Gain Therapeutics (NASDAQ:GANX) is developing oral small-molecule drugs aimed at neurodegenerative diseases, with its lead focus on Parkinson’s disease, company CEO Gene Mack said during a fireside chat at a Roth Capital Partners conference. The discussion, hosted by Roth managing director and senior biotech analyst Boobalan Pachaiyappan, centered on Parkinson’s unmet need, the company’s drug-discovery platform, early clinical findings for lead candidate GT-02287, and next steps toward a Phase 2 trial.
Focus on disease biology beyond symptomatic relief
Mack said current Parkinson’s treatments are largely limited to symptomatic approaches such as L-DOPA and related therapies, and that Gain’s goal is to “get to the biology” driving disease progression. He described the company’s approach as aiming to create a “backbone of therapy” that starts with disease biology and could, if successful, make symptomatic therapy more effective and longer lasting.
Magellan platform and the GT-02287 approach
Mack said Gain’s Magellan platform was built to automate complex binding-kinetics calculations used in small-molecule design. He emphasized that the company is not seeking to inhibit protein activity by targeting an active site, but instead to bind in ways that stabilize proteins and promote activity, a “gain of function” approach.
GT-02287 targets the enzyme glucocerebrosidase (GCase), which Mack described as important to Parkinson’s pathophysiology, including in patients with GBA1 gene mutations where GCase may be misfolded or dysfunctional. He said the company has shown it can stabilize the protein and help it traffic within cells so it can carry out maintenance functions, including in the lysosome and mitochondria.
Mack also noted that decreased GCase activity is not limited to patients with GBA1 mutations, suggesting that idiopathic Parkinson’s patients could also potentially benefit from increased GCase activity. He described GCase as an enzyme involved in breaking down lipid substrates that can otherwise build up in a toxic manner.
Clinical update: safety and biomarker signals
Pachaiyappan and Mack discussed Gain’s clinical path, starting with a healthy-volunteer study and moving into an open-label Phase 1b study in Parkinson’s patients, including both idiopathic Parkinson’s disease (IPD) and GBA1-PD patients. Mack referenced a 90-day dataset that included biomarker analysis, presented at the ADPD conference, and said additional readouts at later timepoints are planned, including day 270 data expected in the second half of the year.
In healthy volunteers, Mack said the program focused on safety and tolerability and reported some nausea. He added that nausea did not appear in the Parkinson’s patient population. He described GCase as “finicky,” influenced by circadian rhythms and diet, making controlled assessment easier in a healthy-volunteer setting than in longer patient studies.
Mack said Gain has demonstrated central target engagement “from multiple perspectives” and pointed to downstream biomarker changes as evidence of a gain-of-function effect. He highlighted cerebrospinal fluid (CSF) reductions in a lipid marker tied to the GCase pathway:
- Glucosylsphingosine in CSF: Mack said elevated levels are associated with Parkinson’s and that GT-02287 lowered this marker in patients, which he framed as evidence of affecting disease biology.
- DOPA decarboxylase: He said this enzyme is elevated in patients with high CSF glucosylsphingosine and “also comes down” in the presence of GT-02287.
Mack said clinicians at ADPD were skeptical about early clinical outcomes given the short duration of follow-up in a slow-moving disease, but were not skeptical about the biomarker data and wanted to see more.
Clinical outcomes and expectations for longer follow-up
On clinical measures, Mack said the gold standard for approval is improvement on MDS-UPDRS (Unified Parkinson’s Disease Rating Scale) endpoints. He characterized the Phase 1b study as signal-finding and said its primary intent was to show biological evidence that the GCase pathway is being impacted, which he said the company achieved.
For the day 270 readout, Mack said the company is looking for durability and stability in UPDRS scores, emphasizing that the goal is to stop decline rather than “flashy” improvements. “We cannot repair dead brain tissue,” he said, but argued that slowing progression—patients “not getting any worse”—could be meaningful.
Phase 2 planning and FDA discussions
Mack said the company is in discussions with the U.S. Food and Drug Administration and expects to start Phase 2 in the third quarter of this year, with U.S. trial sites. He said dialogue with the FDA had been disrupted earlier in the year due to a government shutdown and a change in reviewers, and that the agency requested additional preclinical toxicology data, which Gain submitted earlier in the month. He said the company expects feedback “in a couple weeks.”
On patient selection, Mack said the company wants to keep options open and, for now, plans to enroll an all-comers Parkinson’s population rather than pre-select based on CSF glucosylsphingosine levels, in part because CSF testing requires a lumbar puncture. He said roughly half of patients with usable CSF samples in the Phase 1b study had elevated glucosylsphingosine levels, and he described plans to stratify Phase 2 patients based on high versus low levels.
Mack said CSF collection would also enable an alpha-synuclein seeding assay to confirm Parkinson’s diagnosis. He added that Gain does not yet fully understand how the high/low glucosylsphingosine dynamic ties to GBA1 genetic status, describing that as part of what Phase 2 should clarify.
For endpoints, Mack said the Phase 2 study will focus on MDS-UPDRS Part 2 and Part 3, with an emphasis on Part 2 as the “gold standard” for approval supported by Part 3.
He also said the Phase 2 trial is expected to enroll over 100 patients and that the company will try to enrich for a higher-than-background proportion of GBA1 patients through advocacy and genetic-profiling groups, noting that approximately 10% to 15% of Parkinson’s patients have a GBA1 mutation and that a similar proportion was seen in Phase 1b.
In a brief discussion of pipeline beyond GT-02287, Mack said Gain has backup molecules that also target GCase and are structurally distinct. He described GT-04686 as a follow-on program that could potentially offer advantages such as higher potency and convenience, framing the effort as part of lifecycle management.
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.
