We are a clinical-stage biopharmaceutical company headquartered in South San Francisco, California and focused on drug development, rescue and discovery, as well as regenerative medicine.
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.
Major Depressive Disorder
The World Health Organization (WHO) estimates that “depression is the leading cause of disability worldwide, and is a major contributor to the global burden of disease.” Major Depressive Disorder 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.
In NIH studies, the NMDA receptor antagonist ketamine produced rapid, robust antidepressant effects in patients with Major Depressive Disorder. These studies introduced a new paradigm for the research and development of antidepressants with a rapid-onset action, in stark contrast to other FDA-approved antidepressants. Despite these promising results, however, ketamine’s potential as a long term antidepressant medication is severely limited due to its addictive nature, anesthetic properties, capacity to produce dissociative effects, even when administered at low doses, and the invasiveness of intravenous (IV) administration, its most common route of administration. AV-101 and ketamine regulate the NMDA receptor. However, AV-101 selectively targets the glycine-coagonist (glycineB) site within the NMDA receptor and does not precipitate the serious adverse effects of ketamine, making AV-101 a potential breakthrough treatment for Major Depressive Disorder.
Stem Cell Technology
We believe better cells lead to better medicines™ and that the key to making better cells is precisely controlling the differentiation of human pluripotent stem cells (hPSCs), which are the building blocks of all cells of the human body. Our stem cell technology platform, which we refer to as Human Clinical Trials in a Test Tube, is based on a combination of proprietary and exclusively licensed technologies for controlling the differentiation of hPSCs and producing the multiple types of mature, non-transformed, functional, adult human cells that we use, or plan to use, to reproduce complex human biology and disease and assess, in vitro, the potential therapeutic benefits and safety risks of new drug candidates.
We have used our VSTA-CMs™, our hPSC-derived human cardiomyocytes (heart cells) to design and develop CardioSafe 3D™, our novel, customized in vitro bioassay system for predicting potential cardiotoxicity of new drug candidates, including drug rescue candidates. We believe CardioSafe 3D is more comprehensive and clinically predictive than the hERG assay, currently the only in vitro cardiac safety assay required by FDA guidelines. Our stem cell-derived hepatocytes (VSTA-heps™), highly-functional, non-transformed, mature human hepatocytes (liver cells), are the foundation of LiverSafe 3D™, our second novel, customized bioassay system for predicting potential liver toxicity of new drug candidates, including potential drug metabolism issues and adverse drug-drug interactions. 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 believe our Human Clinical Trials in a Test Tube platform, anchored by VSTA-CMs, VSTA-heps, CardioSafe 3D and LiverSafe 3D, offers a new paradigm for evaluating and predicting potential heart and liver toxicity of new drug candidates, including drug rescue candidates, early in development, long before costly, high risk human clinical trials.
We believe using CardioSafe 3D and LiverSafe 3D for our drug rescue programs is the highest-value near term commercial application of the human cells we produce and the novel, customized bioassay systems we have designed and developed. Our drug rescue activities are currently focused on producing for our internal drug development pipeline new, safer variants of still-promising cancer 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 refer to these still-promising new drug candidates as Drug Rescue Candidates™. Our drug rescue strategy involves using CardioSafe 3D to assess the toxicity that caused the Drug Rescue Candidates to be terminated, and then apply our human biological insight to produce a new, safer version of each terminated Drug Rescue Candidate and develop it internally as a new, proprietary drug candidate. We refer to the new, proprietary, safer versions of Drug Rescue Candidates we are focused on producing as Drug Rescue Variants™. We intend to develop each optimized Drug Rescue Variant internally to establish preclinical proof-of-concept (POC), as to both efficacy and safety, in customary in vitro and in vivo models, as well as in CardioSafe 3D.
Regenerative medicine and drug discovery
Although we believe the best and most valuable near term commercial application of our stem cell technology platform is for small molecule drug rescue and development, we also believe stem cell technology-based regenerative medicine has the potential to transform healthcare in the U.S. over the next two decades by altering the fundamental mechanisms of disease and help slow rapidly rising healthcare costs in the U.S. We plan to explore nonclinical opportunities to leverage our stem cell technology platform for regenerative medicine purposes, with emphasis on developing novel human disease models for discovery of small molecule drugs and biologics with regenerative and therapeutic potential. Among our key objectives will be to explore regenerative medicine opportunities through pilot nonclinical proof-of-concept studies, after which we intend to assess any potential opportunities for further development and commercialization of therapeutically and commercially promising regenerative medicine programs, either on our own or with strategic partners.