Ultra-Long-Acting Polymeric Injectable Multi-Purpose Prevention Technology for Contraception and HIV Prevention

用于避孕和艾滋病毒预防的超长效聚合物注射多用途预防技术

基本信息

批准号：
10392508
负责人：
Soumya Rahima Benhabbour
金额：
$ 76.91万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-13 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392508
关键词：
AIDS prevention Accelerated Phase Address Adverse event Affinity Africa Animal Model Anti-Retroviral Agents Centers for Disease Control and Prevention (U.S.)Cervical Characteristics Contraceptive Agents Contraceptive Usage Contraceptive methods Copper Intrauterine Devices Country Data Development Drug Delivery Systems Drug Design Drug Implants Drug Kinetics Engineering Epidemic Etonogestrel Evaluation Event Excipients Female Formulation Fostering Goals Grant HIV HIV Infections HIV risk HIV/STD Health Benefit Implant In Situ In Vitro Inbred BALB C Mice Incidence Infection Injectable Injections Intramuscular Lead Liquid substance Macaca Macaca nemestrina Measures Medroxyprogesterone 17-Acetate Methods Modeling Mucous Membrane Oral Patients Performance Pharmaceutical Preparations Pharmacology Placebos Plasma Polymers Pregnancy Prevention Process Progestins Property Prophylactic treatment Public Health Regimen Research Personnel Safety Sexual Transmission Subcutaneous Injections Suspensions Tail Technology Testing Time Tissues Toxic effect User Compliance Vagina Woman allergic response breakthrough infection chemical property controlled release cost effective design drug release kinetics efficacy evaluation efficacy study experience high risk implant design in vivo innovation men nanoformulation nanoparticle nonhuman primate novel novel therapeutics pathogen pharmacometrics pre-clinical pre-exposure prophylaxis pregnancy prevention prevent prophylactic sex simian human immunodeficiency virus tool transmission process unintended pregnancy viral transmission

项目摘要

PROJECT SUMMARY Globally, over 50% of those infected with HIV are women, and annually, ~50% of all pregnancies are unplanned. Therefore, there is a critical need to promote female-controlled methods of multipurpose prevention technologies (MPTs) and delivery strategies that can be disassociated from the sex act. Injectable formulations are well tolerated by men and women, are efficacious for contraception, and have high patient acceptability and compliance1-4. Innovations recently introduced into the field of systemic PrEP are long-acting (LA) formulations of antiretrovirals (ARVs) that stably release drugs over many weeks as nano-formulations and have activity in animal models of prevention5-7 and in humans8-10. Currently, there are two different LA formulations being considered for HIV prevention: a LA form of rilpivirine (RPV/TMC278) and a LA form of cabotegavir (CAB/GSK744)9, 11-12. Injections of these LA ARVs requires a 4-week ‘lead-in’ regimen using oral cabotegravir or rilpivirine to fulfil current safety considerations as once injected these agents have detectable levels for months and the drug cannot be removed or have its clearance accelerated. Despite these advances in HIV PrEP, currently there are no LA injectable MPT formulations in development mainly because of limitations of current LA injectable formulations utilizing nanoparticle suspensions whereby two drugs cannot be combined into a single injection. In this R01 grant and building on our existing data, we propose a comprehensive evaluation of a first-in-line injectable MPT that offers durable and sustained protection from HIV transmission, high efficacy of contraception, increased user compliance, and the ability to be removed in case of unanticipated adverse events or when considering discontinuation from the LA HIV PrEP and/or contraception. We will achieve this goal by developing a liquid MPT formulation utilizing excipients that form a biodegradable depot after subcutaneous injection (in-situ forming implant (ISFI)). We propose a comprehensive evaluation of this novel drug delivery approach using a highly relevant macaque model of mucosal simian/human immunodeficiency virus (SHIV) as an invaluable preclinical tool to assess the efficacy of the ISFI against SHIV acquisition. This cutting-edge combined approach will be utilized to evaluate the scientific premise of our proposal to investigate whether sustained protection against HIV acquisition and pregnancy can be achieved using a unique and highly innovative ultra-long-acting coitally-independent MPT ISFI formulation.

项目概要在全球范围内，超过 50% 的艾滋病毒感染者是女性，每年约有 50% 的怀孕是计划外的。因此，迫切需要推广女性控制的多用途预防技术（MPT）和可以与性行为分离的给药策略是很好的。男女均可耐受，避孕有效，患者接受度高合规性1-4 最近引入系统性 PrEP 领域的创新是长效 (LA) 制剂。抗逆转录病毒药物 (ARV) 可以纳米制剂形式在数周内稳定释放药物，并具有以下活性：预防动物模型5-7 和人类8-10 目前，有两种不同的LA 配方。考虑用于预防艾滋病毒：LA 形式的利匹韦林 (RPV/TMC278) 和 LA 形式的卡博加韦 (CAB/GSK744)9, 11-12 注射这些 LA 抗逆转录病毒药物需要使用口服卡博特韦或 4 周的“导入”方案。利匹韦林满足当前的安全考虑，因为一旦注射，这些药物的浓度可在数月内检测到尽管 HIV PrEP 取得了这些进展，但药物仍无法被去除或加速清除。目前尚无正在开发的 LA 可注射 MPT 制剂，主要是因为目前的局限性 LA 注射制剂采用纳米颗粒悬浮液，两种药物不能组合成一个在本次 R01 拨款中，我们根据现有数据提出了一项综合评估。一线注射 MPT，可提供持久且持续的 HIV 传播保护，高效避孕、提高用户依从性以及在发生意外不良事件时能够将其移除或者当考虑停止 LA HIV PrEP 和/或避孕时，我们将通过以下方式实现这一目标。使用赋形剂开发液体 MPT 制剂，这些赋形剂在皮下注射后形成可生物降解的储库我们建议对这种新型药物输送进行全面评估。使用高度相关的粘膜猿/人类免疫缺陷病毒（SHIV）猕猴模型作为方法这是评估 ISFI 对抗 SHIV 感染功效的宝贵临床前工具。将采用组合方法来评估我们提议的科学前提，以调查是否使用独特且高度有效的方法可以实现针对艾滋病毒感染和怀孕的持续保护。创新的超长效独立性交 MPT ISFI 配方。