fingolimod / Generic mfg. - LARVOL DELTA

Fingolimod in combination with bortezomib demonstrates synergistic tumor inhibition and bone anabolic effects in myeloma bone disease (ASH 2025) - "In mouse bone explants, fingolimod (10-100 nM) demonstrated dual effects:increasing osteoblast markers (alkaline phosphatase, osteocalcin mRNA) and osteocyte differentiation(DMP1 mRNA) while simultaneously suppressing osteoclast markers (ACP5/TRAcP, cathepsin K mRNA),contrasting with zoledronic acid's exclusive osteoclast inhibition. Fingolimod, at clinically achievable doses, synergizes with bortezomib through dualmechanisms: 1) direct disruption of sphingolipid-mediated survival pathways in tumor cells 2) remodelingthe BME by coupled osteoclast inhibition/osteoblast activation, including systemic osteo-protection,suggesting neutralization of circulating osteolytic factors. Future work includes validation in PDX models,sphingolipid-risk biomarker development, and Phase Ib trials in relapsed/refractory MM with bonedisease. Fingolimod's established safety profile as an oral multiple sclerosis therapy enables rapid clinicaltranslation."

Combination therapy • IO biomarker • CNS Disorders • Hematological Malignancies • Multiple Myeloma • Multiple Sclerosis • Oncology • Orthopedics • Plasmacytoma • BCL2 • CTSK • IL6 • MCL1 • SPHK2 • TNFA • TRAP

Sphingosine-1-phosphate receptor modulators overcome FLT3 inhibitor resistance in Acute Myeloid Leukemia with FLT3-ITD and NRAS mutations through sphingosine kinase 1/AKT pathway downregulation. (ASH 2025) - "SphK1 is linked toFLT3 inhibitor resistance, as prolonged sorafenib exposure was shown to activate the Sphk1/S1P axis.Here we studied the efficacy of targeting Sphk1 with sphingosine-1-phosphate receptor (S1PR)modulators in conjunction with FLT3 inhibitors to overcome FLT3 inhibitor resistance mediated by NRASmutations in AML cells with FLT3-ITD. MethodsMOLM-14 and MV4-11 human FLT3-ITD AML cell lines with NRAS mutations including G12D, G12S, G12C,Q61K and Q61H and FLT3-ITD AML patient blasts with G13V and G13D mutations were cultured with theFLT3 inhibitors gilteritinib (10 nM) or quizartinib (1 nM) and/or the S1PR modulators fingolimod (FTY720; 2.5 μM) or mocravimod (KRP203; 5 μM)...ConclusionsThe S1PR agonists fingolimod (FTY720) and mocravimod (KRP203) resensitize FLT3-ITD AML cellsharboring G12D, G12S, Q61K, and Q61H, but not G12C, NRAS mutations to FLT3 inhibitors. The datasupport potential clinical efficacy of combination regimens with these clinically applicable..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ANXA5 • BAD • FLT3 • NRAS • SPHK1 • STAT5

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

Radiotherapy of extramedullary acute myeloid leukemias overcomes resistance to checkpoint blockade that is enhanced by natural killer cell depletion (ASH 2025) - "To depleteCD8+ T cells, CD4+ T cells, or NK cells, mice were treated with anti-CD8 (clone YTS-169), anti-CD4 (cloneGK1.5), or anti-NK1.1 (clone PK136) neutralizing antibodies i.p. at the start of irradiation and every 3 days.To inhibit lymphocyte egress from tumor-draining lymph nodes, mice were treated with 25 μg of FTY720i.p... Irradiated extramedullary AML improved survival and cleared systemic leukemia in micetreated with checkpoint blockade. Depletion of NK cells further enhanced survival, indicating that NK cellsregulated anti-leukemia immune responses induced by radiation and anti-PDL1. These results suggestthat focal radiotherapy and immune checkpoint inhibition may enhance anti-leukemia immuneresponses in AML patients."

