NEW YORK – Gain Therapeutics is exploring whether a drug targeting the enzyme glucocerebrosidase, or GCase, could treat Parkinson's disease not only for patients with certain mutations in the gene that encodes the protein but also for those with sporadic disease.
The Bethesda, Maryland-based biotech is preparing to launch by year-end a Phase Ib trial to begin testing the drug in patients with Parkinson's, after completing enrollment in a Phase I trial of healthy volunteers. The Phase Ib trial will include a mix of patients with Parkinson's associated with mutations in the GBA1 gene and those with sporadic Parkinson's. Gain Therapeutics hasn't decided yet whether it will seek regulatory approval for the experimental treatment specifically in GBA1-associated Parkinson's or also in sporadic Parkinson's. However, it is hoping for success in both populations in upcoming clinical trials, according to Jonas Hannestad, the company's chief medical officer.
Gain Therapeutics has been developing GT-02287, a daily oral allosteric small molecule and its lead candidate, as a drug to slow or potentially halt progression of Parkinson's by restoring function of GCase in the brain. GCase is a lysosomal enzyme that can become dysfunctional due to certain mutations in the GBA1 gene, which also increase a carrier's risk of developing Parkinson's. It's not clear exactly how GBA1 genetic variants lead to Parkinson's, but it may be related to the protein produced by the mutated gene's inability to break down substances such as alpha-synuclein, a hallmark of the chronic, progressive neurodegenerative disease.
Most cases of Parkinson's are sporadic or idiopathic, meaning the cause is unknown. However, there are some genetic risk factors like GBA1 mutations, which are the most common and occur in up to 15 percent of Parkinson's patients, though estimates vary. These variants don't cause the disease, but Parkinson's patients with GBA1 mutations tend to suffer from earlier onset and faster disease progression.
There's a need for new Parkinson's treatments, particularly disease-modifying treatments, Hannestad said. There isn't a cure for Parkinson's, and standard care typically involves taking drugs to increase or supplement dopamine in the brain to alleviate symptoms.
While these drugs are effective at controlling symptoms, particularly during early stages of the disease, the underlying disease processes continue to advance, he added. "Many good treatments have been approved for Parkinson's," he said, but they only address the symptoms. Hannestad is hoping GT-02287 will be one of the first disease-modifying treatments for Parkinson's.
Gain Therapeutics this summer finished dosing healthy volunteers with GT-02287 in a randomized-controlled Phase I trial that launched in Australia late last year. Investigators observed favorable safety and tolerability in the clinical trial, as well as a 53 percent increase in GCase activity among those who received GT-02287 for two weeks.
In the open-label Phase Ib trial that Gain Therapeutics expects to kick off before the end of 2024, Parkinson's patients will receive GT-02287 for three months as investigators continue to evaluate the drug's safety, Hannestad said. Gain Therapeutics also plans to assess biomarkers such as GCase activity, levels of substrates of GCase, and alpha-synuclein aggregation, which would indicate whether the drug is having the intended effect.
For the Phase Ib trial, the company will enroll not only patients with GBA1-associated Parkinson's but also those with idiopathic Parkinson's. The firm is hoping the drug will have activity in those with the idiopathic form of the disease, since GCase can become dysfunctional even in patients without GBA1 mutations due to age-related stress factors and lower GCase activity has been observed in some patients with idiopathic Parkinson's.
There are also many idiopathic Parkinson's patients who don't have decreased GCase activity. Still, Gain Therapeutics is interested in exploring whether increasing GCase can address other underlying issues, such as alpha-synuclein aggregation, lysosomal dysfunction, mitochondrial function, and neuroinflammation. These disease signals have been observed in patients with GBA1-associated Parkinson's and idiopathic Parkinson's, Hannestad said, and the company is investigating whether they could be ameliorated by increasing GCase activity with GT-02287.
"The mechanism, presumably, would work well in people who have a GBA1 variant that's associated with Parkinson's disease," Hannestad said. "But it's also possible this mechanism of action could work in people who don't have a GBA1 mutation."
The company will likely enroll 15 to 30 patients in the Phase Ib trial, although the cohort size isn't yet finalized. In addition to the outcomes researchers are tracking in the entire patient population, the company will also compare GCase activity and other biomarkers between patients with GBA1-associated Parkinson's and sporadic Parkinson's, which will inform future clinical trial designs as the company decides whether to develop GT-02287 in a biomarker-defined or broader, all-comer population.
Gain Therapeutics only recently began publicly discussing GT-02287 as a potential treatment for sporadic Parkinson's. The company had previously described it as an investigational treatment for GBA1 Parkinson's disease but earlier this year began talking about exploring GT-02287 for treating Parkinson's with or without a GBA1 mutation. The company became hopeful about the drug's ability to reach a broader population after seeing its effects in animal models, Hannestad noted.
In preclinical animal models of both GBA1 and idiopathic Parkinson's, investigators reported that GT-02287 improved deficits in motor and cognitive function and prevented the development of new deficits in cognition. These improvements were sustained for more than a week even after the drug was withdrawn, suggesting a disease-modifying effect, the company said. In in vitro models, the drug also reduced biomarkers associated with neurodegeneration such as alpha-synuclein and plasma neurofilament light chain.
Gain Therapeutics isn't the only company looking toward GCase as a target. London-based Spur Therapeutics this week said it plans to develop a gene therapy for patients with GBA1-associated Parkinson's that's designed to deliver an engineered version of GCase. The firm is initiating investigational new drug (IND)-enabling studies in this setting, after the gene therapy showed promising activity in treating Gaucher disease in an ongoing Phase I/II trial. Lexington, Massachusetts-based Voyager Therapeutics earlier this year said it would develop a gene therapy for patients with Parkinson's as well as other conditions linked with GBA1.
Gain Therapeutics, which also has offices in Barcelona and Lugano, Switzerland, has received funding from various groups supporting GT-02287's development in Parkinson's, including the Michael J. Fox Foundation for Parkinson's Research, the Silverstein Foundation for Parkinson's with GBA, and Eurostars-2, an R&D funding program for small and medium-sized companies in Europe. Separately, Gain Therapeutics is also exploring GT-02287 as a potential treatment for Gaucher disease, Alzheimer's disease, and dementia with Lewy bodies, though it hasn't begun clinical testing in any of those indications.
Hannestad said he hopes to wrap up the Phase Ib trial in Parkinson's patients in about a year, so Gain Therapeutics can begin exploring GT-02287's benefits within a larger clinical trial. Last month, the firm said it had submitted a pre-IND package for a placebo-controlled Phase II trial of GT-02287 in Parkinson's that it hopes to discuss with the US Food and Drug Administration. With the agency's blessing, the company could launch that study next year.
Gain Therapeutics plans to continue to study GT-02287's effect in patients with GBA1-associated and sporadic Parkinson's within that trial. "We are hopeful that this drug could be beneficial to all patients with Parkinson's disease," Hannestad said. "But this will ultimately be determined by patient data."