Glucocerebrosidase Target Engagement and Therapeutic Plasma and Cerebrospinal Fluid Levels After GT-02287 Administration in Healthy Volunteers.

BACKGROUND

Variants in the GBA1 gene can increase the risk of Parkinson's disease (PD) by reducing glucocerebrosidase (GCase) activity, disrupting lysosomal and mitochondrial function, and increasing alpha-synuclein aggregation. The molecule GT-02287 prevents misfolding of GCase and ameliorates downstream pathway abnormalities.

OBJECTIVES

To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GT-02287.

METHODS

The safety, tolerability, and plasma pharmacokinetics of single and multiple oral doses were evaluated in 73 healthy volunteers, and GT-02287 levels in cerebrospinal fluid (CSF) and GCase activity in blood were measured.

RESULTS

All dose levels tested were safe and generally well-tolerated. No serious or severe adverse events occurred. The most common events were nausea and headache. Plasma and CSF exposures were within the projected therapeutic range, and GCase activity increased after GT-02287 administration.

CONCLUSIONS

GT-02287 was safe and well-tolerated in healthy volunteers. Plasma and CSF levels were consistent with levels in rodents that modulate PD biology. © 2025 International Parkinson and Movement Disorder Society.