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

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

Engineered small extracellular vesicles targeting regulatory T cells via CD40L signaling in multiple sclerosis (ECTRIMS 2024) - "Recently, a phase 2 trial for frexalimab, a second-generation anti-CD40L monoclonal antibody, showed results favoring the effect to reduce MRI lesions... This study suggests that engineered sEV targeting CD40L signaling exert immunological effects on PBMC of MS patients and demonstrate therapeutic benefits in an MS animal model. Further investigations regarding pathomechanisms of engineered sEVs-CD40 including immune tolerance via Treg and additional beneficial effects favoring sEV over monoclonal antibodies are needed."

CNS Disorders • Multiple Sclerosis • CD40LG • FOXP3 • IFNG • IL17A

Safety and Efficacy of Frexalimab in the Treatment of Relapsing Multiple Sclerosis: 18-month Results from the Phase 2 Open-Label Extension (ECTRIMS 2024) - P2 | "Frexalimab continues to show favourable safety and sustained reduction in disease activity in participants with RMS as assessed by MRI outcomes through 18 months. These findings support further development of frexalimab in phase 3 MS trials as a high-efficacy, non-lymphocyte-depleting therapy."

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

Exploratory MRI Outcomes and Plasma NfL Levels in Frexalimab-Treated Participants with Relapsing Multiple Sclerosis: Week 48 Results from the Phase 2 Open-Label Extension (ECTRIMS 2024) - P2 | "These exploratory MRI and pNfL data contribute to understanding the effect of frexalimab on chronic neuroinflammation and neurodegeneration, and support further investigations in both RMS and non-relapsing secondary progressive MS (nrSPMS)."

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

Exploratory Biomarker Analyses Support Frexalimab Mechanism of Action in Participants with Relapsing Multiple Sclerosis (ECTRIMS 2024) - P2 | "These exploratory analyses confirm that inhibition of the CD40/CD40L costimulatory pathway by frexalimab leads to modulation of adaptive and innate immune cell function and their crosstalk, further supporting its potential to address neuro-inflammation in MS."

Biomarker • IO biomarker • CNS Disorders • Inflammation • Multiple Sclerosis • CCL19 • CD40LG • CD5 • CXCL13 • FCER2 • IL12A • Plasma NfL • TNFRSF8

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 | Not yet recruiting | Sponsor: Sanofi

New P2 trial • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Lupus Nephritis • Nephrology

Safety and Efficacy of Frexalimab in Relapsing Multiple Sclerosis: 48-Week Results from the Phase 2 Open-Label Extension (EAN 2024) - P2 | "Frexalimab continued to show favorable safety and efficacy in RMS participants through W48. These data support its further development as a potential high- efficacy, non- lymphocytedepleting treatment option in MS."

Clinical • P2 data • CNS Disorders • Multiple Sclerosis • CD40LG

Frexalimab Reduces Plasma Neurofilament Light Chain in Relapsing Multiple Sclerosis: Week 48 Data from a Phase 2 Trial (EAN 2024) - P2 | "The observed reduction in pNfL through W48 provides evidence that frexalimab markedly reduces neuroaxonal damage in pwRMS."

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

Media Update: Frexalimab new phase 2 data showed reduction of key biomarker of nerve cell damage in relapsing MS (GlobeNewswire) - P2 | N=129 | NCT04879628 | Sponsor: Sanofi | "Sanofi’s CD40L monoclonal antibody, frexalimab, reduced a key biomarker associated with multiple sclerosis nerve cell damage in patients with relapsing MS, supporting the rationale for this novel mechanism in MS phase 3 studies aiming to delay disability progression. New phase 2 results showed significant reduction in plasma levels of neurofilament light chain (NfL) after one year of treatment, a biomarker of nerve cell damage that is typically elevated in people living with MS. These data were presented at the 10th Congress of the European Academy of Neurology (EAN) in Helsinki, Finland....Participants receiving high-dose frexalimab experienced a 41% reduction in plasma NfL levels from baseline (11.5 [1.9]) to week 48 (6.8 [2.0]), the greatest NfL level reduction across the four treatment groups."

P2 data • CNS Disorders • Immunology • Multiple Sclerosis

FABULINUS—A Randomized, Controlled Trial with FrexalimAB, to Assess Endogenous Insulin Secretion in New-Onset Stage 3 Type 1 Diabetes Adults and Adolescents (ADA 2024) - P2 | "FABULINUS is an innovative combined proof-of-concept and dose-finding study tailored to specific clinical development requirements for ß-cell preservation in T1D."

Clinical • Late-breaking abstract • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus • CD40LG

Safety and Efficacy of Frexalimab in Relapsing Multiple Sclerosis: 48- Week Results from the Phase 2 Open-Label Extension (CMSC 2024) - P2 | "Frexalimab continued to show favorable safety and efficacy in participants with RMS through W48. These data support its further development as a potential high-efficacy, non–lymphocyte-depleting treatment option in MS."

Clinical • P2 data • CNS Disorders • Multiple Sclerosis • Pain • CD40LG

Frexalimab in Relapsing Multiple Sclerosis and Nonrelapsing Secondary Progressive Multiple Sclerosis: Design of Phase 3 FREXALT and FREVIVA Trials (CMSC 2024) - P2, P3 | "Planned enrollment is 1400 participants randomly assigned 1:1 to frexalimab or teriflunomide. These phase 3 trials will assess the efficacy and safety of frexalimab in patients with RMS and nrSPMS, which is a population with no approved therapeutic options."

P3 data • CNS Disorders • Multiple Sclerosis • CD40LG

Efficacy of Frexalimab on Physical and Psychological Impacts and Fatigue in Relapsing Multiple Sclerosis: Findings From Patient-Reported Outcomes in a Phase 2 Trial (CMSC 2024) - P2 | "These preliminary findings suggest that frexalimab may improve physical impact and fatigue in people with RMS."

Clinical • P2 data • Patient reported outcomes • CNS Disorders • Multiple Sclerosis • CD40LG