venglustat (GZ402671) / Sanofi - LARVOL DELTA

LEAP2MONO Subgroup Analyses Demonstrate Neurologic Efficacy With Venglustat While Maintaining Systemic Control in GD3 (SSIEM 2026) - P3 | "Subgroup analyses showed a consistent direction of treatment effect across prespecified strata. Notably, a more pronounced effect was observed in patients <18 years of age."

Clinical • Ataxia • CNS Disorders • Epilepsy • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Movement Disorders

Cognition and Ataxia Benefits of Venglustat in GD3: Prespecified Analyses of Neurologic Endpoints in LEAP2MONO (SSIEM 2026) - P3 | "LEAP2MONO efficacy analyses demonstrate clinically meaningful neurologic benefits with venglustat across cognitive and motor functions. The observed pattern, including population-level improvement and consistent domain-level effects, supports a disease-modifying effect on neurologic trajectory in GD3. Greater response magnitude in younger patients supports earlier intervention."

Ataxia • Movement Disorders

Managed Access Program of Venglustat in Pediatric and Adult Patients With Type 3 Gaucher Disease (GD3). (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Sanofi

New trial • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Pediatrics

VENGLUSTAT DEMONSTRATES SUPERIOR NEUROLOGIC EFFICACY WHILE MAINTAINING SYSTEMIC CONTROL IN GAUCHER DISEASE TYPE 3: RESULTS FROM THE PHASE 3 LEAP2MONO TRIAL (EHA 2026) - P3 | "Summary/Conclusion LEAP2MONO is the first trial evaluating the brain-penetrant glucosylceramide synthase inhibitor VEN, in pediatric and adult pts with GD3. The trial demonstrates that VEN controls both CNS and systemic manifestations of GD3."

Clinical • P3 data • Ataxia • CNS Disorders • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Movement Disorders • Musculoskeletal Pain • Orthopedics • Rare Diseases

Press Release: Sanofi’s venglustat accepted for priority review in the US to treat type 3 Gaucher disease (GlobeNewswire) - "The target action date for the FDA decision is November 25, 2026....The NDA is supported by positive data from the LEAP2MONO phase 3 study (clinical study identifier: NCT05222906), evaluating the efficacy and safety of venglustat in adults and pediatric patients, with neurological manifestations of GD3, who previously achieved stabilization of systemic manifestations with enzyme replacement therapy (ERT)."

FDA filing • PDUFA • Priority review • Gaucher Disease

Press Release: Sanofi’s venglustat earns Breakthrough Therapy designation in the US for type 3 Gaucher disease (Sanofi Press Release) - "The designation is based on data from the LEAP2MONO phase 3 study (clinical study identifier: NCT05222906) in which patients receiving venglustat demonstrated statistically significant improvements in neurological symptoms measured by a global test score that included assessments for ataxia (mSARA) and cognition (RBANS) compared with patients receiving the enzyme replacement therapy (ERT), imiglucerase (p=0.007)....Sanofi will pursue global regulatory filings for venglustat in GD3 during 2026."

Breakthrough therapy • Filing • Gaucher Disease

Underlying Mechanisms of GBA1 in Parkinson's Disease and Dementia with Lewy Bodies: Narrative Review. (PubMed, Genes (Basel)) - "While Venglustat effectively reduced GC levels, a key marker associated with GBA1-PD, the lack of clinical improvement led to the discontinuation of its development for this indication. GBA1-mediated lysosomal and lipid dysregulation represents a key pathogenic axis in PD and DLB. Understanding these mechanisms provides crucial insight into disease progression and highlights emerging therapeutic strategies-such as pharmacological chaperones, substrate reduction therapies, and gene-targeted approaches-aimed at restoring GCase function and lysosomal homeostasis to slow or prevent neurodegeneration."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Gaucher Disease • Lewy Body Disease • Movement Disorders • Parkinson's Disease • Targeted Protein Degradation • GBA • GBA1

Historical Control Analysis Demonstrates Greater Long-Term Reduction in Plasma Globotriaosylceramide (Gb3) by Venglustat Compared With Placebo or Agalsidase Beta in Male Patients With Classic Fabry Disease. (PubMed, Mol Genet Genomic Med) - "Venglustat showed significantly greater reductions in plasma GL-3 concentrations than placebo after 6 months and agalsidase beta after 24 and 36 months. These findings support the potential of long-term venglustat treatment to reduce GL-3 accumulation in patients with classic FD. Further studies are needed to confirm clinical benefit."

Biomarker • Clinical • Journal • Fabry Disease • Genetic Disorders

Safety and tolerability of pegunigalsidase alfa: Insights from a single site experience from the Expanded Access Program in the United States (SSIEM 2023) - P | "The enrollment reasons included poor tolerability of agalsidase beta (AB), disease progression on AB, and worsening of proteinuria on migalastat...One ERT-naïve male with classic FD enrolled due to poor tolerability with venglustat and withdrew after experiencing a serious adverse event (SAE) of hypersensitivity reaction with the third PA infusion (antidrug antibody [ADA]-negative at baseline [BL])... PA is a novel ERT that is well tolerated in patients with FD. While healthcare providers should remain vigilant for possible hypersensitivity reactions, PA may offer the benefit of reduced infusion duration and lower premedication burden for some patients with poor tolerability with other ERTs."

