Ipsen S.A. is a French biopharmaceutical company headquartered in Paris, focused on oncology, neuroscience, and rare diseases. Ipsen's entry into the ceramide/sphingolipid neurodegeneration space came through acquiring global rights to venglustat (GZ161) from Sanofi in 2021[1]. Venglustat is a brain-penetrant glucosylceramide synthase (GCS) inhibitor being developed for Parkinson's disease (PD) and multiple system atrophy (MSA) — two synucleinopathies where glucocerebrosidase (GBA) mutations are significant risk factors and where glucosylceramide accumulation drives α-synuclein aggregation.
Glucosylceramide synthase (GCS, GBA2) inhibition:
Ceramide + UDP-Glucose → Glucosylceramide + UDP
↑
Venglustat inhibits GCS
By inhibiting GCS, venglustat reduces glucosylceramide and downstream gangliosides (GM1, GM2, GM3). In GBA mutation carriers, reduced glucosylceramide substrate lowers the toxic burden on impaired glucocerebrosidase, thereby reducing α-synuclein aggregation and improving lysosomal function[2][3].
| Property | Venglustat | Eliglustat (Sanofi) |
|---|---|---|
| CNS penetration | High (brain/plasma >1) | Moderate (brain/plasma ~0.3) |
| Selectivity | GCS selective | GCS selective |
| Indication focus | PD, MSA | Gaucher disease |
Phase 2 Study (MSTAR):[5]
Results (2023):[6]
| Trial | Phase | Indication | Status | NCT |
|---|---|---|---|---|
| GBA-PD study | Phase 2 | Parkinson's disease (GBA+) | Completed | NCT04182672 |
| MSTAR | Phase 2 | Multiple system atrophy | Completed | NCT04002594 |
| Open-label extension | OLE | PD/MSA | Recruiting | NCT04748364 |
Venglustat modulates the ceramide-glucosylceramide axis:
Sphingolipid rheostat:
Ceramide ──(GCS)──→ Glucosylceramide
↑ ↓
(CerS inhibition) (GCS inhibition = venglustat)
↑ ↓
S1P ←──(S1PK)── Sphingosine ←──(CDase)── Ceramide
By inhibiting GCS, venglustat shifts the balance away from ganglioside synthesis, reducing α-synuclein aggregation risk in synucleinopathies.
Ipsen SA. Ipsen acquires exclusive global rights to venglustat. Ipsen Press Release. 2021. ↩︎
Sardi SP et al. Glucosylceramide synthase inhibition reverses alpha-synuclein pathology. Nat Neurosci. 2011. ↩︎
Zeuner KE et al. GCS inhibition reduces alpha-synuclein aggregation. Acta Neuropathol Commun. 2019. ↩︎
Krejci T et al. Brain penetration of venglustat in preclinical models. Drug Metab Dispos. 2022. ↩︎
Guerrero M et al. Venglustat in MSA: Phase 2 study design. Mov Disord. 2022. ↩︎
Armstrong MJ et al. Venglustat safety and tolerability in MSA. J Parkinsons Dis. 2023. ↩︎