating and neurodegenerative diseases. Targeting molecular pathways involved in myelination offers significant potential for improving disease outcomes and developing advanced therapeutic strategies."

Journal • CNS Disorders • Immunology • Inflammation • Metabolic Disorders • Multiple Sclerosis • Solid Tumor

Efficacy and safety of mesenchymal stem cell transplantation for progressive multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials with clinical implications for patient stratification and treatment optimization. (PubMed, Front Immunol) - "Only two agents (ocrelizumab and siponimod) have modest efficacy, and no effective therapies exist for non-active disease. Given the very low to moderate certainty, further high-quality RCTs are warranted.This systematic review and meta-analysis was conducted in strict accordance with the Cochrane Handbook for Systematic Reviews of Interventions (version 6.5) and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines[24, 25]. The study protocol was prospectively registered on the International Prospective Register of Systematic Reviews (PROSPERO, registration number: CRD420261301154) prior to literature screening and data extraction."

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

Intracerebral Hemorrhage Induces Monocyte TNF Signaling in Patients That Is Suppressed by BAF312. (PubMed, Ann Clin Transl Neurol) - "These findings demonstrate broad peripheral leukocyte activation after ICH and suggest that during ICH, BAF312 suppresses both lymphoid and myeloid responses. The positive association of monocyte TNF signaling with better outcome points to the positive role of monocytes during the subacute stage of ICH and supports a complex role of monocytes in this disease. Larger studies will determine the extent to which these findings apply beyond the small cohort examined here."

Journal • Cardiovascular • Cerebral Hemorrhage • Hematological Disorders • Inflammation

Treatment Outcomes of Advanced Combination Therapy in Multiple Sclerosis-Inflammatory Bowel Disease Overlap: Single-centre study. (CNSF 2026) - "MS DMTs were ofatumumab (n=5), cladribine (n=3), siponimod (n=1)...Outcomes included IBD remission with MS clinical/radiologic stability in seven patients, a Crohn's flare on fingolimod resolving after switch to cladribine (n=1), and concurrent MS and Crohn's flares five years post-cladribine requiring dual immunotherapy initiation (n=1). Two patients had simple infections.ConclusionsUp to three quarter of patients achieved MS-IBD stability with newer DMTs, either as monotherapy or dual therapy, underscoring the feasibility of individualized, multidisciplinary care in this rare overlap population."

Clinical • Combination therapy • Metastases • CNS Disorders

Clinical and MRI Outcomes of Siponimod versus Ocrelizumab in Secondary Progressive Multiple Sclerosis: A Real-world Study (EAN 2026) - "In SPMS, short-term clinical outcomes were comparable between SIP and OCR, whereas MRI activity at 18 months differed, with higher odds of new lesions under SIP. When disability endpoints fail to discriminate over short follow-up, suppression of subclinical inflammatory MRI activity may represent the key differentiator guiding treatment choice, particularly in patients with residual inflammatory activity."

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

Endothelial sphingosine 1-phosphate receptor-1 promotes inflammation-induced thrombus formation through ß-arrestin-biased signaling (ISTH 2026) - "In activated endothelium, S1P enhanced TF activity when bound to albumin, but not when bound to HDL, indicating augmentation of TF activity by S1P mediated through β -arrestin, rather than G α i. Siponimod, a β -arrestin-biased S1PR1 agonist used for treatment of multiple sclerosis, potentiated TF activity. In contrast, SAR247799, a Gα i-biased agonist, had 100-fold less prothrombotic activity...B:Knockdown of S1PR1, but not S1PR3, inhibits TNFa- stimulated FXa generation in endothelium. Page 3 DOI*10.1016/j.rpth.2026.103759"

CNS Disorders • Hematological Disorders • Infectious Disease • Inflammation • Multiple Sclerosis • Septic Shock • Thrombosis • S1PR1 • TNFA

Comparative effectiveness of IV pulses cyclophosphamide versus siponimod on disability accrual in secondary progressive multiple sclerosis (EAN 2026) - "The preliminary analysis of the first three years of this study in SPMS suggests a superior effectiveness of CY vs. SIP on disability progression and NEDA-2."

HEOR • CNS Disorders • Multiple Sclerosis

Efficacy, Safety, and Neurofilaments Evaluation in Secondary Progressive Multiple Sclerosis Patients Treated with Siponimod (EAN 2026) - No abstract available

Clinical • CNS Disorders • Multiple Sclerosis

PBPK Modeling and Clinical Data Reveal Reduced Impact of CYP3A4 and CYP2C9 Inhibitors on Elimination of Siponimod. (PubMed, Clin Transl Sci) - "The presented work includes clinical data describing the impact of the CYP3A4 inhibitor clarithromycin on siponimod metabolism and the results of updated physiologically based pharmacokinetic (PBPK) modeling. Co-administration of fluconazole, a moderate CYP3A4 and CYP2C9 inhibitor, was predicted to result in < 2-fold net AUC increase, except for the genotype CYP2C9*2*2, where a 2.2-fold net AUC increase compared to the CYP2C9 wild type without fluconazole co-treatment was observed. Siponimod Cmax and AUC were comparable across CYP2C9 genotypes during dose titration in the absence or presence of fluconazole, suggesting no impact on the effectiveness of the dose titration regimen."

Clinical data • Journal • CNS Disorders • Inflammation • Multiple Sclerosis • CYP2C9 • CYP3A4

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

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

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

Progression to Wheelchair in Secondary Progressive Multiple Sclerosis and Impact of Siponimod: Post Hoc Analyses From the EXPAND Study. (PubMed, Eur J Neurol) - "Siponimod reduced the risk of requiring a wheelchair in participants with SPMS versus participants receiving placebo, with a greater effect in those with active disease. Time to requiring a wheelchair is a highly relevant treatment goal and an important indicator of treatment effect in patients with SPMS."

Journal • Retrospective data • CNS Disorders • Multiple Sclerosis

Ozanimod-Associated Lymphopenia In Relapsing Multiple Sclerosis: Incidence, Association with Infection, and Impacts of Extended-Interval Dosing (CMSC 2026) - "Fingolimod and siponimod lead to lower mean lymphocyte counts than ozanimod, but clinically significant lymphopenia can still occur on ozanimod. In this real-world treatment cohort, lymphocyte counts declined more substantially on ozanimod than reported in clinical trials. Lower nadir ALC correlated with infection risk, but infection rates did not differ meaningfully from baseline. Interestingly, male gender was strongly protective against high-grade lymphopenia."

Lymphopenia • CNS Disorders • Multiple Sclerosis

Evaluating the Experience of SPMS Patients Undergoing Siponimod Treatment (JSNE 2026) - No abstract available

Clinical • Multiple Sclerosis

Switching from siponimod to ofatumumab in two cases of secondary progressive multiple sclerosis (JSNE 2026) - No abstract available

Clinical • CNS Disorders • Multiple Sclerosis