Mayzent (siponimod) / Novartis - LARVOL DELTA

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

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

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

BAF312 Inhibits the Growth of Glioma and Promotes the Normalization of Tumor Blood Vessels. (PubMed, FASEB J) - "BAF312 exhibits significant anti-glioma activity through mechanisms involving cell cycle arrest, apoptosis induction, and vascular normalization, highlighting its potential as a repurposed therapeutic agent. This study offers preclinical evidence supporting the anti-glioma effects of BAF312; though further investigation is warranted to evaluate combinatorial efficacy with conventional therapies and address immunosuppressive effects limiting monotherapy application."

Journal • Brain Cancer • CNS Disorders • Glioma • Multiple Sclerosis • Oncology • Solid Tumor • CD8 • PDGFRB • S1PR1 • SKP2

Japanese medicinal drug labeling for use in the clinical setting as informed by pharmacogenomic data on cytochrome P450 enzymes obtained from in silico studies. (PubMed, Drug Metab Pharmacokinet) - "Such associations include genetic variants of uridine diphosphate glucuronosyltransferase 1A1 for irinotecan, nudix hydrolase 15 for thiopurine drugs, and cytochrome P450 (P450) 2C9 for siponimod. For P450 variants CYP2C9∗3, CYP2C19∗2, CYP2C19∗3, CYP2D6∗10, and CYP3A4∗16, we propose using the enzymatic activity parameters obtained from in vitro functional analysis of the drug-metabolizing enzymes for multiple substrate drugs to predict the effects of these variants on human pharmacokinetics. Consequently, in patients prescribed only a single drug, anything more than a "moderate effect" on plasma exposure should be mentioned as a caution in the drug labels; such effects are likely caused by enzyme polymorphisms resulting in similar effects to drug-drug interactions."

Biomarker • Journal • CYP2C19 • CYP2C9 • CYP3A4 • NUDT15

Survey Among Healthcare Professionals and MS Patients to Assess Their Understanding of RMP Materials (clinicaltrials.gov) - P=N/A | N=335 | Completed | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Completed

Trial completion • CNS Disorders • Multiple Sclerosis

De-Escalation Treatment Strategies From Natalizumab in Patients With Relapsing Multiple Sclerosis in Austria. (PubMed, Eur J Neurol) - "Our findings reveal an increased risk of relapses and EDSS worsening following de-escalation from NTZ. Additionally, relapse probability and EDSS progression were influenced by ARR during transition and EDSS scores at the end of the transition period."

Journal • CNS Disorders • Multiple Sclerosis

The Comparative Effectiveness and Tolerability of Sphingosine-1-Phosphate Receptor Modulators in Patients With Multiple Sclerosis: A Network Meta-Analysis of Randomized Controlled Trials. (PubMed, Ann Clin Transl Neurol) - "Fingolimod (1.25 mg) and ozanimod (1 mg) had the best efficacy, and siponimod (1.25 mg and 0.25 mg) had the best safety profile among the S1PRM. Further longitudinal studies should be conducted to assess the long-term effects of these drugs on patient-reported outcomes."

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

Clinical Pharmacogenetics: Results After Implementation of Preemptive Tests in Daily Routine. (PubMed, J Pers Med) - "We do not recommend testing CYP2C19*17 prior to clopidogrel prescription, as it does not translate into a dosing recommendation. TPMT*3B may be considered just to confirm TPMT*3A due to its linkage with TPMT*3C. Similarly, we do not recommend the routine testing of CYP2C9*2 prior to siponimod prescription, as it does not inform therapeutic decisions according to the current drug label."

Biomarker • Journal • Oncology • CYP2C19 • CYP2C9

Comparative Effectiveness of Fumarates Versus Sphingosine-1-Phosphate Receptor Modulators in Black Patients with Multiple Sclerosis. (PubMed, Neurol Ther) - "This real-world, claims-based analysis demonstrates that fumarates and S1P receptor modulators have similar effectiveness in reducing relapses among Black PwMS, with > 72% of patients in both treatment groups remaining relapse-free at 24 months. Given the underrepresentation of Black patients in MS clinical trials, these results provide valuable real-world evidence to guide treatment decisions for this population."

HEOR • Journal • CNS Disorders • Multiple Sclerosis

Personalized Treatment Response in Progressive MS: Can the Patient's Profile Influence the Outcome? (PubMed, Brain Behav) - "This analysis demonstrated the ability to define responders to a therapy based on their baseline profile and evaluate the treatment effect on multiple endpoints, showing that the benefit on different outcomes can vary across patients."

