Objective: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of VQ-101 in healthy volunteers (HVs), and individuals with Parkinson’s disease (PD) with and without GBA1 mutations.
Background: Individuals with PD who carry a heterozygous GBA1 mutation (GBA-PD) display a more aggressive clinical presentation of disease. Single GBA1 mutations lead to approximately a 30% reduction in glucocerebrosidase (GCase) activity, resulting in lysosome dysfunction and accumulation of misfolded alpha synuclein (aSyn). In GBA-PD-derived dopaminergic neurons, VQ-101 showed a concentration-dependent increase in lysosomal GCase activity, with 50% GCase activation leading to significant blockage of insoluble aSyn accumulation.
Method: VQ-101 was evaluated in single and multiple ascending doses (up to 14 days in HVs and up to 84 days in participants with PD); target engagement was assessed by measuring lysosomal GCase activity using a validated live cell assay in fresh blood samples. Markers of pathway engagement (sphingolipids) and other PD-associated biomarkers were also explored in CSF and plasma.
Results: This Phase 1a/b study randomized approximately 90 HVs and 70 PD patients to receive VQ-101 or placebo in a double-blind fashion. No serious adverse events or discontinuations due to adverse events (AEs) were reported. Most AEs (97%) were mild in severity, transient and often associated to study procedures rather than study drug. VQ-101 showed full CNS penetrance (Kp,uu,CSF ≥1). Exposures increased with escalating doses and were not influenced by food intake. VQ-101 showed dose-dependent and sustained (>50% activation observed at Ctrough) lysosomal GCase activation following single and multiple doses in both HVs and in individuals with PD.
Conclusion: VQ-101 was well tolerated at all dose levels evaluated in both HVs and participants with PD, with and without a GBA1 mutation. VQ-101 has a favorable CSF and plasma PK profile, supporting once daily oral dosing and demonstrated dose-dependent target engagement. These results, together with preclinical data, support the potential for VQ-101 to slow or stop the progression of PD by increasing GCase activity and blocking the accumulation of misfolded aSyn.
To cite this abstract in AMA style:
M. Facheris, D. Ysselstein, J. van Dervalk, E. Thijssen, L. Pagan, G. Valstar, C. Schotborgh, P. Kremer, M. Hagey, J. Cederbaum, J. Sullivan, K. Hunt, O. Siddiqui. VQ-101, a CNS-Penetrant Small Molecule Allosteric Activator of Glucocerebrosidase (GCase), Demonstrates Favorable Tolerability and Sustained Activation of Lysosomal GCase in Individuals with Parkinson’s Disease [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/vq-101-a-cns-penetrant-small-molecule-allosteric-activator-of-glucocerebrosidase-gcase-demonstrates-favorable-tolerability-and-sustained-activation-of-lysosomal-gcase-in-individuals-with-parkinson/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/vq-101-a-cns-penetrant-small-molecule-allosteric-activator-of-glucocerebrosidase-gcase-demonstrates-favorable-tolerability-and-sustained-activation-of-lysosomal-gcase-in-individuals-with-parkinson/