Gain Therapeutics shared important updates at the AD/PD 2025 International Conference on Alzheimer’s and Parkinson’s Diseases. The company presented new preclinical data as well as detailing the design of its ongoing Phase 1b study for its lead candidate, GT-02287.
GT-02287: A Promising Approach for Parkinson’s Disease
GT-02287, is in clinical development for the treatment of Parkinson’s disease (PD) with or without a GBA1 mutation. The orally administered, brain-penetrant small molecule is an allosteric enzyme modulator that restores the function of the lysosomal enzyme glucocerebrosidase (GCase) which becomes misfolded and impaired due to mutations in the GBA1 gene, the most common genetic abnormality associated with PD, or other age-related stress factors.
Preclinical models of both GBA1-associated and idiopathic Parkinson’s disease (iPD) showed:
- Rescue of motor deficits and improvement in complex behaviors (e.g., nesting)
- Long-lasting benefits even after drug withdrawal, suggesting disease-modifying potential
- Reductions in key biomarkers of neurodegeneration and inflammation such as:
- Aggregated α-synuclein
- LAMP-1 (lysosomal marker)
- IRE-1 (ER stress marker)
- Miro1 (mitophagy marker)
- Phospho-Tau and Iba-1
These data further support GT-02287 as a next-generation therapeutic candidate with potential to modify the course of PD rather than merely treat symptoms.
Why GBA1 Matters in Parkinson’s
Variants in GBA1, the gene that encodes GCase, are the most common genetic risk factor for PD. These mutations lead to disrupted lysosomal function, increased α-synuclein aggregation, and early-onset, faster-progressing PD with more severe cognitive symptoms. However, even idiopathic PD patients without GBA1 mutations often show GCase deficits, suggesting a broader relevance for targeting GCase in the PD population.
Phase 1b Study: Design and Objectives
Gain’s Phase 1b clinical study is currently enrolling up to 20 participants with Parkinson’s disease, including both GBA1 variant carriers (GBA1-PD) and patients with sporadic (idiopathic) PD. The study aims to characterize safety, pharmacokinetics (PK), and pharmacodynamics over a 90-day treatment period.
Study Overview:
- Type: Open-label, multi-site clinical study
- Dose: 13.5 mg/kg/day (adjustable between 11.3–15.0 mg/kg)
- Duration: 90 days of treatment + 15-day follow-up
- Key Criteria:
- Ages 30–85
- Diagnosed PD (≤7 years from diagnosis)
- Modified Hoehn & Yahr stage 1 to ≤3
- No significant motor fluctuations or dementia
- No LRRK2 or other known pathogenic mutations aside from GBA1
What the Study Measures
Primary Endpoint
- Safety and tolerability via adverse events, labs, ECGs, vitals, and neurological exams
Secondary Endpoints
- Single-dose and steady-state PK including Cmax, Tmax, AUC, and accumulation ratio
Exploratory Endpoints
- Pharmacodynamic response in key biomarkers:
- CSF and blood-based markers:
- GCase protein levels
- Glucosylceramide (GlcCer) and Glucosylsphingosine (GlcSph)
- α-synuclein (total, aggregated, and phosphorylated)
- Mitochondrial and lysosomal markers
- Inflammatory cytokines
- CSF concentration of GT-02287 after 12 weeks
- Clinical outcomes over 90 days using scales such as:
- MDS-UPDRS
- Montreal Cognitive Assessment (MoCA)
- PDQ-39 (Quality of Life)
- GDS-15 (Depression)
- Schwab & England ADL
- CSF and blood-based markers:
These data will directly inform the design of a Phase 2 randomized, double-blind, placebo-controlled study planned for the second half of 2025.
What’s Next?
- Biomarker readout from currently enrolled participants: mid-2025
- Full Phase 1b data (after 90-day treatment): Q4 2025
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