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

• 批准号: 10583510
• 负责人: Soumya Rahima Benhabbour
• 金额: $ 77.02万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/10583510
• 关键词: AIDS prevention; Accelerated Phase; Acceleration; Address; Adverse event; Affinity; Africa; Animal Model; Anti-Retroviral Agents; Cervical; Characteristics; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Copper Intrauterine Devices; Country; Data; Development; Drug Delivery Systems; Drug Kinetics; Engineering; Epidemic; Etonogestrel; Evaluation; Event; Excipients; Female; Formulation; Fostering; Goals; Grant; HIV; HIV Infections; HIV risk; HIV/STD; Health Benefit; Human; Implant; Implantable Infusion Pumps; 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; Mus; Oral; Patients; Performance; Pharmaceutical Preparations; Placebos; Plasma; Polymers; Pregnancy; Prevention; Process; Progestins; Property; Prophylactic treatment; Public Health; Regimen; Research Personnel; Safety; Sexual Transmission; Subcutaneous Injections; Suspensions; System; Tail; Technology; Testing; Time; Tissues; Toxic effect; User Compliance; Vagina; Viral; 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; manufacture; men; nanoformulation; nanoparticle; nonhuman primate; novel; novel therapeutics; pathogen; pharmacologic; pharmacometrics; pre-clinical; pre-exposure prophylaxis; pregnancy prevention; prevent; prophylactic; safety assessment; sex; simian human immunodeficiency virus; tool; transmission process; unintended pregnancy; viral transmission

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.

项目摘要 在全球范围内，50%以上的艾滋病毒感染者是妇女，每年约有50%的怀孕是计划外的。 因此，迫切需要推广由女性控制的多用途预防技术方法 （MPTs）和交付策略，可以从性行为分离。注射制剂很好地 男性和女性都能耐受，避孕有效，患者可接受性高， 合规1 -4.最近引入全身性PrEP领域的创新是长效（LA）制剂 抗逆转录病毒药物（ARV），作为纳米制剂在数周内稳定释放药物， 预防的动物模型5 -7和人类8 -10。目前，有两种不同的LA制剂， 考虑用于HIV预防：LA形式的利匹韦林（RPV/TMC 278）和LA形式的卡替加韦 (CAB/GSK744）9，11-12。这些LA ARV的注射需要使用口服cabotegravir或cabotegravir的4周“导入”方案。 利匹韦林满足当前的安全性考虑，因为一旦注射，这些药物在数月内可检测到水平 并且药物不能被去除或加速其清除。尽管在艾滋病毒PrEP方面取得了这些进展， 目前，主要由于目前的限制，没有开发LA可注射MPT制剂。 使用纳米颗粒悬浮液的LA注射制剂，其中两种药物不能组合成 单次注射。在此R 01赠款和我们现有的数据基础上，我们提出了一个全面的评估， 一种一线注射MPT，提供持久和持续的艾滋病毒传播保护， 避孕，提高用户依从性，以及在发生非预期不良事件时能够移除 或考虑停止LA HIV PrEP和/或避孕时。我们将通过以下方式实现这一目标： 开发利用赋形剂的液体MPT制剂，所述赋形剂在皮下给药后形成可生物降解的储库， 注射（原位形成植入物（ISFI））。我们提出了一个全面的评价这种新的药物输送 方法使用粘膜猿猴/人类免疫缺陷病毒（SHIV）的高度相关猕猴模型， 评估ISFI对SHIV感染有效性的宝贵临床前工具。这项尖端 将采用综合方法来评估我们建议的科学前提，以调查是否 使用一种独特的、高度安全的方法， 创新的超长效不依赖性交的MPT ISFI制剂。