By focusing on metabolic pathways implicated in CNS disorders by human genetics, Leal can work with well-understood enzymes and targets. This simplifies the development process compared to pursuing novel, poorly understood CNS-specific pathways, providing a clearer path to drug development.
Instead of targeting complex downstream glutamate receptors, Leal Therapeutics inhibits a single upstream enzyme, glutaminase. This mechanistically simpler approach avoids the off-target effects of receptor-based drugs and allows for direct, quantifiable measurement of target engagement, a major advantage in CNS trials.
Leal's work shows the link between the brain and metabolism is bidirectional. While developing drugs for CNS disorders, they discovered that engaging metabolic targets within the CNS can produce powerful peripheral effects, like selective fat loss, creating unexpected therapeutic opportunities in massive markets like obesity.
In the difficult CNS space, novel drugs often fail because of an inability to prove target engagement in humans. By choosing metabolic targets, Leal can use clear biomarkers from blood tests or imaging to de-risk its programs and provide early proof of efficacy to investors, clinicians, and partners.
Leal Therapeutics intentionally built a team capable of developing both oral small molecules and nucleic acid drugs. This dual-modality platform provides strategic agility, allowing them to select the optimal therapeutic approach for a given disease, such as an intrathecal ASO for ALS and a brain-penetrant small molecule for broader indications.
Asa Abeliovich's career shift from academia to biotech was fueled by a growing disparity between deep genetic understanding of CNS disorders and the lack of effective clinical treatments. This gap represents a clear opportunity for scientifically-minded founders to translate knowledge into tangible therapies for patients.