Sanofi’s Venglustat Receives FDA Breakthrough Therapy Designation for Type 3 Gaucher Disease
The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to venglustat, an investigational oral glucosylceramide synthase (GCSi) inhibitor developed by Sanofi, for the treatment of neurological manifestations of Gaucher disease type 3 (GD3). This rare lysosomal storage disorder currently has limited treatment options for its neurological symptoms.
Understanding Gaucher Disease Type 3
Gaucher disease (GD) is a rare inherited disorder caused by a deficiency in the enzyme glucocerebrosidase. This deficiency leads to the buildup of glycosphingolipids (GSL) in organs like the spleen, liver, bone marrow and lungs. There are three main types of GD:
- GD1: Does not involve the central nervous system (CNS).
- GD2: Characterized by rapid neurological decline and severe neurocognitive symptoms.
- GD3: Exhibits a slower, more variable progression and symptom severity.
In GD3, the accumulation of GSL in the CNS can cause neurological symptoms alongside the systemic manifestations common in other GD types, such as enlarged liver and spleen, anemia, and bone disease. Current treatments primarily address the systemic symptoms, leaving a significant unmet need for therapies targeting the neurological aspects of GD3.
How Venglustat Works
Venglustat is designed to reduce the abnormal accumulation of GSL. Crucially, it is formulated to cross the blood-brain barrier, allowing it to directly target the underlying pathology causing neurological dysfunction in GD3 patients. It functions as a glucosylceramide synthase inhibitor (GCSi).
LEAP2MONO Study Results
The Breakthrough Therapy designation is based on positive data from the Phase 3 LEAP2MONO study (NCT05222906). The study demonstrated that patients receiving venglustat experienced statistically significant improvements in neurological symptoms compared to those receiving enzyme replacement therapy (ERT) imiglucerase (p=0.007). These improvements were measured using a global test score that assessed ataxia (mSARA) and cognition (RBANS).
Venglustat was generally well-tolerated in the study. The most commonly reported adverse events in the venglustat arm were headache (14.3%), nausea (14.3%), spleen enlargement (14.3%), and diarrhea (14.3%). These were generally comparable to, or less frequent than, those observed in the imiglucerase arm.
Breakthrough Therapy Designation and Future Plans
The FDA’s Breakthrough Therapy designation is designed to expedite the development and review of drugs for serious or life-threatening conditions, based on preliminary clinical evidence indicating a substantial improvement over available therapies. Venglustat has also received Rapid Track designation and orphan drug status in the U.S., EU, and Japan for GD3.
Sanofi plans to pursue global regulatory filings for venglustat in GD3 throughout 2026.
Statements from Sanofi
“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 Director of Clinical Development, Rare Diseases at Sanofi. “The positive results from the LEAP2MONO study are an encouraging step forward in the research and development process, and we will continue to collaborate with the FDA to advance this potential treatment option.”
Sources: