frexalimab (SAR441344) / ImmuNext, Sanofi, Royalty - LARVOL DELTA

FrexalimAB in Preservation of Endogenous insULIN Secretion Compared to Placebo in adUlts and Adolescents on Top of inSulin Therapy (FABULINUS) (clinicaltrials.gov) - P2 | N=192 | Recruiting | Sponsor: Sanofi | Trial completion date: Oct 2028 ➔ Aug 2031

Trial completion date • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

Monoclonal Antibodies as Therapeutic Agents in Autoimmune and Neurodegenerative Diseases of the Central Nervous System: Current Evidence on Molecular Mechanisms and Future Directions. (PubMed, Int J Mol Sci) - "Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Immunology • Inflammation • Movement Disorders • Multiple Sclerosis • Neuromyelitis Optica Spectrum Disorder • Parkinson's Disease • Rare Diseases • CD20 • CD52 • IL6

ECTRIMS 2025: Frexalimab shows long-term benefits for MS patients (Multiple Sclerosis News Today) - "The data showed that rates of new or enlarging lesions and of lesions with active inflammation remained low through 120 weeks, or about 2.5 years...Relapse rates were also low — with 88% of participants on a high dose of frexalimab remaining relapse-free — and disability scores remained stable throughout the studies, the data showed...In this part, both frexalimab groups had significantly fewer lesions with active inflammation (up to 89% less), as well as new and enlarging lesions (up to 92% less) than the placebo....Relapse rates were also low across groups, though the lowest relapse rate — 0.09 relapses per year — was observed in the patient group who were always on the high, intravenous dose of frexalimab."

P2 data • Multiple Sclerosis

SCD40L in Cerebrospinal Fluid Before and After Autologous Hematopoietic Stem Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (ECTRIMS 2025) - "A recent phase II trial showed that the CD40L monoclonal antibody frexalimab significantly reduced active lesions in relapsing-remitting MS (RRMS)...Patients had received a median of two prior DMTs; 14% were treatment-naïve, 36% had received 1st line, and 50% 2nd line treatment (natalizumab or rituximab)... sCD40L is elevated in MS, correlates with disease activity, and decreases after AHSCT. Baseline sCD40L may be a prognostic biomarker for post-transplant inflammatory activity."

IO biomarker • Bone Marrow Transplantation • CNS Disorders • Inflammation • Multiple Sclerosis • Transplantation • CD40LG

Meningeal B cell aggregates are targeted by an antibody to CD40L in a spontaneous animal model of MS (ECTRIMS 2025) - "Recently, anti-CD40L antibody frexalimab, was shown to reduce disease activity in MS patients... In conclusion, anti-CD40L treatment might be beneficial in progressive MS as it can potentially eliminate meningeal B cell aggregates, prevent astrocyte damage and increase anti-inflammatory properties of immune cells within the CNS compartment."

Preclinical • Multiple Sclerosis • Solid Tumor • CD40LG • IL10

Safety and Efficacy of Frexalimab in Participants With Relapsing Multiple Sclerosis: 2.5-Year Results From the Phase 2 Open-label Extension (ECTRIMS 2025) - P2 | "Frexalimab continues to show favourable safety and sustained reduction in disease activity in pwRMS through 2.5 years, supporting its further development in phase 3 trials as a potential high-efficacy, non-lymphocyte-depleting therapy."

Clinical • P2 data • Back Pain • CNS Disorders • Infectious Disease • Multiple Sclerosis • Musculoskeletal Pain • Novel Coronavirus Disease • CD40LG

Frexalimab (CD40 ligand), glofitamab (CD20CD3), and others (ECTRIMS 2025) - No abstract available

CD40LG

Long-term Treatment Effect of Frexalimab on NfL and Plasma Biomarkers of Adaptive and Innate Immunity (ECTRIMS 2025) - P2 | "These biomarker results support the emerging understanding of frexalimab's mechanism of action targeting the co-stimulation of adaptive and innate immune cells, thought to contribute to both acute and chronic neuroinflammation in MS."

