Abstract. Abuse of synthetic opioids is a rapidly intensifying public health problem with more than 70,000 reported US overdose deaths in 2022. Currently available medications to reverse opioid intoxication include an intranasal formulation of the opioid antagonist naloxone, commonly known as Narcan. While this medication can be lifesaving, it has many drawbacks including decreased efficacy against more potent fentanyl analogs, a short duration of action, and a side-effect profile that includes precipitated opioid withdrawal. To address this direst public health problem, we recently developed a novel candidate medication for blocking the harmful effects of synthetic opioids known as CSX-1004, a monoclonal antibody (mAb) with high binding affinity and specificity to fentanyl and related analogs. Mechanistically, CSX-1004 directly sequesters fentanyl and related analogs in peripheral blood to mitigate opioid effects in the brain without interacting with the target µ-opioid receptors. In preclinical studies, we found that intravenous (IV) administration of CSX-1004 can effectively reverse and prevent (>10-fold) fentanyl-induced respiratory depression in rodents and non-human primates (NHP) with durable efficacy that lasts over 3 weeks. Moreover, CSX-1004 has passed key GLP toxicology and GMP manufacturing milestones, enabling an investigational new drug (IND) filling for the target indication of preventing fentanyl analog overdose via IV mAb administration. These findings have encouraged the idea that CSX-1004 therapy could also play a clinically important role in treating fentanyl-related OUD. Given that current medications for OUD (e.g., buprenorphine, methadone, naltrexone) show unsatisfactory treatment retention and relapse rates, there is a clear need for new medication strategies for OUD, which is a major focus of NIDA’s mission. In response to PAR-22-200, we propose to first conduct proof-of-concept studies that will evaluate the potency, efficacy, and duration of action of IV CSX-1004 in blocking fentanyl-taking and reinstatement of fentanyl-primed drug-seeking in drug vs food choice self-administration procedures in NHP (Aim 1). After establishing IV CSX- 1004's effectiveness in monkeys (Aim 1), we will further develop and optimize CSX-1004 as a subcutaneous (SC) fentanyl-related OUD medication in Aim 2, which will permit its use in a wider clinical setting compared to the required in-patient setting for IV mAb treatment. Aim 2 activities will include reformulation, manufacturing, testing in NHP self-administration, and rodent toxicology studies. After successfully achieving the UG3 phase milestones, UH3 phase studies will be initiated to a) document how CSX-1004 precludes fentanyl from entering the brain to prevent dysregulation of abuse-related neural activity in NHP using PET/fMRI; and b) evaluate if CSX-1004 induces naloxone-like withdrawal in fentanyl-dependent monkeys (Aim 3). Lastly, we will complete the GLP toxicology and GMP manufacturing activities necessary to support IND filing of SC CSX-1004 for the OUD indication (Aim 4). Together, we anticipate our systematic program of studies in NHPs to generate essential information that will support IND activities and future biologics license applications (BLA) related to CSX-1004.

Narrative. The rise in fentanyl abuse has caused a drastic increase in overdose deaths attributed to synthetic opioids (now over 70,000 per year in the United States). In response to this public health crisis, Cessation Therapeutics has identified a novel monoclonal antibody drug candidate known as CSX-1004 that can prevent and reverse the effects of synthetic opioids. This grant proposal aims to investigate CSX-1004 in translational animal models for fentanyl-related opioid use disorder (OUD) and develop it as a medication for treating OUD by accomplishing the required drug development activities related to toxicology, manufacturing, and regulatory filing.