Journal • CNS Disorders • Multiple Sclerosis

What Is the Evidence on Immunomodulators and Immunosuppressants for Progressive Multiple Sclerosis? - A Cochrane Review Summary with Commentary. (PubMed, NeuroRehabilitation) - "Also, rituximab, natalizumab, siponimod, and ocrelizumab probably do not increase the risk for treatment discontinuation due to AEs, while laquinimod may not increase the risk treatment discontinuation due to AEs.ConclusionsCompared with placebo, two-, and three-year treatment with rituximab or interferon beta-1b, respectively, probably slightly reduce relapses in PMS people. A slight increase of treatment discontinuation due to AEs has been reported for rituximab, interferon beta-1b, interferon beta-1a, immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab. No reliable evidence is available for disability progression and SAEs with available DMTs compared to placebo."

Journal • CNS Disorders • Multiple Sclerosis

A disproportionality analysis of nervous system adverse events associated with disease-modifying therapies in multiple sclerosis: insights from the FDA adverse event reporting system (FAERS). (PubMed, J Neurol) - "This study highlights significant differences in the nervous system AEs profiles of DMTs, with SI, NA, FI, and TE showing higher risks of nervous system AEs. These findings underscore the importance of vigilant monitoring and personalized treatment strategies to mitigate nervous system risks in MS patients. Further research is needed to confirm these associations and investigate the mechanisms that underlie them."

Adverse events • Journal • CNS Disorders • Cognitive Disorders • Developmental Disorders • Multiple Sclerosis

Assessment of Real-World Adverse Events Associated with Ozanimod in Relapsing Remitting Multiple Sclerosis (RRMS) (ISPOR 2025) - "AE reports and patient outcomes were extracted for all instances where DMTs (ozanimod, dimethyl fumarate, monomethyl fumarate, diroximel fumarate, fingolimod, ponesimod, siponimod, teriflunomide, cladribine, alemtuzumab, natalizumab, ocrelizumab, ublituximab, and ofatumumab) were the ‘primary suspect’ for the AE... Based on this descriptive analysis of the FAERS data, ozanimod has a lower proportion of AEs linked to serious outcomes than the other DMTs. Ozanimod generally had a larger share of the ten labeled AEs compared with the other DMTs; however, these labeled AEs made up a small percentage of all the AEs reported for ozanimod and the other DMTs."

Adverse events • Clinical • Real-world • Real-world evidence • Back Pain • Cardiovascular • CNS Disorders • Hypertension • Hypotension • Infectious Disease • Multiple Sclerosis • Musculoskeletal Pain • Pain • Respiratory Diseases

Study to Assess the Efficacy of Mayzent on Microglia in Secondary Progressive Multiple Sclerosis (clinicaltrials.gov) - P2/3 | N=8 | Terminated | Sponsor: State University of New York at Buffalo | N=18 ➔ 8 | Completed ➔ Terminated; Lack of recruitment

Enrollment change • Trial termination • CNS Disorders • Multiple Sclerosis

Safety assessment of switching from fingolimod to siponimod: An Italian multicenter prospective study. (PubMed, J Neurol Sci) - "During the 6-month observation period, switching from fingolimod to siponimod was safe in terms of disease reactivation and tolerability."

Journal • CNS Disorders • Melanoma • Multiple Sclerosis • Oncology • Solid Tumor

S1PR4-dependent effects of Etrasimod on primary human myeloid immune cell activation. (PubMed, Front Pharmacol) - "Primary human macrophages, plasmacytoid dendritic cells and neutrophils were pretreated with S1P, Etrasimod (S1PR1/4/5), Ozanimod (S1PR1/5), Siponimod (S1PR1/5), CYM 50308 (S1PR4 agonist) and CYM 50358 (S1PR4 antagonist), and then stimulated with Zymosan A, ODN 2336 and PMA, respectively. Regarding receptor dynamics, we show that Etrasimod induces internalization of S1PR4. Taken together, our data show that S1PR4 takes on an essential role in the regulation of various immunological functions, and that Etrasimod can act as a superagonist/functional antagonist of S1PR4."