Biomarker • IO biomarker • Inflammation • Multiple Sclerosis • CD27 • CD40LG • CXCL13 • NEFL • Plasma NfL

Safety and efficacy of frexalimab in relapsing multiple sclerosis: 2-Year results from phase 2 open-label extension (EAN 2025) - P2 | "Frexalimab continues to show favorable safety and sustained reduction in disease activity in pwRMS through W96, supporting its further development in phase-3 trials as a potential high-efficacy, non-lymphocyte-depleting therapy."

Clinical • P2 data • CNS Disorders • Infectious Disease • Multiple Sclerosis • Novel Coronavirus Disease • CD40LG

Frexalimab reduces plasma neurofilament light chain in relapsing multiple sclerosis: Week 72 data from phase 2 trial (EAN 2025) - P2 | "The observed reduction in NfL through W72 indicates that frexalimab markedly reduces neuroaxonal damage in pwRMS."

IO biomarker • P2 data • CNS Disorders • Multiple Sclerosis • CD40LG • NEFL • Plasma NfL

The role of microglia in multiple sclerosis: implications for treatment with Bruton's tyrosine kinase inhibitors. (PubMed, Front Immunol) - "BTK inhibitors and other novel treatments for MS, including masitinib and frexalimab, show promise in modulating microglial function and influencing the disease progression rate. The multifaceted roles of microglia in CNS development, immune surveillance, and particularly in the pathogenesis of MS highlight the potential of targeting microglial functions in MS treatment. Emerging research on the involvement of microglia in MS pathophysiology offers promising avenues for developing novel therapies, especially for progressive MS, potentially improving patient outcomes in this debilitating disease."

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

Fabulinus-A randomized, controlled study with frexalimab to examine the endogenous insulin secretion with newly occurring type 1 diabetes stage 3 in adults and adolescents (DDG 2025) - P2 | "Fabulinus is an innovative combined proof-of-concept and dose finding study that is tailored to the specific requirements for clinical development to maintain ß cells at T1D. Encore submission. This study and support from Medical Writing financed by Sanofi."

Clinical • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus • CD40LG

APATURA: Efficacy and Safety of Frexalimab (SAR441344) in the Treatment of Systemic Lupus Erythematosus (clinicaltrials.gov) - P2 | N=116 | Recruiting | Sponsor: Sanofi | Trial primary completion date: Sep 2025 ➔ Jul 2026

Trial primary completion date • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Safety and Efficacy of Frexalimab from the Phase 2 Open-label Extension in Participants with Relapsing Multiple Sclerosis: 2-year Results (S3.006). (PubMed, Neurology) - P2 | "Montalban has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zenas BioPharma. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Bristows . Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff."

Clinical • Journal • P2 data • CNS Disorders • Infectious Disease • Multiple Sclerosis • Novel Coronavirus Disease • Pain • CD40LG

Safety and Efficacy of Frexalimab from the Phase 2 Open-label Extension in Participants with Relapsing Multiple Sclerosis: 2-year Results (AAN 2025) - P2 | "Frexalimab continues to show favorable safety and sustained reduction in disease activity in pwRMS through W96, supporting its further development in phase 3 trials as a potential high-efficacy, non-lymphocyte-depleting therapy."

Clinical • P2 data • CNS Disorders • Infectious Disease • Multiple Sclerosis • Novel Coronavirus Disease • Pain • CD40LG

CD40L-Activated Microglia Mediate Neuronal Insult in a Human iPSC-Derived Tri-Culture System (ACTRIMS Forum 2025) - "This study demonstrates that CD40+ microglia undergo morphological and functional changes when co-stimulated by CD40L and IFN-γ, leading to secretion of cytokines. Further, co-stimulation of a neuron, astrocyte, microglia tri-culture elicits a microglia-dependent loss of neuronal activity. Thus, CD40/CD40L interaction and its inhibition by an anti-CD40L antibody have implications in potential MS therapy."

CNS Disorders • Multiple Sclerosis • CD40LG • IFNG

In-Vivo Toxicity and Safety Profile of Frexalimab, a Second-Generation Anti-CD40L Antibody in Nonhuman Primate Models (ACTRIMS Forum 2025) - "Preclinical data indicate that frexalimab is a potent CD40L antagonist with immunosuppressive function demonstrated by effective inhibition of TDAR following KLH challenge. Frexalimab was well-tolerated at all doses in a 13-wk rhesus monkey toxicology study and did not exhibit thromboembolic risks associated with first-generation antibodies."