Checkpoint block • Checkpoint inhibition • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Solid Tumor • CD8

Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors. (PubMed, bioRxiv) - "Moreover, FTY720 co-treatment resensitized G12D NRAS -mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS -mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy of these combinations."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • NRAS • SPHK1

Evaluation of Disease Modifying Therapies and Prognostic Factors Affecting Multiple Sclerosis Progression in a Local Centre of Hong Kong. (PubMed, Pragmat Obs Res) - "Interferons (annualised relapse rate (ARR) reduction 0.492, p <0.001) and fingolimod (ARR reduction 0.557, p = 0.038) had significant ARR reductions in our cohort. Overall treatment persistence were comparable, but teriflunomide had more discontinuation due to side effects and/or intolerance (hazard ratio (HR) 7.50, p = 0.029)...This study illustrated the complexity of managing MS patients. Patients' clinical characteristics, disease activity, risk appetite and treatment side effects should be taken in consideration to reach an informed decision on the use of DMTs in our local MS patients."

Biomarker • Journal • CNS Disorders • Multiple Sclerosis

Cerebellar Subregional Atrophy in Relapsing-Remitting Multiple Sclerosis: Stage-dependent Dynamics and Pharmacological Modulation. (PubMed, Brain Res Bull) - "This study demonstrated stage-specific patterns of cerebellar atrophy in RRMS and the heterogeneous, stage-dependent effects of DMTs on posterior cerebellar subregions. Lobules IX and VIIIb emerged as critical loci linking pharmacological modulation with cognitive outcomes. These findings suggest that these regions may serve as potential imaging biomarkers of therapeutic response and prognosis in MS."

Journal • CNS Disorders • Multiple Sclerosis

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

Fingolimod targets Cushing's disease adenomas in-vitro and in-vivo (SNO 2025) - "PP2A inhibition via PPP1R17 overexpression is a targetable mechanism of CD tumorigenesis. The PP2A agonist fingolimod effectively targeted ATT20 cells both in-vitro and in-vivo. Our results highlight a novel therapeutic strategy for patients with CD."

Preclinical • Cushing’s Disease • Endocrine Disorders

Drug-induced headache reports: a comprehensive disproportionality and time-to-onset pharmacovigilance study using the FAERS database (2018-2024). (PubMed, Front Pain Res (Lausanne)) - "The drugs with the highest headache risk based on ROR included glecaprevir/pibrentasvir (ROR = 10.445), sofosbuvir/velpatasvir (ROR = 9.729), and eptinezumab-jjmr (ROR = 6.775). Top frequently reported drugs were apremilast, treprostinil, and adalimumab...Early-onset headaches (≤7days) were particularly associated with ofatumumab and fingolimod. Late-onset headaches (>90days) were linked to treprostinil and infliximab-dyyb. This large-scale pharmacovigilance study identifies multiple drugs and therapeutic classes with significant associations to headache as an ADR. These findings highlight the need for proactive headache monitoring, particularly during early treatment phases, and warrant further prospective investigations to understand mechanisms and preventive strategies."

Adverse events • Journal • Pain

Reprogramming autoimmunity: inducing antigen-specific tolerance via apoptotic mimicry in an experimental model of multiple sclerosis. (PubMed, J Neuroinflammation) - "Our findings indicate that antigen-specific therapy with PS liposomes mimicking apoptotic bodies downregulates the MOG-specific inflammatory immune response and expands Breg and Treg cells, offering a safe, versatile, and easily applicable approach that strongly supports its potential for near-future clinical translation in MS."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • CD4 • ENTPD1 • FOXP3 • IL10 • TGFB1

Intraperitoneal administration of cationic liposomes containing a TLR3 agonist recruits type I conventional dendritic cells and primes a local CD8+ T cell response. (PubMed, Vaccine) - "This study demonstrates that adjuvants can facilitate recruitment of cDC1s to the peritoneal cavity, a feature that may contribute to the effectiveness of i.p. administration on elicitation of CD8 T cell responses. Furthermore, we demonstrate that CAF09b-induced CD8 T cell responses require BATF3-dependent cDC1 cells. Understanding cDC1 and CD8 T cell dynamics via different immunization routes may aid in the design of more effective vaccine strategies."

