Gain Therapeutics (NASDAQ:GANX) highlighted early clinical and biomarker findings from the first 90 days of its ongoing Phase 1b open-label study evaluating GT-02287 in people with Parkinson’s disease, with management and invited experts focusing on evidence that the drug may modulate glucocerebrosidase (GCase) activity in the brain and reduce glucosylsphingosine, a lipid implicated in disease biology.
Early 90-day clinical readout and study design
President and CEO Gene Mack said the company reported that patients completing the first 90 days of treatment experienced an average improvement of 2.2 points on the combined MDS-UPDRS Part 2 and Part 3 scores. Mack noted that earlier data from the first nine patients suggested a slightly larger improvement, but he said the updated 2.2-point result from 15 patients was “more in line with what we would expect at this stage” given the drug’s proposed mechanism.
Chief Medical Officer Jonas Hannestad provided additional detail on trial conduct and the analysis set. The Phase 1b study includes a 90-day Part 1 (open-label dosing with GT-02287 for all participants) followed by an optional nine-month Part 2 extension (for a total of 12 months). Hannestad said:
- 27 participants were screened, 21 were enrolled, and 19 completed Part 1.
- 15 of the 19 who completed Part 1 elected to continue into the extension.
- Two participants discontinued Part 1 due to adverse events (described as a “variety of adverse events”).
For the MDS-UPDRS analysis, Hannestad said four participants were excluded: two were alpha-synuclein negative at baseline and two were assessed in an “off-state” (without symptomatic dopaminergic support). In the evaluable group, he broke down the 2.2-point combined improvement as 0.6 points on Part 2 and 1.6 points on Part 3. He also noted that among 13 of the 15 evaluable patients, the average improvement was about four points, with two potential outliers the company is continuing to monitor.
Why the company emphasized glucosylsphingosine
The event centered on whether GT-02287 is engaging the intended biology in the central nervous system. Mack said the company believes it has evidence that GT-02287 modulates GCase activity in the brain, and he emphasized newly generated evidence suggesting that modulation may lead to downstream reduction of glucosylsphingosine, described as a substrate implicated in the pathophysiology of Parkinson’s disease and Gaucher disease.
Invited speaker Dr. Roy Alcalay, Chief of the Movement Disorders Division at Tel Aviv Sourasky Medical Center, reviewed the GBA/GCase pathway and argued that glucosylsphingosine may be a more useful biomarker than glucosylceramide. He cited a published study involving venglustat, which reduced glucosylceramide in plasma and cerebrospinal fluid (CSF) but did not demonstrate meaningful benefit on MDS-UPDRS measures. Alcalay said this indicates glucosylceramide levels are not correlated with Parkinson’s outcomes and that “the money is in glucosylsphingosine.” He added that in Gaucher disease, clinicians use glucosylsphingosine as a biomarker to monitor treatment response because glucosylceramide levels can fluctuate and may not correlate with severity.
Biomarker results in CSF and blood
Hannestad said the company is focusing on glucosylsphingosine in CSF because Parkinson’s is a brain disease and plasma levels may not reflect what is happening in the CNS. He stated that, in the company’s dataset, plasma and CSF glucosylsphingosine levels did not correlate.
In CSF, Hannestad reported that participants who had elevated glucosylsphingosine at baseline showed substantial decreases after 90 days of treatment. Participants with baseline levels in what the company believes is the normal range did not show changes, which he framed as consistent with there being no need to lower already normal levels.
Hannestad said a similar pattern was observed in blood: glucosylsphingosine decreased where levels were elevated, with one exception tied to “a certain mutation” believed not to be responsive to the drug’s mechanism, which did not show the same change. He said this mutation-specific observation will be explored further.
Linking biomarkers to symptoms and next steps
Hannestad also described an apparent relationship—based on small numbers—between biomarker changes and clinical scores: patients with decreases in CSF glucosylsphingosine tended to show improvements in UPDRS, while those without decreases did not. In the Q&A, he cautioned that conclusions are limited by sample size but said the pattern could indicate subacute functional benefit from reducing glucosylsphingosine in the brain.
On patient selection for future trials, Hannestad said the company currently lacks broad reference data for CSF glucosylsphingosine because methods to measure the lipid at low levels have only recently become available. He noted that datasets such as the Michael J. Fox Foundation’s PPMI are measuring it, which could enable future correlations with disease characteristics. If the company’s findings hold, he said it is possible future studies could select or stratify patients based on baseline CSF glucosylsphingosine levels.
Regarding regulatory strategy, Hannestad said it is too early to expect the FDA to accept glucosylsphingosine as a surrogate endpoint, and he said the company currently assumes it would need traditional UPDRS-based Phase 3 studies for approval. He added that Parkinson’s programs have not yet had FDA acceptance of other biomarkers, such as dopamine transporter imaging or alpha-synuclein in CSF, as surrogate endpoints.
Mack said Gain has filed an IND and begun discussions with the FDA, and he pointed to plans to initiate a Phase 2 study in 2026, while continuing safety, tolerability, and biomarker analyses in the Phase 1b extension. The company said final Phase 1b results are expected in the second half of the year, around September, with potential updates along the way.
About Gain Therapeutics (NASDAQ:GANX)
Gain Therapeutics, Inc (NASDAQ: GANX) is a clinical-stage biopharmaceutical company focused on precision therapeutics for neurodegenerative and rare diseases. The company leverages its proprietary allosteric modulation platform, AlphaTarget, to discover and optimize small molecule modulators that bind to non-active sites on target proteins. By correcting protein folding and function, Gain aims to provide disease-modifying treatments with improved selectivity and reduced off-target effects.
Gain’s lead clinical candidate, GT-022, is being developed for Gaucher disease, a rare lysosomal storage disorder characterized by deficient enzyme activity.
