Development of a monoclonal antibody to reverse overdose from fentanyl and its analogs: from manufacturing to clinical trials

开发逆转芬太尼及其类似物过量的单克隆抗体：从制造到临床试验

基本信息

批准号：
10615519
负责人：
SANDRA D COMER
金额：
$ 826.74万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10615519
关键词：
Address Adrenergic Agents Animal Model Antibodies Binding Blood Circulation Bradycardia Brain Buffers Buprenorphine COVID-19 pandemic Cell Line Chest Chest wall structure Chinese Hamster Ovary Cell Clinic Clinical Clinical Data Clinical Trials Collaborations Contracts Critical Care Development Dose Double-Blind Method Drug Kinetics Drug Targeting Exposure to FDA approved Family suidae Fentanyl Formulation Funding Future Genes Goals Heroin Human In Vitro Incidence Individual Intervention Investigational Drugs Lead Life Ligands Mediating Medical Methadone Monoclonal Antibodies Mus Naloxone Naltrexone Narcan Opiate Addiction Opioid Opioid Antagonist Opioid Receptor Organ Oryctolagus cuniculus Overdose Overdose reversal Pathway interactions Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phase II/III Trial Phase III Clinical Trials Placebo Control Placebos Population Production Public Health Rattus Reference Standards Refractory Research Rodent Safety Savings Series Stimulant Street Drugs Sufentanil Syndrome Testing Therapeutic Monoclonal Antibodies Toxic effect Toxicology Translations Ventilatory Depression Withdrawal analog carfentanil cell bank clinically relevant efficacy study endogenous opioids fentanyl overdose high risk human subject human tissue humanized monoclonal antibodies immunogenicity in vivo lead candidate meetings non-opioid analgesic novel novel strategies off-target site opioid use disorder participant safety phase 1 designs phase 1 study pre-clinical preclinical efficacy preclinical study prevent research clinical testing respiratory safety study standard care standard of care trafficking

项目摘要

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.

抽象的。该项目寻求资金来完成制造和支持的药代动力学，候选者人性化单克隆人的I期临床试验的功效和安全/毒理学临床前研究抗体（mAb）治疗与涉及芬太尼及其有效类似物的过量用药相关的毒性。致命药物过量的发生率由于扩散而大大增加芬太尼及其类似物的可用性通常在街头药物混合物中发现。致命药物过量总数更多超过2020年的92,000。当前的药物并不总是足以防止或反向过量芬太尼及其类似物。作为当前药物的互补策略，我们的团队已经开发了人性化的mAB 反对芬太尼及其类似物。铅mab有效预防和逆转药物诱导的呼吸道暴露于芬太尼和carfentanil的啮齿动物中的抑郁症和心动过缓。反毒物mab选择性隔离循环中的目标药物。由于它们对目标的选择性，我们的mAb不干扰内源性配体，用于治疗阿片类药物使用障碍（OUD）和过量的FDA批准药物，以及其他关键药物。可以将抗芬太尼mAB与OUD的标准护理治疗共同管理和/或过量的，并且可能对阿片受体拮抗剂提供更长的临床益处。翻译 mabs将受益于偶然或偶然的致命性过量风险过量的人和其他人受益故意暴露于芬太尼和芬太尼类似物。这个UG3/UH3项目提出了一个里程碑驱动的具有预定的GO/NO GO标准的迭代发展计划，以促进芬太尼和它类似于诊所。 AIM1专注于与首席候选人MAB的GMP制造合作伙伴CDMO。 AIM2专注于关键动物模型中的效力和功效研究。 AIM3 专注于GLP毒理学和铅mab的安全性。 AIM4专注于I期临床试验进行首次测试 MAB安全性，药代动力学和免疫原性，然后对健康人的芬太尼进行MAB功效主题。该项目的完成将提供临床数据，以支持未来II-III期试验中的MAB测试。