Journal • Oncology • BATF3 • CD8 • ITGAE • ITGAX

A real-world pharmacovigilance study of FDA adverse event reporting system (FAERS) events for etrasimod. (PubMed, Front Pharmacol) - "A comparative analysis against fingolimod and ozanimod was performed to contextualize findings. The lack of unexpected signals remains reassuring. The frequent reporting of lack of efficacy highlights the need for close monitoring, and the comparative data offer valuable context for clinicians selecting S1P receptor modulator therapy."

Adverse events • Journal • Real-world evidence • Inflammatory Bowel Disease • Macular Edema • Ophthalmology • Pain

Immunosuppressants rewire the gut microbiome-alloimmune axis through time-dependent and tissue-specific mechanisms. (PubMed, Cell Commun Signal) - "Together, our findings show that immunosuppressants elicit complex, time-dependent effects that remodel the gut and exert compartment-specific impacts on lymphoid tissues, differentially affecting gut-draining mesenteric versus peripheral LN. Understanding these relationships offers new opportunities for refining immunosuppressive strategies to reduce treatment-related off-target complications and improve long-term organ transplant outcomes."

Journal • Inflammation • Solid Organ Transplantation • Transplant Rejection • Transplantation

Fingolimod Improves Anxiety-like Behavior and Modulates Sphingosine-1-Phosphate Receptors Gene Expression in a Diabetic Mouse Model. (PubMed, Biomolecules) - "Results indicate an important role of S1PR modulation in T2DM. Moreover, fingolimod affected mRNA levels of proteins engaged in glucose metabolism/insulin signaling and improved the behavior of diabetic mice."

Journal • Preclinical • Diabetes • Inflammation • Metabolic Disorders • Mood Disorders • Psychiatry • Type 2 Diabetes Mellitus • IGF1 • IL6 • S1PR1 • SIRT1 • SLC2A4 • SPHK1 • SPHK2

Wash-out duration and lymphocyte count in switching from fingolimod to ofatumumab: A case report and literature review. (PubMed, J Neuroimmunol) - "Literature review highlights the complexity of factors influencing rebound, including washout duration, lymphocyte count, and disease control during fingolimod therapy. Evidence suggests that initiating ofatumumab treatment without a prolonged washout period may mitigate rebound risk."

Journal • CNS Disorders • Multiple Sclerosis

Sphingosine-1-phosphate (S1P) signaling as a novel therapeutic target for alcohol abuse. (PubMed, bioRxiv) - "Specifically, we observed that two S1P receptor agonists FDA-approved for multiple sclerosis, fingolimod and ozanimod, and the more brain penetrant S1P 1 receptor agonist CYM5442, reduced binge alcohol drinking in the drinking in the dark (DID) paradigm in mice...Notably, CYM5442 was less aversive than naltrexone, an FDA-approved medication for the treatment of alcohol use disorder that shares a similar broad reducing action on alcohol intake and consummatory behavior...Lastly, gene expression analysis by RNA-Seq revealed that S1P regulates a complex set of genes in the transition to alcohol dependence. Overall, our results establish S1P signaling as a novel therapeutic target for alcohol use disorder."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Multiple Sclerosis

Successful Treatment of Progressive Multifocal Leukoencephalopathy With Tenofovir Alafenamide Fumarate. (PubMed, Neurol Neuroimmunol Neuroinflamm) - "This case demonstrates temporal association between TAF initiation and virologic clearance of JCV, suggesting potential antiviral activity."

