Brain-Penetrant Molecule GT-02287 Demonstrates Reversal of Glucosylsphinogosine in Parkinson Disease

In a phase 1b trial update from Gain Therapeutics, results revealed that treatment with GT-02287, a small molecule that restores the function of the lysosomal enzyme glucocerebrosidase (GCase), led to decreased glucosylsphingosine (GluSph) in the cerebrospinal fluid (CSF) of patients with Parkinson disease (PD). This change, observed as an exploratory end point of the study, indicates increased GCase activity in the brain, further supporting GT-02287’s target mechanism of action.¹

"We are excited by the unfolding biomarker evidence of GT-02287 activity and central nervous system target engagement,” Gene Mack, president and chief executive officer at Gain, said in a statement.¹ "To our knowledge, GT-02287 is the first GCase modulator to demonstrate a reduction of GluSph in CSF in people with PD, providing downstream evidence of GCase enhancement in the brain. Further, we believe that reduction in brain GluSph levels will have a direct impact on neuronal health and translate to clinically observable improvements."

In this phase 1b study, 21 patients with PD were enrolled, 19 completed the 90-day dosing period, and 15 (79%) chose to continue in the 9-month extension, or part 2, of the study, which is expected to conclude in September 2026. According to Gain, 90 day results revealed a reversal of CSF GluSph in patients who presented with elevated levels coming into the study. Elevated GluSph reflects GCase dysfunction and has been linked to increased α-synuclein aggregation, mitochondrial impairment, and broader neuronal cellular dysfunction.

Clinically, elevated GluSph has gained attention as a potential pharmacodynamic and stratification biomarker in PD, particular for therapies like GT-02287 that target the GCase-lysosome pathway. Higher GluSph levels have been reported in patients with GBA1 mutations compared with non-carriers, and emerging data suggest elevations may also be present in idiopathic PD, albeit at lower levels. In recent years, CSF GluSph has emerged as a marker of target engagement and pathway normalization, with relevance for patient selection, monitoring treatment response, and understanding heterogeneity in PD biology.

READ MORE: FDA Clears Phase 2a Clinical Trial to Test JOTROL in Patients With Parkinson Disease

GT-02287, an orally bioavailable, brain-penetrant small molecule, is designed to allosterically modulate and restore the activity of GCase, which is impaired in patients with GBA1 mutations and may also be relevant in idiopathic PD. With this mechanism of action, the agent is believed to help correct enzyme misfolding and improve lysosomal and mitochondrial health, reducing α-synuclein accumulation and neuroinflammation in preclinical models.

In the update, Mack added that "With a capital position sufficient to fund operations through the end of the Phase 1b extension and year-end 2026, we look forward to presenting longer follow-up from the study at the AD/PD™ conference in March 2026, observing the effect of GT-02287 treatment on MDS-UPDRS scores in the participants who continued in the nine-month extension, and determining the durability of some of the anecdotal signs of early functional improvement."¹

Prior to the phase 1b study, GT-02287 was studied in another phase 1, single- (SAD) and multiple-ascending dose (MAD) trial of healthy volunteers (n = 72). Overall, results showed that the agent had a favorable safety and tolerability profile at oral doses that led to therapeutic plasma levels, central nervous system exposure, and target engagement. The treatment maintained a good tolerability profile up to the highest planned dose, and was also present in CSF, indicating target engagement.²

At the recently concluded International Congress of Parkinson’s Disease and Movement Disorders (MDS), held October 5-9 in Hawaii, interim data from the PD-related phase 1b study was presented. During the meeting, NeurologyLive® sat down with Jonas Hannestad, MD, PhD, chief medical officer at Gain, to discuss the findings and what the data revealed about the therapy’s potential. In the clip below, he spoke about the positive safety data presented, as well as the preceding phase 1 trial in healthy volunteers.

REFERENCES
1. Gain Therapeutics Announces Positive Results in Key Exploratory Endpoint from its Phase 1b Clinical Study of GT-02287 in People with Parkinson’s Disease. News release. Gain Therapeutics. December 18, 2025. Accessed December 19, 2025. https://gaintherapeutics.com/newsroom/press-releases/press-releases-2025/gain-therapeutics-announces-positive-results-in-key-exploratory-endpoint-from-its-phase-1b-clinical-study-of-gt-02287-in-people-with-parkinsons-disease
2. Gain Therapeutics Announces Positive Topline Results from the Phase 1 Clinical Trial of GT-02287, a Novel GCase-Targeting Small Molecule Therapy for Parkinson’s Disease. News release. Gain Therapeutics. August 29, 2024. Accessed December 19, 2025. https://finance.yahoo.com/news/gain-therapeutics-announces-positive-topline-113000099.html