Agalsidase Beta

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 announced Monday mixed results from a pair of pivotal studies of venglustat in two rare lysosomal storage disorders, with the oral glucosylceramide synthase inhibitor (GCSi) recording a hit in type 3 Gaucher disease (GD3) and a miss in Fabry disease. The contrasting outcomes are the latest to emerge from the company's late-stage pipeline, following differing results earlier this year from the investigational OX40-ligand-blocking monoclonal antibody amlitelimab in two atopic dermatitis trials.The Phase III LEAP2MONO study randomised 43 adult and paediatric patients with neurological manifestations of GD3 to receive venglustat once-daily or enzyme replacement therapy (ERT). The trial's primary endpoints were change in Scale for Assessment and Rating of Ataxia (SARA) modified total score and change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total scale index score, with key secondary goals including percent change in spleen volume, liver volume and platelet count, as well as change in haemoglobin levels.Results showed that venglustat demonstrated statistically significant improvements in neurological symptoms as measured by both SARA and RBANS at week 52 compared to ERT. Sanofi added that the therapy also achieved three out of the four key secondary endpoints, performing as well as ERT on non-neurological outcomes, including changes in spleen volume, liver volume and haemoglobin levels.Regulatory filings in GD3"What excites us most is the potential to address critical unmet medical needs. A daily pill could make a serious difference for Gaucher patients facing neurological challenges," said Houman Ashrafian, head of R&D at Sanofi. The company indicated that based on the results, it will pursue global regulatory filings for venglustat in GD3.Sanofi currently markets the injectable therapy Cerezyme (imiglucerase) for Gaucher disease, as well as the oral drug Cerdelga (eliglustat) for those with type 1 disease. The drugmaker's portfolio also includes the injectable therapy Fabrazyme (agalsidase beta) for Fabry disease. However, the latest results dent its hopes of adding an oral Fabry disease therapy to its arsenal.Fabry setbackThe Phase III PERIDOT study randomised 122 patients aged 16 years and older with Fabry disease to receive venglustat or placebo. Sanofi noted that the trial failed to hit its primary endpoint of percent change from baseline on patient-defined most bothersome symptoms, as assessed by the Fabry Disease Patient-Reported Outcome (FD-PRO) instrument.According to the company, reductions in neuropathic and abdominal pain were observed in both study arms. Additional analyses of the data are ongoing, while the late-stage CARAT trial evaluating the effect of venglustat on left cardiac ventricular mass index in men and women with Fabry disease is ongoing.Findings from both LEAP2MONO and PERIDOT are scheduled to be presented this week at the annual WORLDSymposium.Aside from the positive results in GD3, Venglustat, which works by reducing the abnormal accumulation of sugar-and-fat molecules in cells and organs, has racked up a number of study failures. In 2024, Sanofi disclosed that the Phase III AMETHIST trial for GM2 gangliosidosis was discontinued based on “the absence of positive trends” for clinical endpoints, adding to a pivotal Phase II/III study setback in autosomal dominant polycystic kidney disease and another in Parkinson's disease with GBA mutations.