ABSTRACT. This project seeks funding to complete manufacturing and IND-supporting pharmacokinetic, efficacy, and safety/toxicology preclinical studies for a Phase I clinical trial of a candidate humanized monoclonal antibody (mAb) to treat and reverse toxicity associated with overdose involving fentanyl and its potent analogs. The incidence of fatal drug overdoses has dramatically increased due to the proliferation and widespread availability of fentanyl and its analogs, often found in street drug mixtures. Fatal drug overdoses totaled more than 92,000 in 2020. Current medications are not always sufficient to prevent or reverse overdose from fentanyl and its analogs. As a complementary strategy to current medications, our team has developed humanized mAbs against fentanyl and its analogs. Lead mAbs are effective in preventing and reversing drug-induced respiratory depression and bradycardia in rodents exposed to fentanyl and carfentanil. Anti-drug mAbs selectively sequester the target drug from circulation. Due to their selectivity for the target(s), our mAbs do not interfere with endogenous ligands, FDA-approved medications for treating opioid use disorders (OUD) and overdose, and other critical medications. Anti-fentanyl mAbs can be co-administered with standard of care treatments for OUD and/or overdose, and may offer longer-lasting clinical benefits over opioid receptor antagonists. Translation of mAbs will benefit those with an OUD and other individuals at high-risk of fatal overdoses from accidental or deliberate exposure to fentanyl and fentanyl analogs. This UG3/UH3 project proposes a milestone-driven iterative developmental plan with predetermined go/no go criteria to advance a mAb against fentanyl and its analogs to the clinic. AIM1 focuses on the GMP manufacturing of a lead candidate mAb in collaboration with a partner CDMO. AIM2 focuses on IND-enabling potency and efficacy studies in key animal models. AIM3 focuses on the GLP toxicology and safety of the lead mAb. AIM4 focuses on Phase I clinical trials to first test mAb safety, pharmacokinetics, and immunogenicity, and then mAb efficacy against fentanyl in healthy human subjects. Completion of this project will provide clinical data to support mAb testing in future Phase II-III trials.

Public health narrative. Opioid-related fatalities have dramatically increased, driven by the proliferation and widespread availability of fentanyl, carfentanil, and other potent analogs. Fentanyl and its derivatives have also been implicated in accidental or deliberate fatal overdoses in both civilian and defense scenarios. To address this public health threat, this project seeks to advance to the clinic humanized monoclonal antibodies to provide a novel non-pharmacological medical intervention to reverse and treat overdose from fentanyl and its potent analogs.