Clinical • Cardiovascular • Fabry Disease • Genetic Disorders • Immunology • Movement Disorders • Renal Disease • Ventricular Tachycardia

The AMETHIST phase 3 trial of venglustat in patients with GM2 gangliosidoses and related diseases: baseline characteristics (SSIEM 2023) - P3 | "Baseline characteristics in the secondary population (n=16) were mean age 12 years, juvenile/adolescent-onset GM2 (n=7), GM1 gangliosidosis (n=7), sialidosis type 1 (n=1), juvenile/adult galactosialidosis (n=1). AMETHIST is the first larger-scale clinical trial that will address relative benefits and risk of a treatment (venglustat) for late-onset GM2 gangliosidoses."

Clinical • P3 data • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

Venglustat in GM2 Gangliosidoses and Related Disorders: Results of the AMETHIST Randomized Controlled and Basket Trials. (PubMed, Genet Med) - "In adults with late-onset GM2 gangliosidoses, oral venglustat decreased CSF GM2 concentrations but without clinical improvement in the endpoints assessed. No new safety findings were observed."

Clinical • Journal • Pan tumor • Dyslipidemia • Genetic Disorders • Infectious Disease • Lysosomal Storage Diseases • Metabolic Disorders • Novel Coronavirus Disease • Pain

Precision medicine and music therapy for Parkinson's Disease. (PubMed, Clin Park Relat Disord) - "Finding: Our analysis revealed that precision medicine approaches, including GBA1-targeted venglustat and LRRK2 kinase inhibitors, show significant promise in clinical trials when guided by genetic profiling... The strategic integration of precision medicine and music therapy offers a novel, patient-centered framework for PD management that simultaneously targets pathological mechanisms and functional outcomes. Future implementation should focus on overcoming accessibility barriers, conducting large-scale longitudinal studies, and developing integrated treatment protocols that combine genetic insights with personalized neuromodulation approaches."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

New drugs available for Fabry disease. (PubMed, Kidney Blood Press Res) - "This review focuses exclusively on newly available drugs and future therapeutic approaches for treating FD, including migalastat, pegunigalsidase alfa, substrate reduction therapy (SRT), and gene therapy. Migalastat provides benefits such as oral administration and non-immunogenicity; however, it is only appropriate for patients with "amenable" GLA variants. The recently approved pegunigalsidase alfa is a pegylated form of α-Gal A manufactured in plant cell cultures, with apparent reduced immune response and prolonged circulating half-life. SRT (venglustat, lucerastat) reduces Gb3 synthesis, helping to normalize metabolic processes while offering certain advantages such as oral administration, non-immunogenic properties, and the possible crossing of the blood-brain barrier. Clinical trials in human and animal model studies are currently investigating ex-vivo and in-vivo gene therapy techniques, showing positive early outcomes. Messages: The ongoing development..."

Journal • Review • Cardiovascular • Fabry Disease • Gene Therapies • Genetic Disorders

PROGNOSTIC COVARIATE ADJUSTMENT USING PD COURSE MAP IN THE MOVES -PD STUDY (ADPD 2025) - "Aims: To evaluate the increase in statistical power achieved by prognostic covariate adjustment in a post-hoc analysis of the MOVES -PDa phase 2 trial, which assessed venglustat in GBA1 -associated Parkinson's disease... Regulatory agencies recognize prognostic covariate adjustment as a valid method to enhance statistical power. Our findings demonstrate that prognostic covariates derived from PD Course Map reduced the variance of the outcome in the MOVES -PD data, resulting in improved confidence intervals for the interpretation of the phase 2 data. Variance reduction would translate in lower sample size in future trials."

CNS Disorders • Movement Disorders • Parkinson's Disease • GBA

SIMULATION OF TIME -TO-WORSENING OUTCOME IN THE MOVES -PD STUDY: IMPACT OF PROGNOSTIC COVARIATE ADJUSTMENT (ADPD 2025) - "Aims: To assess a time -to-worsening outcome in MOVES -PDa, a randomized Phase 2 trial evaluating venglustat in GBA1 -associated Parkinson's disease and evaluate the effect of adjusting this outcome with prognostic covariates... Time-to-worsening outcome proved more sensitive than continuous outcomes in MOVES -PD . Categorized prognostic covariates further enhanced sensitivity, underscoring the potential of this approach for designing future trials with time -to-event outcomes."

