GCase-Targeting Parkinson Drug GT-02287 Shows Target Engagement, Encouraging Safety in Early-Stage Study

Jonas Hannestad, MD, PHD, chief medical officer at Gain

Newly announced data from a phase 1 study of healthy volunteers showed that treatment with Gain Therapeutics’ GT-02287, a novel glucocerebrosidase (GCase)-targeting therapy in development for Parkinson disease (PD), was safe and well tolerated, with peripheral target engagement demonstrated. To date, the therapy is on track to have patients with PD dosed in the phase 1b portion of the trial, starting later this year.¹

Discovered via Gain’s Site-directed Enzyme Enhancement Therapy (SEE-Tx) drug discovery program, GT-02287 is an orally administered, brain-penetrant small molecule that is designed to restore the function of GCase. In the phase 1 study, which included 72 healthy volunteers, the agent maintained good tolerability up to the highest planned dose levels across all age groups. The PD therapeutic also was shown to be present in the cerebrospinal fluid (CSF), indicating target engagement.

The trial is a randomized, double-blind study that features both a single- (SAD) and multiple-ascending dose (MAD) component. Results showed a favorable safety and tolerability profile at oral doses that led to therapeutic plasma levels, central nervous system exposure, and target engagement, further supporting its potential as a treatment for patients with PD with or without a GBA1 mutation.

"On the heels of this data, we expect to initiate a trial in people with Parkinson’s disease by Q4 2024 with the goal of demonstrating safety and tolerability in patients with Parkinson disease and to obtain proof of mechanism based on relevant biomarkers," Jonas Hannestad, MD, PHD, chief medical officer at Gain, said in a statement.¹ "We anticipate having data from Parkinson’s disease patients by mid-point 2025."

Earlier this year, the company presented data from a different study that highlighted the potential of GT-02287 as a treatment for GBA1-mutated PD. In the study, the company applied its proprietary computational drug discovery platform to the recognition of the orally bioavailable and brain penetrant GT-02287. Investigators then had GCase function, endoplasmic reticulum (ER) stress, and protein quality control assessed in patient derived fibroblasts harboring mutated GCase. Additionally, researchers used a mutated GCase-HaloTag-HEK293 cell-based model to measure GCase transport to the lysosome.²

Presented at the 2024 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD), investigators observed that L44P GCase had an enhanced association with ER chaperones as well as bonded to calnexin and brain ischemic preconditioning to greater extent than N370S through treatment with GT-02287. Notably, L444P GCase triggered an unfolded protein response (UPR) and fibroblasts of L444P GCase showed a higher level of the ER stress marker BiP.

READ MORE: FDA Approves Medtronic’s Deep Brain Stimulation Technology for Asleep Capabilities

Further, in the results, investigators observed that GT-02287 mitigated UPR by reducing BiP levels and other selected UPR markers, inhibiting proteasomal degradation of L444P GCase. All told, this improvement instability facilitated GCase trafficking into lysosomes, where it could process its substrate efficiently for lysosomal and cellular health.

At the time, Joanne Taylor, PhD, senior vice president of research at Gain, told NeurologyLive, "The results imply that, because we can affect each aspect of the disease cascade caused by misfolded GCase, for patients with GBA1-PD, or even patients not carrying a mutation in GBA1 (the gene that encodes GCase) but who also have dysfunctional GCase, as has been shown in cases of idiopathic PD, we can restore neuronal cell health and prevent neuronal cell death, holding out the promise of a disease modifying therapy."

"The next stages of the research are to show that similar mechanisms occur in our animal models of the disease and in patients treated with the compound in clinical trials. We can do this by testing cells and body fluids derived from treated patients, compared with control groups. Confirmation of these mechanisms in patients will confirm the likelihood of our compound being a potential disease-modifying treatment for PD," she added.

Earlier this year, Taylor sat down to discuss some thoughts on GT-02287, its mechanism of action, and implications from the preclinical data. She talked about how GT-02287 aims to address the cellular dysfunctions associated with PD by targeting the GCase. Beyond PD, she spoke about the evidence that suggests GT-02287, might have applications in other neurodegenerative diseases such as Alzheimer disease. In the clip below, she discussed the phase 1 trial, and the biomarkers being studied to detect the agent’s neuroprotective effects in healthy patients.

REFERENCES
1. 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 August 29, 2024. https://finance.yahoo.com/news/gain-therapeutics-announces-positive-topline-113000099.html
2. Gain Therapeutics Presents Data at the AD/PD™ 2024 Conference Demonstrating the Mechanism of Action of GT-02287, its Clinical Stage GCase Regulator for the Treatment of Parkinson’s Disease. News Release. Gain Therapeutics. Published March 5, 2024. Accessed August 29, 2024. https://www.gaintherapeutics.com/index.php/newsroom/press-releases/press-releases-2024/ainherapeuticsresentsataatthe2024onfere20240305050502