We are a clinical-stage biopharmaceutical company developing innovative medicine for cancer and diseases and conditions involving the central nervous system.
AV-101 is a novel, orally-available, non-sedating, non-hallucinogenic, Phase 2 clinical-stage drug candidate for Major Depressive Disorder, as well as chronic neuropathic pain, epilepsy and neurodegenerative diseases, such as Parkinson’s disease and Huntington’s disease. AV-101 is a pro-drug that efficiently crosses the blood-brain barrier and is rapidly converted into 7-chlorokynurenic acid (7-Cl-KYNA) by astrocytes, which is released into the synaptic spaces. 7-Cl-KYNA is a well-characterized, potent and highly selective antagonist of N-methyl-D-aspartate (NMDA) receptors due to its antagonistic binding to the glycine-coagonist (glycineB) site of the NMDA receptor.
Current evidence suggests that AV-101’s antagonism of NMDA signaling may provide rapid-onset antidepressant effects in the treatment of Major Depressive Disorder. In addition, as confirmed in Phase 1 clinical studies, targeting the glycineB coagonist site of the NMDA receptor does not have the adverse effects typically associated with classic NMDA receptor antagonists, such as ketamine and other NMDA channel blockers. The fact that AV-101 is a safe, well-tolerated, oral drug, with strong preclinical data in three animal models of depression, suggests that AV-101 is a potential breakthrough treatment for Major Depressive Disorder.
We have completed preclinical studies and Phase 1 clinical safety studies supporting Phase 2 clinical development of AV-101 in multiple CNS indications. 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, to begin in early-2015. 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 350 million people worldwide, including nearly 7% of adults in the United States.
In NIH studies, the NMDA receptor channel blocker ketamine produced rapid, robust antidepressant effects in patients with Major Depressive Disorder. These NIH studies introduced a new paradigm for the research and development of antidepressants with rapid-onset action, in stark contrast to FDA-approved antidepressants. Despite the promising results in the NIH studies, however, ketamine’s potential to become long-term, widely-used antidepressant medication is severely limited due to its well-established addictive nature, anesthetic properties, capacity to produce dissociative side effects, and the invasiveness and inconvenience of required intravenous administration. AV-101 and ketamine both regulate the NMDA receptor. However, AV-101 selectively targets the glycineB site within the NMDA receptor and does not precipitate the serious adverse effects of ketamine or other NMDA channel blockers. As a result, we believe orally-available AV-101 has the potential to deliver the therapeutic benefits of ketamine in Major Depressive Disorder, but without ketamine’s side effects or required i.v. administration, making AV-101 a potential breakthrough treatment for Major Depressive Disorder.
Stem Cell Technology and Drug Rescue
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 Human Clinical Trials in a Test Tube platform is based on a combination of proprietary and exclusively licensed stem cell technology for controlling the differentiation of hPSCs and producing the multiple types of mature, non-transformed, functional, adult human cells that we use to reproduce complex human biology and disease and assess the potential therapeutic benefits and safety risks of new drug candidates long before animal or human studies.
We use our our stem cell-derived human cardiomyocytes (heart cells), VSTA-CMs™, in CardioSafe 3D™, our novel, customized in vitro bioassay system for predicting potential heart toxicity of new drug 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. We use our stem cell-derived hepatocytes, VSTA-heps™, are 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.
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.