Understanding the Therapeutic Potential of GT-02287 in GBA-Parkinson Disease

Jonas Hannestad, MD, PhD

Parkinson disease (PD) is a neurodegenerative disease with multifactorial etiologies resulting from a complex interplay of genetic and environmental factors. Although the etiology of PD has been considered mostly idiopathic, recent studies have suggested a strong influence of genetic factors on the risk of PD, with a heritability of up to 30%. Among 90 susceptibility loci linked to the risk of PD, GBA1 variants, the most common genetic risk factor, have recently gained attention, with drug development accelerating.

At the 2024 International Congress of Parkinson’s Disease and Movement Disorders, held September 27 to October 1, in Philadelphia, Pennsylvania, Gain Therapeutics presented data from a phase 1 first-in-human study assessing its investigational agent GT-02287 in healthy volunteers. The agent, an orally-bioavailable, brain-penetrant molecule, is in development for patients with PD with or without a GBA1 mutation. In the study, healthy men (n = 40) and women (n = 33) were randomly assigned 3:1 to either GT-02287 or placebo for a 14-day period.

All told, the therapy was safe and generally well tolerated at single (2.4, 4.8, 7.7, 10.0, and 15.0 mg/kg) and multiple (4.8, 7.7, 10.0, and 13.5 mg/kg) doses, with nausea and headache as the most common AEs. Most notably, the pharmacokinetic profile of GT-02287 was linear across the tested dose ranges, and plasma exposures were within the projected therapeutic range. Overall, glucocerebrosidase (GCase) activity increased in participants who received the active therapy but not in those on placebo, further supporting its target engagement.

Shortly after the meeting, Jonas Hannestad, MD, PhD, chief medical officer at Gain, sat down with NeurologyLive® to discuss the results, and the promise behind GT-02287 in GBA-PD. In the conversation, Hannestad explained the origins of the investigational agent and the role of a computational platform. Hannestad also talked about the study’s conduct, the most notable safety findings, and the next steps for a phase 1b study. He stressed that the goal is to explore whether GT-02287 could benefit both GBA1 mutation carriers and those with sporadic PD, as the pathways overlap in both groups.

NeurologyLive: What makes GT-02287’s mechanism of action unique to treat PD?

Jonas Hannestad, MD, PhD: GT-02287 is a small molecule developed in-house at Game Therapeutics. It started with a computational platform the company developed several years ago, which they used to find drugs or small molecules that could bind to different enzymes. One of these enzymes was GCase, the enzyme mutated in Gaucher disease. This drug came from that computational screen, and after it was synthesized and tested in vitro and in vivo, it was found to have beneficial effects in systems where GCase is mutated or deficient.

Initially, we considered developing this compound for Gaucher disease, but due to the existing therapies, we decided to focus on Parkinson’s disease (PD). About 10% of people with Parkinson's have a mutation in the GBA1 gene, which is also mutated in Gaucher disease. A mutation in one allele increases the risk of developing Parkinson’s by three to five times. So we’re targeting this population, but we also believe the compound could work for people with PD who don't have the GBA1 mutation. That’s the origin story of this compound.

How was the phase 1 study conducted, and what were the greatest takeaways from the recent findings?

The phase 1 study we conducted was a fairly standard study in healthy volunteers. It had a single ascending dose part and a multiple ascending dose part, and its main goals were to evaluate the safety and tolerability of the compound. Before moving into humans, we had done numerous in vitro and in vivo studies to test for potential risks.

I think two interesting aspects of this study were that we included both men and women and allowed for a wider age range than usual. Many phase 1 studies focus solely on men to avoid concerns about pregnancy, but we wanted to get a broader sense of the tolerability profile. We also included participants up to 65 years old, with about 15% over 50, which is important since Parkinson’s predominantly affects middle-aged and older individuals.

As for the findings, we dosed both the single and multiple parts up to the levels we wanted to test, and we didn’t encounter any dose-limiting toxicities. The compound was well tolerated overall, though there was some nausea at higher doses, but it was mild, and no one vomited. We didn’t see any concerning safety signals, such as ECG abnormalities or issues with vital signs. Pharmacokinetically, the drug is given orally, absorbed well, and reached plasma levels in the range where we believe it needs to be based on animal data.

Crucially, we confirmed the drug gets into the brain by measuring its levels in cerebrospinal fluid (CSF). We also measured the activity of the GCase enzyme, and those who received the drug showed an increase in enzyme activity compared to placebo.

What does the phase 1b study look like?

The data from the phase 1 study in healthy volunteers is valuable, but there are some things we couldn’t do, like measure disease-related biomarkers. So, the phase 1b study will focus on measuring various biomarkers in people with Parkinson’s. These include lysosomal function, mitochondrial function, inflammation, GCase activity, and synuclein aggregation. We’ll also assess safety and tolerability in an older population—mostly people between 50 and 75—since Parkinson’s primarily affects that group.

We’ll enroll a mix of patients with GBA1 mutations and those with sporadic Parkinson’s to compare biomarker responses between the two groups. This will give us more insight into how the drug works in both populations.

From an organizational standpoint, what are the considerations when designing a trial for such a novel mechanism?

One key decision is whether this compound should be developed primarily for people with GBA1 variants or for a broader population, as the pathways that are abnormal in both GBA1-related and sporadic Parkinson’s overlap to a great extent. As a company, we want to develop the drug in a way that allows us to offer it to as many patients as possible if it’s effective.

The first step is a small phase 1b study to assess tolerability and gather initial biomarker evidence. The next step will likely be a phase 2 study, where we may focus on one population or include both. Since this is potentially a disease-modifying drug, demonstrating its effects is more challenging than with symptomatic treatments, which require larger and longer trials. These are the discussions we’re currently having as we move forward.