Glucocerebrosidase (GCase) is a lysosomal enzyme involved in sphingolipid homeostasis. While heterozygous loss-of-function mutations in GBA1 result in decreased GCase activity and represent a major risk factor for the development of PD (GBA-PD), a reduction in GCase activity has been linked to alpha-synuclein (aSyn) misfolding and lysosomal dysfunction also in iPD.

VQ-101 is a fully CNS penetrant allosteric activator of both mutated and wild-type forms of lysosomal GCase and has shown to significantly increase GCase activity in GBA-PD patients. Preclinically, GCase activation by VQ-101 of at least 50% demonstrated significant blockage of misfolded aSyn accumulation in GBA-PD-derived dopaminergic neurons.

Seventy-two individuals with iPD or GBA-PD were recruited in a Ph1b study and randomized to VQ-101 or placebo for 28 days and then invited to participate in an open-label extension for 8 additional weeks. GCase activation was assessed in fresh blood samples using an analytically validated live-cell GCase assay at the start of dosing and at several time points during the dosing period.

Thirty-six iPD patients enrolled in the study at doses of 150 mg/day (n=20) and 300 mg/day (n=16). VQ-101 was generally safe and well tolerated and showed full CNS penetrance. Activation of lysosomal GCase of >50% was observed in individuals with iPD and was sustained through the course of dosing.

Consistent with previously reported data in GBA-PD, VQ-101 confirmed its favorable safety profile, full CNS penetrance, and sustained activation of GCase in iPD individuals. These results, together with preclinical data, support the potential for VQ-101 to slow or stop the progression of PD by increasing lysosomal GCase activity, restoring lysosomal function, and consequently blocking the accumulation of misfolded aSyn.