Neuroscience continues to represent a challenging area for drug developers. Even with skyrocketing rates of neuropsychiatric diseases like anxiety disorders and depression, particularly during the pandemic, patients have been limited to medicines with mixed efficacy and unavoidable side effects. Meanwhile, many pharmaceutical companies have slashed neuroscience pipelines, slowing the progress of new medicines.
Engrail Therapeutics is employing an optimized approach to the stymied field. The San Diego-based company was founded in 2019 to build and advance a precision neuroscience pipeline based on established therapeutic pathways and drug classes, allowing development of targeted drugs with higher probabilities of success. Engrail has since attracted significant investment from high-quality investors such as F-Prime Capital, Forbion, and Norwest Venture Partners in addition to continued investment from founding investor Pivotal Life Sciences.
Capitalizing on existing knowledge
“Our development programs share a single strategy of utilizing an improved understanding of neural circuits to build on existing successes with increasing precision, as opposed to starting over with brand-new targets,” said CEO and co-founder Vikram Sudarsan. For example, Engrail’s lead clinical stage program, ENX-102, represents a new class of anxiolytic therapy that leverages a similar yet more precise mechanism than benzodiazepines, facilitating the potential for efficacious, safe, and chronic use without the major liabilities that have hamstrung the older class. ENX-102 is a highly specific GABAA α2,3,5-positive allosteric modulator that is in development for the treatment of generalized anxiety disorder (GAD).
Based on robust preclinical data and a pharmacodynamic biomarker-driven phase 1 trial, Engrail has advanced ENX-102 into a phase 2 study with a data readout expected in the second half of 2025.
“A better biological understanding has enabled us to utilize biomarkers showing that ENX-102 gets into the brain and engages the target, with pharmacodynamic data suggesting it will perform better than the standard of care,” said Kimberly Vanover, CSO of Engrail. “Through a sophisticated phase 1 trial, we showed excellent target engagement, a vastly improved safety profile over benzodiazepines, and sufficient half-life for daily dosing.”
The ENX-102 program leverages the extensive neuroscience and drug development expertise at the company. Sudarsan, a neurobiologist by training, has spent the past decade helping build and grow life-science companies. Vanover previously played a key role in the development of neuropsychiatric medications like Caplyta (lumateperone) and Nuplazid (pimavanserin).
Reducing unwanted effects
ENX-102 targets GABAA, an inhibitory neurotransmitter receptor which is implicated in many diseases, including anxiety. “The GABAA receptor is a well-understood therapeutic target, having been modulated by various drugs including benzodiazepines for decades,” said Vanover. “Those drugs can be effective for reducing anxiety, seizures, and pain, but come with troublesome side effects like cognitive impairment, abuse potential, and sedation.”
The negative effects have meant that benzodiazepines cannot be given as chronic first-line treatments for GAD, despite some advantages like the speed with which they begin working. “This has left a huge unmet need among the more than 5 million patients in the US being treated for GAD, more than 60% of whom fail initial lines of therapy,” said Sudarsan.
Over 20 years of research have demonstrated the potential of more-selective GABAA drugs to deliver the positive effects of benzodiazepines without the addictive or sedative effects. One receptor subtype in GABAA, the α1 subunit, appears to account for many of the undesirable side effects, whereas stimulating the α2, α3, and α5 subunits should avoid these drawbacks while maintaining therapeutic impact.
Developing a promising portfolio
Engrail’s precision-targeting approach to improving on what works well could be a game-changer in neuroscience. “Developing drugs in this space has always been a difficult endeavor, which is why so many pharmaceutical companies have divested over the years,” said Sudarsan. “We are de-risking by focusing on drugs backed by rigorous science, with a strong neurobiological rationale toward a mechanism of action and a clear regulatory path.”
Engrail is well capitalized to advance its pipeline into the clinic and generate a variety of meaningful data over the next couple of years. Beyond ENX-102, Engrail has also developed ENX-104, which has entered the clinic. ENX-104 is a highly selective dopamine D2/D3 antagonist with potential to treat anhedonia associated with major depressive disorder. Engrail is also developing ENX-205, a single molecule with novel pharmacology combining 5-hydroxytryptamine serotonin receptor 1A (5-HT1A) agonism, 5-HT2A agonism, and D2/D3 antagonism. This profile is expected to yield psychedelic-like efficacy without hallucinations for posttraumatic stress disorder as well as mood disorders. Rounding out the Engrail portfolio, ENX-203 is a copper ionophore that may have life-enhancing and life-saving effects in children with Menkes disease, an ultra-rare and fatal genetic disorder of copper metabolism.