ABSTRACT In 2017, more than 47,000 Americans died from an opioid overdose, according to the Centers for Disease Control and Prevention, causing a National Emergency. A significant number of overdose cases were due to abuse of prescription opioids. More than 25 million Americans suffer from chronic pain, a complex and highly debilitating medical condition for which effective or safe treatments are still lacking. Chronic pain does not respond well to existing pharmacotherapy as evidenced by the fact that >50% patients are refractory to current medications such as opioids, gabapentin, pregabalin, tricyclic antidepressants and. Thus, there is a critical unmet need for innovative pharmacological solutions to develop alternative treatment options for pain that would provide better efficacy with the risk for addiction and abuse. AnaBios has developed ANB-504, a lead small molecule dual inhibitor of two sodium channels specifically expressed in sensory neurons and implicated in numerous forms of chronic pain. ANB-504 shows potent dose- dependent inhibition of action potentials in human sensory neurons, across all pathological pain states studied to date. These results were confirmed by observing ANB-504-induced analgesia in a rodent model of pain. ANB- 504 exhibits drug-like properties, shows no cytotoxicity or genotoxicity flags, has good metabolic stability across species, a clean off-target pharmacology profile, no propensity for DDI, good bioavailability, low clearance and no evidence of CNS or cardiovascular toxicities. The current proposal aims at conducting all the FDA-mandated studies to support an IND application which would allow initiating human dosing in a Phase 1 clinical study. The proposal includes the manufacturing of ANB-504 in an amount sufficient for conducting non-clinical in vitro and in vivo studies. One of the early milestones in the program will be the development and validation of analytical methods which will enable quantification of the drug during in vitro and in vivo studies and will allow establishing equivalency of composition and purity for subsequent clinical batches. Next, the program will address the determination of the absorption, distribution, metabolism and excretion of the drug in animal models and the pharmacokinetics properties. At this time, we will also investigate the specific metabolic pathways and metabolic products generated following the administration of ANB-504 and the propensity of the drug to be involved in drug-drug interactions. The toxicity and safety of the drug will then be assessed in two model species in both single dosing regimen as well a prolonged multi-dosing regimen. These studies will examine safety and toxicity outcomes for multiple organ systems and will provide critical information for the selection of the first in human dosing. The last step in the proposed program will be the compilation of all the studies into a comprehensive regulatory-compliant data package for submission to the FDA.

NARRATIVE Prescription opioid drug abuse and overdose-related deaths have now reached epidemic proportions in the USA. The development of new, more effective and non-addictive pain drugs to treat chronic pain will be critical to address the opioid abuse crisis as well as the needs of chronic pain patients. AnaBios will advance the development of a novel first-in class non-addictive analgesic drug with high potential to treat chronic pain conditions associated with neuropathy and/or inflammation. The program will generate the data required to obtain regulatory clearance to initiate clinical studies to validate the new drug’s efficacy and safety.