Sanofi's Venglustat Receives FDA Breakthrough Therapy Designation for Type 3 Gaucher Disease

Sanofi (EURONEXT: SAN; NASDAQ: SNY), a Paris-headquartered biopharma company, announced that the US FDA has granted Breakthrough Therapy designation to venglustat, an oral, brain-penetrant glucosylceramide synthase inhibitor (GCSi), for the treatment of neurological manifestations of type 3 Gaucher disease (GD3). Venglustat had previously received FDA Fast Track designation for GD3 and orphan drug designation for GD3 in the US, EU, and Japan.

The Breakthrough Therapy designation was supported by data from the Phase III LEAP2MONO study (NCT05222906), a double-blind, double-dummy, active-comparator trial that randomized 43 adults and adolescents aged 12 and older with GD3 in a 1:1 ratio to receive either once-daily oral venglustat or intravenous enzyme replacement therapy (ERT) with imiglucerase every two weeks. All enrolled patients had been on ERT for at least three years and had achieved therapeutic goals for systemic disease. The co-primary endpoints were change from baseline to week 52 in modified Scale for the Assessment and Rating of Ataxia (mSARA) total score and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total scale index score. Patients receiving venglustat demonstrated statistically significant improvements on a global test score encompassing both ataxia and cognition assessments compared to those on ERT (p=0.007). The most commonly reported adverse events in the venglustat arm were headache (14.3% vs. 18.2% for ERT), nausea (14.3% vs. 4.5%), spleen enlargement (14.3% vs. 0%), and diarrhea (14.3% vs. 0%). No new safety signals were identified. The study remains ongoing, with open-label extension data expected.

Sanofi is also conducting a Phase II trial (NCT02843035) evaluating venglustat in combination with imiglucerase in adults with GD3, measuring cerebrospinal fluid biomarkers including lyso-GL1 and GL-1. Additional Phase III trials are active or have been completed for the same indication.

Research context

Gaucher disease is a rare lysosomal storage disorder caused by deficiency of glucocerebrosidase, resulting in accumulation of glycosphingolipids in the spleen, liver, bone marrow, lungs, and, in neuronopathic forms, the central nervous system. GD3 is distinguished from type 1 by the presence of neurological involvement, including ataxia, cognitive decline, and oculomotor dysfunction, alongside systemic manifestations. ERT with imiglucerase or velaglucerase alfa addresses visceral and hematologic symptoms but does not cross the blood-brain barrier, leaving neurological deterioration untreated. No therapy is currently approved for the neurological manifestations of GD3. Miglustat, an oral substrate reduction therapy approved for type 1 Gaucher disease, has been explored in combination with ERT for GD3, but evidence of neurological benefit remains limited and it lacks regulatory approval for this indication.

Venglustat is differentiated from existing Gaucher disease treatments by its capacity to penetrate the blood-brain barrier, directly targeting glycosphingolipid accumulation in the CNS. Unlike ERT, which requires intravenous infusion and acts only on peripheral tissues, venglustat is administered orally and is designed to address both systemic and neurological pathology. The LEAP2MONO trial's use of validated neurological endpoints — mSARA for ataxia and RBANS for cognition — reflects an approach oriented toward demonstrating CNS-specific efficacy, a domain where ERT has consistently failed to show benefit. Sanofi has stated it will pursue global regulatory filings for venglustat in GD3 during 2026.

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