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

Innovative approaches in neural stem cell therapy: a comprehensive review of mechanisms and applications. (PubMed, Am J Stem Cells) - "Neural stem cells (NSCs) combined with pharmacological agents, such as FTY720, enhance remyelination and neural repair in multiple sclerosis (MS) and spinal cord injuries (SCI)...While these mechanisms demonstrate remarkable therapeutic potential, challenges such as cost, scalability, and safety remain. This review provides a comprehensive analysis of these mechanisms, highlighting their contributions to the future of regenerative medicine and personalized therapeutic strategies."

Journal • Review • CNS Disorders • Genetic Disorders • Huntington's Disease • Inflammation • Movement Disorders • Multiple Sclerosis • Musculoskeletal Diseases • Orthopedics • Parkinson's Disease • Transplantation

YopP modulates bacterial virulence and systemic dissemination in Peyer´s patches during murine Yersinia enterocolitica infection. (PubMed, Med Microbiol Immunol) - "Additionally, inhibition of cytotoxicity by suramin treatment in mice promoted wild-type Ye (Ye WT) dissemination to levels comparable to Ye ΔyopP...Blocking DC migration by FTY720 treatment in Ye ΔyopP-infected mice significantly reduced the MLN bacterial burden, indicating that YopP regulates Ye-transporting DCs from PP to MLN. Overall, our findings provide insights into how YopP participates in host-pathogen interactions, seemingly benefiting the host while simultaneously facilitating bacterial evasion from early immune clearance. These findings contribute to understanding the impact of YopP on the clinical outcome of Ye infection."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Inflammation • IL10 • ITGAM

S1PR1-MYPT1 Maintains Coronary Endothelial Barrier in Pressure-Overloaded Hearts. (PubMed, Hypertension) - "Mice with EC-specifically MYPT1-deficient (Mypt1ΔEC) also showed coronary endothelial hyperpermeability, and treatment with the S1PR1 agonist FTY720 failed in alleviating the pathological effects. At 1 month post-transverse aortic constriction, both Mypt1ΔEC and S1pr1ΔEC mice displayed aggravated pathological cardiac remodeling. These findings suggest that the S1PR1-MYPT1 signaling is crucial for coronary endothelial permeability and myocardial microenvironmental homeostasis under pressure overload, targeting which may offer therapeutic potential for related heart diseases."

Journal • Cardiovascular • Heart Failure • Inflammation • Oncology • S1PR1 • TNFA

Sun Pharma UK Limited is conducting a precautionary recall of a single batch of Fingolimod SUN 0.5 mg hard capsules due to reports of capsule breakage on removing from the blister. (GOV.UK) - "No other batches of Fingolimod SUN 0.5mg hard capsules are impacted....Patients who have received Fingolimod SUN 0.5mg hard capsules from batch HAF2945A are advised to continue to take the capsules and, where possible, pierce the foil before removing the capsule."

Commercial • Immunology

Safety of disease-modifying therapies in multiple sclerosis: real-world data from the Austrian MS Treatment Registry (AMSTR). (PubMed, J Neurol) - "The safety data from the AMSTR do not reveal any new safety issues, particularly regarding neoplasms and infections. Hence, people with MS as well as their treating neurologists are reassured to continue treatment with DMT, as the benefit-risk profile of DMT could be reaffirmed."

Journal • Real-world evidence • Basal Cell Carcinoma • CNS Disorders • Endocrine Disorders • Infectious Disease • Multiple Sclerosis • Non-melanoma Skin Cancer • Oncology

Fingolimod targets Cushing’s disease adenomas in-vitro and in-vivo (WFNOS 2025) - "PP2A inhibition via PPP1R17 overexpression is a targetable mechanism of CD tumorigenesis. The PP2A agonist fingolimod effectively targeted ATT20 cells both in-vitro and in-vivo. Our results highlight a novel therapeutic strategy for patients with CD."

Preclinical • Cushing’s Disease • Endocrine Disorders