AV-101 (4-Cl-KYN) is a novel, orally-available, non-sedating, non-hallucinogenic, clinical-stage prodrug candidate for Major Depressive Disorder, as well as other diseases and disorders involving the central nervous system (CNS), including chronic neuropathic pain, epilepsy and neurodegenerative diseases, such as Parkinson’s disease and Huntington’s disease. After crossing the blood-brain barrier and reaching brain astrocytes, AV-101 is rapidly and enzymatically converted into 7-chlorokynurenic acid (7-Cl-KYNA), a well-characterized, potent and selective antagonist of N-methyl-D-aspartate (NMDA) receptors, acting by blocking the glycine-coagonist (glycineB) site within the NMDA receptor. Current evidence suggests that AV-101’s antagonism of NMDA signaling via the glycineB site of the NMDA receptor may provide rapid-onset antidepressant effects in the treatment of Major Depressive Disorder. In addition, targeting the glycineB coagonist site of the NMDA receptor may bypass potential adverse effects typically associated with classic NMDA receptor antagonists, such as ketamine, without impacting potential clinical benefits, making AV-101 a potential breakthrough treatment for Major Depressive Disorder and multiple CNS-related diseases and disorders. We have completed preclinical studies supporting the potential therapeutic uses of AV-101 in Major Depressive Disorder, epilepsy, neuropathic pain and Parkinson’s disease, and completed Phase 1 clinical safety studies, demonstrating that AV-101 is safe with no adverse effects, very well-tolerated and has good oral bioavailability. To date, the U.S. National Institutes of Health (NIH) has awarded us $8.8 million of grant funding for our successful preclinical and Phase 1 clinical development of AV-101. We are now in discussions with the NIH regarding Phase 2 clinical development of AV-101 in Major Depressive Disorder, which affects approximately 17% of the world population, including nearly 7% of adults in the United States. Although treatment interventions are available, a large percentage of Major Depressive Disorder patients remain symptomatic following traditional treatments, which, even when effective, often take many weeks before therapeutic benefits are achieved.
We apply our proprietary human pluripotent stem cell (hPSC) technology to produce VSTA-CMs
™, our mature, adult human cardiomyocytes (human heart cells) differentiated from hPSCs Using our VSTA-CMs
, we have developed and validated CardioSafe
3D™, our suite of novel, customized in vitro
bioassays for predicting the cardiotoxicity profile of small molecule drug candidates, including promising drug rescue candidates and drug rescue variants, long before they are ever tested in animals or humans. We believe CardioSafe
3D is capable of predicting the in vivo
cardiac effects, both toxic and non-toxic, of small molecule drug candidates more comprehensively and efficiently than conventional surrogate safety models often used in drug development, including the FDA-required in vitro
hERG assay and other preclinical models using live animals or animal, transformed or immortalized cells. Our CardioSafe
3D drug rescue activities are focused on producing for our internal drug development pipeline new safer variants of promising drug candidates previously discovered, optimized and tested for efficacy by pharmaceutical companies and others but terminated before FDA approval due to unexpected heart toxicity. We are currently preparing to begin our initial CardioSafe
3D drug rescue program.
We also apply our proprietary hPSC technology to produce VSTA-heps
™, our highly-functional, non-transformed, mature, human hepatocytes (human liver cells) derived from hPSCs. We believe our VSTA-heps
have more functionally useful life-span in culture than, and overcome numerous problems related to, commercially-available primary (cadaver) hepatocytes currently used in FDA-required in vitro
hepatocyte assays for drug metabolism, including limited supply, unknown health status of the donor and genetic differences. We are using our VSTA-heps
to develop LiverSafe
3D, our second novel customized bioassay system for drug rescue and development. We believe LiverSafe
3D will enable us to assess new drug candidates, including drug rescue candidates and drug rescue variants, for potential liver toxicity and metabolism-based safety issues resulting in adverse drug-drug interactions, early in development, long before animal and human testing. Drug-related liver toxicity and adverse drug metabolism, as a group, represent one of the top-two reasons for safety-related drug failure during clinical development.