Journal • CNS Disorders • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Multiple Sclerosis • Ulcerative Colitis • CCL20 • CXCL5 • IFNA1 • S1PR1

SIPO1-AD: Repurposing Siponimod for Alzheimer's Disease (clinicaltrials.gov) - P2 | N=105 | Not yet recruiting | Sponsor: St. Joseph's Hospital and Medical Center, Phoenix | Initiation date: Nov 2024 ➔ Jul 2025

Trial initiation date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Changes in fatigue, depression, and QOL due to continuous administration of siponimod (JSNE 2025) - No abstract available

CNS Disorders • Depression • Fatigue • Mood Disorders • Psychiatry

Multiple Sclerosis Disease-Modifying Treatment Algorithms: 2025 Positioning of the Portuguese Multiple Sclerosis Study Group. (PubMed, Acta Med Port) - "Recent advances in MS treatment include the development and approval of several new disease-modifying therapies (DMTs) such as ocrelizumab, cladribine, siponimod, and others, thus expanding options for relapsing-remitting MS (RRMS). This document provides evidence- and clinical practice-based recommendations to optimize decision-making during MS management in Portuguese centers. The experts aim to prompt the urgent revision of national MS treatment frameworks, incorporating the latest advancements in MS research and international guidelines, to reduce the socio-economic burden on the national healthcare system and improve the long-term health outcomes of MS patients."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Pediatrics

Safety and tolerability of conversion to siponimod from other disease-modifying therapies in patients with advancing forms of relapsing MS: Results from the EXCHANGE study. (PubMed, Mult Scler) - P3 | "Conversion to siponimod from other DMTs was found to be generally well tolerated. Patients switching from other S1P-receptor modulators may be able to immediately transition to the siponimod maintenance dose without effects on HR."

Journal • Cardiovascular • CNS Disorders • Multiple Sclerosis • Pain

Lymphopenia associated with sphingosine 1-phosphate receptor modulators (S1PRMs) in multiple sclerosis: analysis of European pharmacovigilance data. (PubMed, Pharmacol Rep) - "The most relevant clinical implication of the disproportionality analysis is to increase the awareness of the risk of lymphopenia related to these drugs, thus supporting proactive monitoring and optimizing treatment strategies for people with MS."

Adverse events • Journal • CNS Disorders • Multiple Sclerosis

Effect of Sphingosine 1 Phosphate Receptor Modulators on Fatigue Among Multiple Sclerosis Patients (P6-1.017). (PubMed, Neurology) - "We found 5 studies, 3 of which were randomized to injectable DMT, Standard DMT (interferon and glatiramer acetate), and teriflunomide, respectively...Fingolimod and ponesimod were found to be effective in improving fatigue among PwMS; no studies have been found on ozanimod and Siponimod...The institution of Dr. Bernitsas has received research support from Roche/Genentech."

Clinical • Journal • Review • CNS Disorders • Fatigue • Multiple Sclerosis

Identifying cardiovascular toxicity associated with sphingosine 1-phosphate receptor modulators: A case-control study based on the FDA adverse event reporting system. (PubMed, Int Immunopharmacol) - "In this study, signals of bradyarrhythmias, hypertension, QT interval prolongation, central nervous system ischemia, tachyarrhythmias, and ischaemic heart disease were significant with one or more S1PR modulators, which warrant clinical attention and ongoing monitoring."

Adverse events • Journal • Cardiovascular • CNS Disorders • Coronary Artery Disease • Heart Failure • Hypertension • Multiple Sclerosis • Rare Diseases

Herpes Zoster Infections With Multiple Sclerosis Disease-Modifying Therapies: A Real-World Pharmacovigilance Study. (PubMed, Neurol Clin Pract) - "We queried the Food and Drug Administration Adverse Event Reporting System (FAERS) and OpenVigil 2.1 for reports of HZ involving immunosuppressive MS DMTs (ocrelizumab [OCR], ofatumumab [OFT], rituximab [RTX], natalizumab [NTZ], alemtuzumab, dimethyl fumarate and diroximel fumarate [DRF], fingolimod [FING], siponimod [SIP], ozanimod [OZ], mitoxantrone [MITO], cladribine [CLAD], and teriflunomide [TERF]) and calculated reporting odds ratios and their 95% CIs...Immunosuppressive MS DMTs are associated with greater HZ reporting in the FAERS. These findings emphasize the importance of pre-DMT HZ vaccination because of avoidable HZ infections."

Adverse events • Journal • Real-world evidence • CNS Disorders • Herpes Zoster • Infectious Disease • Multiple Sclerosis • Varicella Zoster