In preclinical models, treatment with GT-02287 restored GCase enzymatic function, reduced aggregated a-synuclein, neuroinflammation and neuronal death, increased dopamine levels, and improved motor function.
According to an announcement from Gain Therapeutics, dosing has commenced for the phase 1 trial of GT-02287, an agent in development for the treatment of GBA1 Parkinson disease (PD), the most common genetic form of PD. So far, 2 healthy individuals have received dosing in the single-center, placebo-controlled study.1
"Initiating first-in-human dosing with GT-02287 is an important milestone for Gain as we enter a new era as a clinical-stage company,” Matthias Alder, chief executive officer, Gain Therapeutics, said in statement.1 "I am very proud of the work accomplished by the entire Gain team to get us to this stage today, and we are eager to advance our understanding of the safety, tolerability and effect of GT-02287 in humans. This represents another major step forward toward providing a treatment for Parkinson’s patients and their families impacted by this devastating disease."
The trial is randomized, double-blind study that features both a single- (SAD) and multiple-ascending dose (MAD) component. Mainly intended to evaluate the safety and tolerability of GT-02287, the study includes several secondary objectives such as the pharmacokinetics of SAD and MAD dose levels to identify a maximum tolerated dose as well as identify recommended doses for further clinical development. The trial will also assess the agent’s impact on the lysosomal enzyme glucocerebrosidase (GCase), which becomes misfolded and dysfunctional because of the GBA1 gene mutation.
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. The agent’s mechanism of action has held up in preclinical models, as investigators have observed restored GCase enzymatic function, reduced aggregated α-synuclein, neuroinflammation and neuronal death, increased dopamine levels, and improved motor function.
Data presented at the 2022 International Parkinson and Movement Disorder Society Annual Meeting indicated that the therapy demonstrated evidence of pharmacological efficacy in conduritol ß-epoxide (CBE) plus α-synuclein preformed fibril (PFF)-treated mice. CBE, a covalent inhibitor that reacts with the catalytic site of GCase and inactivates the enzyme, was used to cause a partial defect of GCase activity comparable to heterozygotes patients with GBA1 PD. Three days following insult with CBE, neuronal cultures were fixed and stained for tyrosine hydroxylase, a marker for dopaminergic neurons. Overall, GT-02287 produced a statistically significant therapeutic effect on both the mesencephalic neurite network and overall lysosomal health.2
"Today marks an important step for Gain in the journey to bring a novel, potentially disease-modifying therapy to patients for whom only symptom-focused therapeutics exist," Robin Ely, MD, director, Integrative and Regenerative Medicine, and director, National Gaucher Foundation, said in a statement.1 "If GT-02287 proves successful in disrupting the disease process in GBA1 Parkinson’s, its fundamental mechanism of action could play a crucial role in addressing various neurodegenerative diseases, including Gaucher, idiopathic Parkinson’s, dementia with Lewy bodies, and Alzheimer’s disease."
At the more recent 2023 International Congress of Parkinson’s Disease and Movement Disorders, held August 27-31, Gain presented data from a mouse model showing that GT-02287 leads to a significant reduction of plasma neurofilament light (NfL) levels, a marker of neuroaxonal damage. This was significant considering how NfL has been viewed by regulatory agencies and those in the field. For context, earlier this year the FDA approved Biogen’s tofersen (Qalsody), an agent for SOD1 forms of amyotrophic lateral sclerosis, based on reductions in NfL levels.3
1. Gain Theraprutics announces dosing of first two subjects in phase 1 clinical trial of GT-02287, a novel CGase-targeting small molecule therapy for GBA1 Parkinson’s disease. News release. Gain Therapeutics. October 4, 2023. Accessed October 6, 2023. https://www.globenewswire.com/news-release/2023/10/04/2754433/0/en/Gain-Therapeutics-Announces-Dosing-of-First-Two-Subjects-in-Phase-1-Clinical-Trial-of-GT-02287-a-Novel-GCase-targeting-Small-Molecule-Therapy-for-GBA1-Parkinson-s-Disease.html
2. Gain Therapeutics presents new preclinical data demonstrating potential disease modifying benefits of its novel brain penetrant small molecule candidate GT-02287 in two preclinical models of Parkinson’s disease. News release. September 19, 2022. Accessed October 6, 2023. https://www.gaintherapeutics.com/investors-media/overview/53-newsroom/press-releases/2020news/386-ainherapeuticsresentsewreclinicalataemonstrati20220919050503.html
3. Gain Therapeutics presents new preclinical data demonstrating a reduction of plasma neurodegeneration biomarker NfL after administration of its drug candidate GT-00287 in GBA1 Parkinson’s disease model. News release. August 28, 2023. Accessed October 6, 2023. https://www.globenewswire.com/news-release/2023/08/28/2732467/0/en/Gain-Therapeutics-Presents-New-Preclinical-Data-Demonstrating-a-Reduction-of-Plasma-Neurodegeneration-Biomarker-NfL-after-Administration-of-its-Drug-Candidate-GT-02287-in-GBA1-Park.html