The AI-powered drug discovery platform Magellan paved the way for GT-02287, a potential disease-modifying treatment for Parkinson’s disease. [Image: Gain Therapeutics]
GCase, short for glucocerebrosidase, targets both lysosomal and mitochondrial dysfunction. In Parkinson’s, the failure of cellular powerhouses (mitochondria) and recycling centers (lysosomes) disrupts essential functions. This breakdown leads to a toxic buildup of glycosphingolipids (fatty substances within cells) and damaging clumps of alpha-synuclein (a misfolded protein), hallmarks of Parkinson’s disease and the cause of Lewy bodies. For a visual explanation of this process, see the diagram several paragraphs below).
GT-02287: Targeting the root cause of Parkinson’s
GT-02287 takes aim at Parkinson’s pathogenesis by restoring GCase function. This strategy triggers a cascade of beneficial effects: reducing harmful buildup within cells, promoting the breakdown of protein clumps associated with the disease, and enhancing the function and survival of brain cells. “It has a beneficial effect through that entire chain of bad effects that otherwise happens over time: removing a toxic glycosphingolipid, removing toxic alpha-synuclein, improving lysosomal function, reducing neuroinflammation,” said Matthias Alder, CEO of Gain Therapeutics. In addition, the therapy promises to improve cell survival and dopamine production. “That then translates logically. as we have shown, into improvement of motor function,” Alder said, referring to the preclinical study.
Promising preclinical results
Matthias Alder
In a Parkinson’s disease mouse model, GT-02287 successfully restored motor function – even when administered after the onset of damage caused by GBA1 gene mutations. The GBA1 gene provides instructions for making GCase. Animals in the most challenging treatment group — those that received treatment eight days following onset of the disease — showed motor improvement from day 14 to day 27, suggesting progressive reversal of neuronal deficit linked to continued treatment duration.
Gain Therapeutics aims to tackle the unmet need in Parkinson’s disease treatment with their drug GT-02287, which has the potential to become the first FDA-approved therapy to slow or stop disease progression. The company has a phase 1 study of GT-02287 underway in healthy volunteers. “It’s a two-part study; one is a single ascending dose part, which is currently ongoing,” Alder said.
The study will then move into multiple ascending doses where the company will treat subjects. “That data will read out in the second quarter of this year, 2024,” Alder said. In the third quarter, the company plans to add a patient cohort to that phase 1 study. “Here, we’ll not only look at safety and tolerability but also various biomarkers that we’ve already examined in our animal models,” Alder explained. “We hope to see similar effects in Parkinson’s patients, which would establish a biomarker-based clinical proof of concept that the drug actually works in patients.”
A diagram illustrating the mechanism of action for GT-02287. The drug candidate addresses the cellular dysfunction caused by GBA1 gene mutations in Parkinson’s disease. The drug actively facilitates the proper folding of misfolded GCase enzymes in the endoplasmic reticulum (ER), enabling their transport to lysosomes where they can effectively break down accumulated substrates, addressing the cellular dysfunction caused by GBA1 gene mutations in Parkinson’s disease. [Image: Gain Therapeutics
NfL Biomarker showcases GT-02287’s potential in Parkinson’s
Speaking of biomarkers, the company is excited about data related to neurofilament light chain (NfL), a protein that works as a scaffold to hold together brain cells. When brain cells die, they release NfL, which can be detected in the bloodstream. “In our animal models, we observed a direct correlation between elevated NfL levels and motor function decline,” Alder said. “When we treated the animals with our drug, we were able to reduce NfL levels back to normal.” Alder notes that this finding suggests that GT-02287 can prevent the death of brain cells in these animals, particularly the dopaminergic neurons crucial for motor control. “Our ultimate goal is to achieve this same effect in patients, potentially slowing or even halting the progression of Parkinson’s disease.”
GT-02287 sparking patient interest
Patients within the Parkinson’s community have expressed “tremendous interest” in Gain’s GT-02287 research, Alder said. “Since we began our Phase 1 clinical trial and described how our drug works, we’ve received numerous inquiries from patients seeking to participate,” he said. “These patients feel a desperate need for a drug that can actually halt the terrible progression of their disease.” Alder also emphasizes the broader significance of this research, noting that, “Everyone — investors, the general public, our own families — understands the widespread impact of neurodegenerative diseases like Parkinson’s and Alzheimer’s.”
Supercomputer and AI drive Gain’s drug discovery strategy
Central to Gain Therapeutics drug development strategy is the use of advanced computational techniques. Gain Therapeutics has partnered with the Swiss National Supercomputing Centre. “It requires supercomputing power to run our models,” Alder said. In particular, the firm uses time on supercomputer clusters to perform molecular dynamics simulations, starting with the 3D structure of a protein.
This is complemented by AI tools like DeepMind’s AlphaFold, which predicts protein structures and helps spot potential binding sites for promising molecules. “During this [process], we measure the interactions of small organic molecules with the protein surface, focusing on binding free energy,” Alder noted. “Then, we take these predicted binding sites and molecules into real-life experiments in our labs to confirm that the computer predictions are correct. The best a computer model can do is make a prediction, but it always needs to be confirmed in real life. We have the capability to do this confirmation in our labs.”
Gain conducts virtual screenings of more than 50 billion compounds. “From there, we run the screening process to identify the small molecules that have the best potential to become a real therapeutic in real life,” Alder said.
Meet Magellan
Gain Therapeutics’ Magellan platform is a central pillar of the company’s AI approach to drug development. “This platform gives us the ability with our computational models to identify binding sites on proteins that are involved in a disease, then allows us to find specific small molecules that fit onto the binding sites that we have identified,” Alder said. He goes on to cite the platform’s success in discovering a binding site on the GCase enzyme.
Magellan is thus the source of “our lead program,” Alder said. “It’s essentially now a clinically validated platform because we’ve been able to show that we can create very valuable programs with it. And it’s been the origin of the entirety of our product pipeline,” he added. “We’re planning to use the platform as we continue to refresh our pipeline, but also in collaborations with industry partners, academic groups, and industry peers who want to accelerate antiviral drug discovery with this computational tool.”
Filed Under: clinical trials, Drug Discovery, Neurological Disease
