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

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

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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.

项目摘要在全球范围内，超过50％的感染艾滋病毒的人是女性，每年约有50％的妊娠计划外。因此，迫切需要促进女性控制的预防技术的方法（MPT）和交付策略，可以与性行为分离。可注射公式很好男性和女人耐受性，有效地避孕，患者的可接受性高，并且合规1-4。最近引入系统准备领域的创新是长效（LA）公式抗逆转录病毒（ARV）在数周内稳定释放药物作为纳米形成，并且具有活性预防动物模型5-7和人类8-10。目前，有两个不同的la公式考虑预防艾滋病毒：la形式的rilpivirine（RPV/TMC278）和la形式的cabotegavir （CAB/GSK744）9，11-12。这些LA ARV的注射需要使用口服Cabotegravir或 rilpivirine以实现当前的安全考虑因素，因为一旦注射这些代理已经检测到了几个月的水平并且该药物无法去除或清除加速。尽管在艾滋病毒准备方面取得了这些进展，但目前，开发中没有LA可注射的MPT公式，这主要是由于当前的局限性利用纳米颗粒悬浮液的LA可注射公式，使两种药物不能合并为单个注射。在这笔R01赠款和基于我们现有数据的基础中，我们提出了对一条在线注射的MPT，可提供耐用且持续的保护，以防止HIV传播，高效率的高效率避孕，用户的依从性增加以及在意外不良事件的情况下删除的能力或考虑从LA HIV准备和/或违规中停用时。我们将通过开发液体MPT公式，利用赋形剂在皮下后形成可生物降解的沉积物注射（原位形成植入物（ISFI））。我们提出对这种新型药物输送的全面评估使用高度相关的粘膜/人免疫缺陷病毒（SHIV）的猕猴模型作为方法评估ISFI对SHIV采集的效率的宝贵临床前工具。这个尖端联合方法将用于评估我们建议的科学前提，以调查是否是否可以使用独特且高度的高度保护对艾滋病毒的持续保护和怀孕创新的超长起作用coIt依赖的MPT ISFI公式。