Sanofi received FDA Breakthrough Therapy designation for venglustat in Type 3 Gaucher disease, highlighting its potential as a brain-penetrant oral therapy targeting neurological involvement, supported by positive Phase II and Phase III clinical data
Written by: Marka Sheshi, Pharm D
Reviewed By: Pharmacally Editorial Team
The U.S. Food and Drug Administration has granted Breakthrough Therapy designation to venglustat, an investigational oral glucosylceramide synthase inhibitor, for the treatment of neurological manifestations of Type 3 Gaucher disease, a rare lysosomal storage disorder with limited treatment options.
The designation is supported by results from the Phase 3 LEAP2MONO study (NCT05222906), where patients receiving venglustat demonstrated statistically significant improvements in neurological outcomes compared with those treated with enzyme replacement therapy imiglucerase. Improvements were measured using a composite global test score incorporating the modified Scale for the Assessment and Rating of Ataxia (mSARA) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (p=0.007).
Venglustat was generally well tolerated in the trial with no new safety signals observed. The most frequently reported adverse events included headache (14.3% in the venglustat arm vs. 18.2% with ERT), nausea (14.3% vs. 4.5%), spleen enlargement (14.3% vs. 0%), and diarrhea (14.3% vs. 0%).
Gaucher disease is an inherited lysosomal storage disorder caused by deficiency of the enzyme glucocerebrosidase, leading to the accumulation of glycosphingolipids in organs such as the spleen, liver, bone marrow, and lungs. While Gaucher disease type 1 lacks central nervous system involvement and Gaucher disease type 2 presents with rapidly progressive neurological decline, Type 3 Gaucher disease is characterized by slower but progressive neurological impairment.
Although systemic manifestations of GD3 such as hepatosplenomegaly, anemia, thrombocytopenia, and bone disease can be managed with enzyme replacement therapy, no approved treatments currently address the neurological aspects of the disease. Venglustat is designed to cross the blood–brain barrier and reduce the abnormal accumulation of glycosphingolipids in the central nervous system, targeting the underlying pathology responsible for neurological symptoms.
“This regulatory milestone recognizes the significant unmet medical need for people living with type 3 Gaucher disease, particularly those experiencing progressive neurological deterioration,” said Karin Knobe, Global Head of Clinical Development, Rare Diseases at Sanofi. She added that the LEAP2MONO findings represent an encouraging step in advancing potential treatment options for patients with GD3.
Venglustat has previously received Fast Track designation from the FDA and Orphan Drug designation in the United States, European Union, and Japan for the treatment of GD3. Sanofi plans to pursue global regulatory filings for venglustat in 2026.
The ongoing LEAP2MONO Phase 3 trial is a double-blind, double-dummy, active-comparator study evaluating once-daily oral venglustat versus intravenous enzyme replacement therapy administered every two weeks in patients aged 12 years and older with GD3.
A total of 43 participants were randomized in a 1:1 ratio to receive either venglustat with placebo infusion or ERT with placebo tablets. The study’s primary endpoints assess changes in neurological function at week 52 using mSARA and RBANS scores, while secondary endpoints evaluate systemic disease markers and biomarkers including cerebrospinal fluid and plasma GL1 and lyso-GL1 levels. Results from the open-label extension phase are expected in the future.
References
Sanofi’s venglustat earns Breakthrough Therapy designation in the US for type 3 Gaucher disease. 2026. 18 March 2026, https://www.sanofi.com/en/media-room/press-releases/2026/2026-03-18-06-00-00-3257888
Study to Evaluate the Efficacy and Safety of Venglustat in Adult and Pediatric Patients with Gaucher Disease Type 3 (LEAP2MONO), ClinicalTrials.gov ID NCT05222906, Study Details | NCT05222906 | Study to Evaluate the Efficacy and Safety of Venglustat in Adult and Pediatric Patients With Gaucher Disease Type 3 | ClinicalTrials.gov
About the Writer
Marka Sheshi | Doctor of Pharmacy
Driven by a deep commitment to clinical excellence, research integrity, and impactful medical writing. With a strong foundation in pharmacotherapy and patient safety, specializes in transforming complex scientific evidence into authoritative, publication-ready content. Passionate about advancing healthcare through precise, evidence-based communication that informs practice, strengthens research visibility, and improves patient outcomes.