Venglustat is an investigational oral therapy being evaluated for the treatment of lysosomal storage disorders, a group of rare inherited genetic conditions. As a substrate reduction therapy, it aims to address the underlying cause of these diseases by limiting the production of harmful molecules that accumulate within cells. This approach differs from therapies that might replace a missing enzyme, instead focusing on preventing the buildup of problematic substances from the outset.
How Venglustat Works
Venglustat operates by inhibiting glucosylceramide synthase (GCS), an enzyme involved in the initial step of glycosphingolipid synthesis. GCS catalyzes the transfer of glucose from UDP-glucose to ceramide, forming glucosylceramide.
By blocking GCS, venglustat reduces the production of glucosylceramide (GL-1), a precursor for more complex glycosphingolipids (GSLs). This lowers the overall levels of these fatty molecules, preventing their abnormal accumulation that can lead to cell dysfunction and disease progression. Studies in healthy volunteers have shown venglustat effectively reduces plasma concentrations of GL-1 and GM3 in a time- and dose-dependent manner, confirming its mechanism of action.
Venglustat’s Role in Lysosomal Storage Disorders
Lysosomal storage disorders (LSDs) are inherited metabolic conditions where specific enzymes are deficient, leading to the accumulation of various substances within lysosomes, the “recycling centers” of cells. This buildup can cause cellular and organ damage. Venglustat is being investigated as a substrate reduction therapy for several of these disorders, including Fabry disease, Gaucher disease, and GM2 gangliosidosis.
Fabry Disease
In Fabry disease, mutations in the GLA gene lead to insufficient levels of alpha-galactosidase A (Gal A), an enzyme responsible for breaking down globotriaosylceramide (Gb3). This deficiency causes Gb3 to accumulate in tissues throughout the body, resulting in organ damage. Venglustat aims to lower Gb3 levels by inhibiting glucosylceramide synthase, reducing Gb3 production and potentially easing Fabry symptoms. Clinical data from a Phase 2a trial showed venglustat treatment led to significant reductions in Gb3 accumulation in cells and blood, with no signs of disease progression over three years in some patients.
Gaucher Disease
For Gaucher disease, particularly the neuronopathic type 3 (GD3), mutations in the GBA1 gene cause reduced acid β-glucosidase activity, leading to the accumulation of glucosylceramide (GL-1) and glucosylsphingosine. These fatty substances primarily build up in macrophages in organs like the spleen, liver, and bone marrow, and also in neurons in the neuronopathic forms. Venglustat, a brain-penetrant glucosylceramide synthase inhibitor, seeks to rebalance glucosylceramide influx with impaired lysosomal recycling, potentially improving both systemic and neurological manifestations. A Phase 2 trial (LEAP) in adults with GD3 receiving enzyme replacement therapy showed venglustat was well-tolerated and led to significant reductions in glucosylceramide and glucosylsphingosine in both plasma and cerebrospinal fluid.
GM2 Gangliosidosis
GM2 gangliosidosis includes conditions like Tay-Sachs and Sandhoff diseases, caused by genetic variations in the HEXA, HEXB, or GM2A genes. These mutations result in a deficient breakdown of gangliosides, particularly ganglioside GM2, leading to its toxic accumulation primarily in the brain. Venglustat is believed to cross the blood-brain barrier and inhibit glucosylceramide synthase, reducing the formation of glucosylceramide-based glycosphingolipids, which are precursors to gangliosides. This mechanism aims to decrease the rate of ganglioside formation, potentially mitigating the abnormal brain development, inflammation, and cell death characteristic of these severe neurological disorders.
Venglustat’s Clinical Journey
Venglustat is currently under clinical investigation, primarily focusing on lysosomal storage disorders, with its safety and efficacy still being evaluated by regulatory authorities. The oral therapy has received fast-track status from the U.S. Food and Drug Administration for Fabry disease, which is expected to accelerate its development and review process.
Currently, Sanofi is conducting two Phase 3 clinical trials for Fabry disease. The PERIDOT trial (NCT05206773), launched in 2022 and still recruiting, is investigating venglustat’s potential to alleviate abdominal and neuropathic pain. Another ongoing global CARAT trial (NCT05280548) is evaluating venglustat’s effects on left ventricular hypertrophy, a common heart complication in Fabry patients.
For Gaucher disease type 3, venglustat is currently in Phase 3 clinical trials. The LEAP2MONO study (NCT05222906) is a Phase 3, double-blind, active-comparator study evaluating the efficacy and safety of daily oral venglustat compared to intravenous enzyme replacement therapy for neurological manifestations and systemic disease stability in adult and pediatric GD3 patients. Early Phase 2 data from the LEAP trial (NCT02843035) showed acceptable safety and tolerability, with preliminary evidence of clinical stability.
Venglustat was also investigated for autosomal dominant polycystic kidney disease (ADPKD) in a pivotal Phase 2/3 study called STAGED-PKD (NCT03523728). However, this clinical program was halted in June 2021 because the study did not meet its futility criteria. An independent analysis of the annualized rate of change in total kidney volume (TKV), the primary endpoint, indicated that venglustat did not provide a meaningful reduction in TKV growth rate. While biomarker data confirmed venglustat effectively inhibits the glycosphingolipid (GSL) pathway, this interim analysis suggested that GSL reduction may not play a significant role in preventing kidney cyst growth, indicating it might not be a primary pathway for ADPKD progression. Despite the halt in ADPKD, Sanofi continues to evaluate venglustat in lysosomal storage disorders such as Gaucher disease type 3, Fabry disease, and GM2 gangliosidosis.