The following article features coverage from the 17th Annual WORLDSymposium meeting. Click here to read more of MPR’s conference coverage.

Venglustat in combination with imiglucerase was associated with enhanced brain connectivity in adults with Gaucher disease type 3 (GD3), according to research presented at the 17th Annual WORLDSymposium.

GD3 is a chronic neuropathic form of Gaucher disease characterized by progressive encephalopathy and is associated with systemic manifestations that typically appear in childhood or adolescence. Venglustat is an investigational oral, selective glucosylceramide (GL-1) synthase inhibitor designed to reduce the production of GL-1, which is expected to reduce the formation of glucosylceramide-based glycosphingolipids.

The 12-month double-blind phase 2 LEAP2IT trial evaluated the efficacy and safety of venglustat in combination with imiglucerase in 11 patients aged 18 years and older with GD3. All patients included in the trial had received enzyme replacement therapy for at least 3 years and had achieved non-neurological therapeutic goals. The primary end points were safety, tolerability, and changes in GL-1 and glucosylsphingosine (lyso-GL-1) concentrations in cerebrospinal fluid (CSF) and plasma. Secondary end points included neurological (eg, functional and volumetric MRI) and systemic disease measures.

Results showed that GL-1 and lyso-GL-1 concentrations were reduced by 69% (± 29.5) and 45% (± 31.8) in plasma and by 68% (± 36.8) and 33% (± 116.1) in CSF, respectively (n=10 patients with measurable drug exposure). Findings also showed that non-neurological manifestations (ie, hemoglobin level, platelet count, spleen volume, liver volume) remained stable.

With regard to neurological measures, the addition of venglustat to imiglucerase was associated with increased functional connectivity across brain regions using resting-state functional magnetic resonance imaging (fMRI); these were most prominent within the sensory, motor, and cerebellar networks considered to be disrupted in GD. Volumetric MRI (vMRI) also showed volume increase in certain brain regions in 8 patients with analyzable vMRI data and measurable venglustat exposure. The regions with volume increase and those with increased fMRI connectivity were reported to overlap. A majority of patients (n=9/11) reported improved scores based on SARA (scale for the assessment and rating of ataxia).

The most common adverse events were mild to moderate in severity, transient and not related to either treatment; no deaths or serious adverse events were reported.

“The presented data provide further proof that venglustat crosses the blood–brain barrier and shows the potential of venglustat combined with imiglucerase to ameliorate neurological manifestations of GD3, for which no treatment is currently available,” the study authors concluded.

Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Schiffmann R, Cox T, Dedieu JF, et al. Venglustat combined with imiglucerase positively affects neurological features and brain connectivity in adults with Gaucher disease type 3. Presented at: 17th Annual WORLDSymposium; February 8-12, 2021. Abstract 223.