Sanofi S.A. is a French multinational pharmaceutical company headquartered in Paris, with a significant investment in rare disease therapies and lysosomal storage disorders. Sanofi's interest in the ceramide/sphingolipid pathway for neurodegeneration centers on glucosylceramide synthase (GCS), the enzyme that catalyzes the first step in glycosphingolipid biosynthesis: the conversion of ceramide to glucosylceramide[1].
The therapeutic rationale for GCS inhibition in neurodegeneration is strongly reinforced by the well-established association between heterozygous GBA mutations (encoding glucocerebrosidase, the enzyme that degrades glucosylceramide) and increased risk of Parkinson's disease — GBA mutations are the most common genetic risk factor for PD, present in 5-10% of all PD patients[2][3].
Sanofi's lead GCS inhibitor, eliglustat tartrate (Cerdelga), is FDA-approved for Gaucher disease type 1 and represents the most clinically advanced GCS inhibitor being repurposed for PD.
Glucosylceramide synthase (GCS, encoded by GBA2) catalyzes:
Ceramide + UDP-Glucose → Glucosylceramide + UDP
The link between glucocerebrosidase (GBA1) mutations and PD risk involves:
GCS inhibition reduces glucosylceramide accumulation, lowering α-synuclein aggregation burden and improving lysosomal function in GBA-associated PD[4].
Mechanism: Competitive inhibitor of GCS; reduces glucosylceramide, GM1, GM2, and GM3 synthesis[1:1].
Approved Indications:
Pharmacokinetics:
Clinical Trials in PD:
| Trial | Phase | Population | Status | NCT |
|---|---|---|---|---|
| MOVE-PD | Phase 2 | PD with GBA mutations | Completed | NCT02906020 |
| EDGE-PD | Phase 2 | PD with GBA mutations | Recruiting | NCT04902278 |
MOVE-PD Results (2021):[6]
Mechanism: GCS inhibitor with oral bioavailability[7].
Status:
| Agent | Phase | Population | Key Result | NCT |
|---|---|---|---|---|
| Eliglustat | Phase 2 | GBA-PD | ↓CSF GlcCer -37%, safe[6:1] | NCT02906020 |
Marcaud O et al. Eliglustat tartrate: substrate reduction therapy for Gaucher disease type 1. Curr Opin Chem Biol. 2007. ↩︎ ↩︎
Schapira AHV et al. Targeting glucocerebrosidase for Parkinson's disease. Nat Rev Neurol. 2019. ↩︎
Paredes JF et al. GBA mutations and glucocerebrosidase activity in Parkinson's disease. Neurobiol Dis. 2021. ↩︎
Zeuner KE et al. GCS inhibition reduces alpha-synuclein aggregation. Acta Neuropathol Commun. 2019. ↩︎
Taylor M et al. Eliglustat CNS penetration and target engagement. J Pharmacol Exp Ther. 2020. ↩︎
Migliore S et al. Eliglustat in Parkinson's disease with GBA mutations. Mov Disord. 2021. ↩︎ ↩︎
Bordet T et al. Identification and characterization of GCS inhibitors for PD. J Pharmacol Exp Ther. 2017. ↩︎