Venglustat’s Phase 2/3 Trial Failure Pushes Sanofi to Drop Kidney Disease Program
On June 1st, Sanofi announced that its glucosylceramide synthase inhibitor, venglustat, has flunked a pivotal Phase 2/3 clinical trial in autosomal dominant polycystic kidney disease (ADPKD) – the most common form of inherited kidney disorder. This is a second blow to the drug, which earlier in January suffered a Phase 2 Parkinson’s trial failure. Sanofi has responded to the setback by halting its ADPKD clinical program altogether. In light of the news, its shares had dipped 1.8% on Tuesday.
ADPKD is the leading cause of kidney transplants, affecting about 140,000 patients in the US. It causes the growth of numerous cysts in the kidneys, leading to excruciating pain and other symptoms such as headaches, urinary tract infections, and hypertension. Currently, there are no FDA-approved therapies for this progressive disease; although there are some potentially useful medications that can be used off-label for symptoms management while slowing down its progression.
Venglustat is one of the promising drug candidates that Sanofi wanted to pursue as a potential breakthrough treatment for lysosomal storage disorders (LSDs) together with ADPKD. The French pharma giant has both completed and active studies evaluating the safety and efficacy of venglustat in various late-stage trials for inherited LSDs, Gaucher disease type 3, Fabry disease, and GM2 gangliosidosis. However, with the latest announcement, the door for venglustat in ADPKD is closed.
Sanofi did not reveal full trial results, but interim data from the STAGED-PKD study confirmed that venglustat did not meaningfully reduce the total kidney volume (TKV) growth rate in ADPKD patients – the primary endpoint in stage 1 of the Phase 2/3 study.
Although biomarker data from the study confirmed reductions in the targeted lipid, GL-1, that accumulates in certain cells, it did not lead to reduced cyst growth. This suggests that reduction of glycosphingolipids (GSLs) may not play a significant role in the prevention of kidney cyst growth, and as such, may not be a primary pathway associated with the progression of ADPKD.
Sanofi’s head of R&D, John Reed, M.D., Ph.D., said, “this outcome is not what we hoped for, especially for these patients. However, our research has furthered the scientific understanding of ADPKD by demonstrating that modulating the GSL pathway is insufficient to restore kidney function in adults affected by this disease”.
Albeit failure in the ADPKD study, Sanofi said that the safety profile of venglustat remains consistent with previously reported results, with more than 500 patients treated across all its clinical programs. This would give it hope for evaluating the candidate in a Phase 3 trial in rare LSD GM2 gangliosidosis and Phase 2 studies in Gaucher and Fabry diseases.
Unlike Sanofi’s broad range of enzyme replacement therapies such as Cerdelga, Cerezyme, Myozyme, and Fabrazyme which have to be delivered by injection, venglustat is an orally administered small-molecule drug. This would give the drug a competitive edge in the market, if successful.
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