CNS Disorders • Movement Disorders • Parkinson's Disease • GBA

LEAP: Venglustat in Combination With Cerezyme in Adult Patients With Gaucher Disease Type 3 With Venglustat Monotherapy Extension (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Genzyme, a Sanofi Company | Trial completion date: Sep 2025 ➔ Oct 2026 | Trial primary completion date: Sep 2025 ➔ Oct 2026

Monotherapy • Trial completion date • Trial primary completion date • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Type 1 Gaucher Disease • GBA

Drug-drug interaction study with itraconazole supplemented with physiologically based pharmacokinetic modelling to characterize the effect of CYP3A inhibitors on venglustat pharmacokinetics. (PubMed, Br J Clin Pharmacol) - "The effect of itraconazole on venglustat exposure was quantified clinically, and a minimal PBPK model was successfully developed, validated and applied to assess DDI effect of additional CYP3A inhibitors on venglustat. The results help to further understand the DDI potential with venglustat and will inform dose recommendations with comedications."

Journal • PK/PD data • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

PERIDOT: A Study to Evaluate the Effect of Venglustat Tablets on Neuropathic and Abdominal Pain in Male and Female Participants ≥16 Years of Age With Fabry Disease (clinicaltrials.gov) - P3 | N=122 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting | Trial completion date: Oct 2025 ➔ Dec 2026 | Trial primary completion date: Nov 2024 ➔ Dec 2025

Enrollment closed • Trial completion date • Trial primary completion date • Fabry Disease • Genetic Disorders • Pain

AMETHIST: A Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of Venglustat in Late-onset GM2 (clinicaltrials.gov) - P3 | N=75 | Terminated | Sponsor: Genzyme, a Sanofi Company | Trial completion date: Feb 2026 ➔ Dec 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2024 ➔ Dec 2024; Discontinued based on the absence of positive trends on clinical endpoints.

Trial completion date • Trial primary completion date • Trial termination • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

CARAT: A Study to Evaluate the Effect of Venglustat Tablets on Left Ventricular Mass Index in Male and Female Adult Participants With Fabry Disease (clinicaltrials.gov) - P3 | N=104 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Jul 2027 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ May 2026 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • Fabry Disease • Genetic Disorders

Inhibiting UGCG prevents PRV infection by decreasing lysosome-associated autophage. (PubMed, Int J Biol Macromol) - "Finally, through in vivo evaluation, this study revealed that UGCG inhibitors, Eliglustat hemitartrate and Ibiglustat, hold promise as potential therapeutics for the treatment of PRV infection. In summary, this study preliminarily elucidates the impact of UGCG on PRV infection and its associated molecular mechanisms, suggesting UGCG could serve as a potential novel target for the prevention and treatment of viral diseases such as PRV."

Journal • Infectious Disease • Metabolic Disorders

LEAP2MONO: Study to Evaluate the Efficacy and Safety of Venglustat in Adult and Pediatric Patients With Gaucher Disease Type 3 (clinicaltrials.gov) - P3 | N=43 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting

Enrollment closed • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Pediatrics • Type 1 Gaucher Disease • GBA

2024 Update of the TSOC Expert Consensus of Fabry Disease. (PubMed, Acta Cardiol Sin) - "Recent advances in pharmacological approach including enzyme replacement therapy (agalsidase alfa or beta), oral chaperone therapy (migalastat), and substrate reduction therapy (venglustat) aim to prevent from irreversible organ damage. Genotype- and gender-based monitoring of treatment effects through biomarker (Lyso-Gb3), renal assessment, and cardiac responses using advanced imaging modalities are key steps to optimizing patient care in FD."

Journal • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Cognitive Disorders • Congestive Heart Failure • Fabry Disease • Fibrosis • Genetic Disorders • Heart Failure • Immunology • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Targeting sphingolipid metabolism in chronic lymphocytic leukemia. (PubMed, Clin Exp Med) - "To evaluate the therapeutic potential of inhibiting GluCer synthesis, we genetically repressed the UGCG pathway using in vitro models of leukemic B cells, in addition to UGCG pharmacological inhibition with approved drugs such as eliglustat and ibiglustat, both individually and in combination with ibrutinib, assessed in cell models and primary CLL patient cells. Inhibitors that target alternative pathways within sphingolipid metabolism, like sphingosine kinases inhibitor SKI-II, also demonstrated promising therapeutic effects both alone and when used in combination with ibrutinib, reinforcing the oncogenic impact of sphingolipids in CLL cells. Targeting sphingolipid metabolism, especially the UGCG pathway, represents a promising therapeutic strategy and as a combination therapy for potential treatment of CLL patients, warranting further investigation."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology

PERIDOT: A Study to Evaluate the Effect of Venglustat Tablets on Neuropathic and Abdominal Pain in Male and Female Participants ≥16 Years of Age With Fabry Disease (clinicaltrials.gov) - P3 | N=114 | Recruiting | Sponsor: Sanofi | Trial completion date: Jul 2026 ➔ Oct 2025

Trial completion date • Fabry Disease • Genetic Disorders • Pain