IO biomarker • Preclinical • Cardiovascular • CNS Disorders • Immunology • Multiple Sclerosis • CD40LG • SELP

Frexalimab, a Second-Generation Anti-CD40L Antibody for the Treatment of Multiple Sclerosis: Insights from Preclinical In-Vitro Studies (ACTRIMS Forum 2025) - P2, P3 | "These preclinical in-vitro data indicate that frexalimab has high affinity for human CD40L, effectively blocks the CD40/CD40L signaling pathway, and has low FcγRIIa binding, supporting the emerging clinical data that frexalimab may be a safe and effective therapeutic option in MS."

IO biomarker • Preclinical • Cardiovascular • CNS Disorders • Multiple Sclerosis • Oncology • CD40LG • CD86 • IFNG • SELP • TNFA

RESULT: A Study to Evaluate the Efficacy and Safety of Frexalimab, SAR442970, or Rilzabrutinib in Participants Aged 16 to 75 Years With Primary Focal Segmental Glomerulosclerosis or Minimal Change Disease (clinicaltrials.gov) - P2 | N=84 | Recruiting | Sponsor: Sanofi | Initiation date: Aug 2024 ➔ Dec 2024

Trial initiation date • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Lupus Nephritis • Nephrology

Frexalimab (SAR441344) as a potential multiautoimmune disorder tackling mAB targeting the CD40-CD40L pathway undergoing clinical trials: a review. (PubMed, Ann Med Surg (Lond)) - "Across multiple trials, its favorable safety profile has proven its superiority over first-generation drugs in minimizing side effects. Indeed, Frexalimab has become a harbinger of hope in the fight against autoimmune diseases and has pioneered a unique and unchallenging way for tackling complex autoimmune diseases in the clinical realm, however, further large-scale trials are needed to establish its therapeutic benefits across different autoimmune conditions."

Journal • Review • CNS Disorders • Diabetes • Fatigue • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Metabolic Disorders • Multiple Sclerosis • Sjogren's Syndrome • Systemic Lupus Erythematosus • Type 1 Diabetes Mellitus • CD40LG

Phase 3 Studies of Frexalimab in MS: Design of FREXALT and FREVIVA Trials (AECF 2024) - No abstract available

P3 data

Exploratory MRI and Plasma NfL: Week 48 Phase 2 Data of Frexalimab in Relapsing MS (AECF 2024) - No abstract available

P2 data • Multiple Sclerosis • Plasma NfL

Phase 2 Safety and Efficacy of Frexalimab in Relapsing MS: 18-Month Results (AECF 2024) - No abstract available

Clinical • P2 data • Multiple Sclerosis

RESULT Umbrella Trial in Primary Focal Segmental Glomerulosclerosis/Minimal Change Disease (KIDNEY WEEK 2024) - "We describe the protocol and operational feasibility for the Renal Efficacy Signaling UmbrelLa Trial (RESULT). RESULT is an innovative global Phase 2a randomized, placebo-controlled umbrella trial that simultaneously evaluates the safety and efficacy of 3 novel therapies targeting immunological pathways implicated in primary FSGS/MCD: frexalimab (anti-CD40L monoclonal antibody), SAR442970 (anti-OX40L and anti-TNFα bispecific), and rilzabrutinib (BTK-inhibitor). This global RESULT Phase 2a trial utilizes an innovative efficacy signal-seeking master protocol to simultaneously evaluate 3 immunologically active therapies in FSGS/MCD and is the first umbrella trial in nephrology. Operational feasibility and stakeholder feedback demonstrate high scientific and medical interest, as well as appropriateness of trial design and assessments."

Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Pediatrics • CD40LG • TNFSF4

RESULT: A Study to Evaluate the Efficacy and Safety of Frexalimab, SAR442970, or Rilzabrutinib in Participants Aged 16 to 75 Years With Primary Focal Segmental Glomerulosclerosis or Minimal Change Disease (clinicaltrials.gov) - P2 | N=84 | Recruiting | Sponsor: Sanofi | Not yet recruiting ➔ Recruiting

Enrollment open • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Lupus Nephritis • Nephrology