Mayzent (siponimod) / Novartis - LARVOL DELTA

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

Effect of Sphingosine 1 Phosphate Receptor Modulators on Fatigue Among Multiple Sclerosis Patients (AAN 2025) - "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. As fatigue has a complex and subjective nature, more studies are required."

Clinical • CNS Disorders • Fatigue • Multiple Sclerosis

Real World Cardiovascular Adverse Events of S1PR Modulators in Multiple Sclerosis (ACTRIMS Forum 2025) - "Background: There are four FDA approved S1PR modulators for treatment of multiple sclerosis (MS): Fingolimod, Siponimod, Ozanimod and Ponesimod. Bradycardia and conduction disorders were the most common cardiac adverse events across all S1PR modulators. Siponimod and Ozanimod were associated with significantly fewer cardiac AEs compared to Fingolimod. This study shows importance of considering the comorbidities and cardiac monitoring when prescribing S1PR modulators."

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

Ozanimod Does Not Directly Impact B Cell Activation, Proliferation, and Memory Recall in Human ex vivo Functional Assays (ACTRIMS Forum 2025) - "A recent retrospective analysis of the DAYBREAK study has demonstrated that all MS patients on ozanimod treatment effectively generate a vaccine-induced antibody response against SARS-CoV-2, though heterogeneity in the magnitude of serologic response was observed, with some patients developing lower antibody levels.Objectives: Our objective was to evaluate whether ozanimod, or other S1P receptor modulators (fingolimod, etrasimod, ponesimod and, siponimod), had a direct impact on primary human B cell function when assessing activation, proliferation, differentiation, and antibody memory recall. We utilized human peripheral blood mononuclear cells (PBMC) or isolated B cells from healthy donors. Results from this work suggest that ozanimod does not directly impact primary human B cell activation, proliferation, differentiation, or memory recall. Findings reinforce the observation that MS patients treated with ozanimod mount an effective immune response with 100%..."

Preclinical • CNS Disorders • Infectious Disease • Multiple Sclerosis • Novel Coronavirus Disease • Respiratory Diseases • Tetanus • CCL3 • CD40LG • CD69 • CSF2 • CXCL8 • IL2 • IL21 • IL2RA • IL6 • TNFA

Baseline Characteristics Across Major Clinical Trials in Progressive Multiple Sclerosis: Insights from ORATORIO, EXPAND, MS-STAT2, HERCULES, and CALLIPER (ACTRIMS Forum 2025) - "Several major trials have explored therapies in this domain, including ORATORIO (ocrelizumab, primary progressive MS, PPMS), EXPAND (siponimod, secondary progressive MS, SPMS), MS-STAT2 (simvastatin, SPMS), and HERCULES (tolebrutinib, non-relapsing SPMS, nrSPMS). The data from this cohort could provide valuable insight into understanding the effects of vidofludimus calcium in a non-active and progressive population. Any impact of vidofludimus calcium on 24-week confirmed disability worsening in this group may therefore primarily reflect its influence on compartmentalized pathology within the CNS. Top line data of the study is expected in April 2025."

Clinical • CNS Disorders • Inflammation • Multiple Sclerosis • NR4A2 • STAT2

TREAT-MS: Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial (clinicaltrials.gov) - P=N/A | N=900 | Active, not recruiting | Sponsor: Johns Hopkins University | Recruiting ➔ Active, not recruiting | Trial completion date: Aug 2025 ➔ Aug 2026 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Multiple Sclerosis

Siponimod inhibits microglial inflammasome activation. (PubMed, Neurosci Res) - "Our data indicate that siponimod achieves its anti-inflammatory effects by inhibiting inflammasome activation in microglia via S1P1 antagonism. This process is inferred to play a crucial role in mitigating the secondary progression of multiple sclerosis, where microglial activation in the gray matter is considered a key pathological factor."

Journal • CNS Disorders • Multiple Sclerosis • CASP1 • IL1B

MRI versus relapse: optimal activity monitoring for management of progressive multiple sclerosis. (PubMed, Brain Commun) - "We separately analysed retrospective data from patients with clinically diagnosed secondary progressive multiple sclerosis in the Adelphi Real-World Disease Specific Programme (a cross-sectional survey) in multiple sclerosis (Adelphi: n = 2554) and the placebo group of the Phase III EXploring the efficacy and safety of siponimod in PAtients with secoNDary progressive multiple sclerosis (EXPAND) trial, [EXPAND-PBO (placebo group of the EXPAND): n = 546] to assess: differences between active/non-active disease in the real-world (characteristics; monitoring); the value of MRI and relapse to indicate disease activity; and the number and characteristics of non-active patients with disease activity in the clinical study...However, in the real-world, fewer non-active patients had received an MRI in the last year than active patients, which is concerning given that most disease activity in EXPAND-PBO was identified via MRI. We highlight difficulties in consistently identifying..."

Journal • CNS Disorders • Inflammation • Multiple Sclerosis

Siponimod supports remyelination in the non-supportive environment. (PubMed, Sci Rep) - "This enhanced recovery was paralleled by the trend of lower densities of Ki67+ proliferating oligodendrocyte progenitor cells. Our findings suggest that Siponimod has modest pro-regenerative capacities, partly explaining the amelioration of disease progression in secondary progressive MS patients."

Journal • CNS Disorders • Multiple Sclerosis • Solid Tumor • MBP • OLIG2

Drug-related macular edema: a real-world FDA Adverse Event Reporting System database study. (PubMed, BMC Pharmacol Toxicol) - "This study utilizes the FAERS database to investigate potential associations between drug use and the occurrence of ME, rapidly identify drugs that may induce the condition, and propose research strategies. These findings hold significant value for guiding clinical medication practices."

Adverse events • Journal • Real-world evidence • Macular Edema • Ophthalmology