Venglustat

Venglustat was once considered as a potential \"pipeline in a pill.\"\n Sanofi’s pipeline features a number of once-hyped candidates that are struggling to deliver in the clinic, and the latest mixed phase 3 data from venglustat continue this trend.The French Big Pharma was studying venglustat, an oral, brain-penetrant glucosylceramide synthase (GCS) inhibitor, in a pair of late-stage studies of rare lysosomal storage disorders. One of these trials, called Peridot, assessed the pill in 122 patients with Fabry disease, while the Leap2Mono trial focused on 43 patients with type 3 Gaucher disease (GD3).The Peridot study missed its primary endpoint of demonstrating superiority in patient-reported improvement of symptoms—namely neuropathic pain in upper and lower extremities, as well as abdominal pain—compared to a placebo cohort. Sanofi explained this failure by pointing to a “reduction in neuropathic and abdominal pain … observed in both study arms.”It was better news in the Leap2Mono study, where the 21 patients who received venglustat saw statistically significant improvements in neurological symptoms at Week 52 as measured by scales for ataxia and for neuropsychological status. The improvement between the venglustat cohort and the 22 patients who received enzyme replacement therapy (ERT) worked out as a p-value of 0.007, Sanofi explained in its Feb. 2 release.When it came to non-neurological secondary endpoints like changes in spleen volume, liver volume and hemoglobin level, venglustat “performed as well as ERT,” according to the pharma.Venglustat was well tolerated, Sanofi said. The most common adverse events were headache, nausea, spleen enlargement and diarrhea—although reports of headache were higher in the ERT cohort.Based on the Leap2Mono data, Sanofi said it will seek regulatory approval for venglustat in GD3. The company already markets the ERT Cerezyme and the oral glucosylceramide synthase inhibitor Cerdelga for the disease.The failure of the Peridot study doesn’t mark the end of Sanofi’s Fabry ambitions, either. As well as its approved Fabry ERT Fabrazyme, Sanofi is still running a phase 3 study of venglustat on left cardiac ventricular mass index in patients with the disease.“These findings underscore Sanofi\'s commitment to rare disease research and the promise we aim to deliver for people living with these conditions,” Sanofi’s head of R&D Houman Ashrafian, Ph.D., said in this morning’s release.“What excites us most is the potential to address critical unmet medical needs,” Ashrafian added. “A daily pill could make a serious difference for Gaucher patients facing neurological challenges.”This morning’s phase 3 readouts continued a run of mixed data for venglustat, which had at one point been hailed as one of Sanofi\'s top prospects and a potential “pipeline in a pill” contender. Those ambitions were blunted as far back as 2021, when venglustat failed midstage studies in both Parkinson’s disease and autosomal dominant polycystic kidney disease. By 2024, venglustat’s options were narrowed down to just Fabry disease and GD3 after Sanofi gave up on GM2 gangliosidosis as an indication “based on the absence of positive trends on clinical endpoints.”While Sanofi remains hopeful of getting venglustat approved for GD3, the Fabry failure this morning also continues a longer-term trend of the drugmaker’s pipeline struggling to achieve its potential. The company’s R&D chief admitted to Fierce last year that clinical setbacks for its anti-OX40L-ligand antibody amlitelimab, its oral TNF inhibitor balinatunfib and its Regeneron-partnered IL-33 candidate itepekimab had resulted in a “mixed” 2025.On an earnings call with journalists last week, Sanofi CEO Paul Hudson directly acknowledged that it had been a “bumpy ride” for R&D.“I\'m well aware of the headlines—we had some challenges,” the CEO said at the time.

Sanofi’s investigational drug, with a track record of mixed results in the clinic, has passed a Phase 3 trial in Gaucher disease, but flunked a separate late-stage study in Fabry disease. The French drugmaker said on Monday that venglustat met the primary endpoint in the 43-patient LEAP2MONO study, achieving “statistically significant improvements” in neurological symptoms of type 3 Gaucher disease at 52 weeks compared with standard-of-care enzyme replacement therapy (ERT). But in Fabry disease, the drug failed to significantly improve certain pain outcomes versus placebo in a separate Phase 3 trial called PERIDOT that enrolled 122 patients. Sanofi said that improvements in neuropathic and abdominal pain were seen in both arms of the study. The company is analyzing the data further and expects to share it at a future medical meeting. In the Gaucher disease trial, neurological improvements were measured using two scales called the Scale for Assessment and Rating of Ataxia (SARA) modified total score and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). SARA looks at signs of muscle coordination, like gait and stance, while RBANS measures cognitive symptoms, including memory and attention. Venglustat also matched ERT on three non-neurological secondary endpoints in LEAP2MONO — change in spleen volume, liver volume and hemoglobin levels. Detailed results from the Gaucher disease study will be presented at the WORLDSymposium in San Diego this week. Venglustat is a glucosylceramide synthase inhibitor that can cross the blood-brain barrier. In 2019, Sanofi noted the drug has pipeline-in-a-pill potential because it could treat three distinct categories of disease — lysosomal storage disorders, ciliopathies and synucleinopathies. But the company stopped working on venglustat for Parkinson’s in early 2021 after the drug flunked a Phase 2 trial . Later that year, it nixed a pivotal trial in autosomal polycystic dominant kidney disease after an independent review showed little difference between treatment and placebo arms. Sanofi’s efforts in Fabry disease are still alive, however. The company is testing venglustat’s effects on left cardiac ventricular mass index in Fabry patients in a third Phase 3 trial called CARAT.