Long-acting multi prevention implant for 2-year contraception and HIV PrEP

用于 2 年避孕和 HIV PrEP 的长效多重预防植入物

• 批准号: 10619811
• 负责人: Alessandro Grattoni
• 金额: $ 83.07万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619811
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Adherence; Adopted; Age; Anti-Retroviral Agents; Cause of Death; Clinical; Cold Chains; Contraceptive Agents; Contraceptive methods; Dapivirine; Developing Countries; Diffusion; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug Stability; Etonogestrel; Exhibits; FDA approved; Formulation; Future; Goals; HIV; HIV Infections; HIV antiretroviral; Health; Hormonal; Human; Implant; Individual; Ion Channel; Kinetics; Lead; Macaca nemestrina; Maternal Mortality; Membrane; Methods; Modernization; Oral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Polymers; Positioning Attribute; Pregnancy; Prevention; Prevention strategy; Preventive; Prodrugs; Progestins; Pump; Rattus; Recommendation; Regimen; Reproductive Health; Research; Resistance; Retrieval; Risk; Safety; Scanning Electron Microscopy; Sexual Health; Stigmatization; Structure; Tail; Technology; Testing; Tissues; Vagina; Vaginal Ring; Virus Diseases; Woman; Work; World Health Organization; clinical development; clinical translation; contraceptive efficacy; design; drug release kinetics; efficacy evaluation; experience; hormonal contraception; hydrophilicity; implantable device; implantation; improved; innovation; low and middle-income countries; nanochannel; nanofluidic; next generation; nonhuman primate; patient oriented; pharmacodynamic model; pill; pre-clinical; pre-exposure prophylaxis; preference; pregnancy prevention; prophylactic; public health relevance; reproductive; response; sexually active; simian human immunodeficiency virus; social stigma; subcutaneous; technology platform; unintended pregnancy; uptake; viral transmission

PROJECT SUMMARY/ABSTRACT Maternal mortality and AIDS are among the leading causes of death in reproductive-age women globally due to unintended pregnancy and the disproportionate burden of HIV infection. While effective prevention methods exist, only 21% of women have access to modern contraceptives and adherence to HIV PrEP regimen is poor in many HIV-endemic regions. Multipurpose prevention technologies (MPT) aim to synchronize contraceptive delivery with HIV PrEP, offering a patient-centered approach to provide dual coverage to sexually active women in a single product. A long-acting unified delivery product that can be administered in a discreet manner could reduce stigma around contraceptives and HIV PrEP, thereby improving uptake and adherence to combination prevention products. Our goal is to develop a long-acting delivery implant of etonogestrel (ENG) and islatravir (ISL) drugamer with an unprecedented 2-year release duration for pregnancy and HIV prevention that eliminates further need of adherence. A new subcutaneous nanofluidic multipurpose implant (NanoMPI) will be brought together with a new polymeric prodrug technology termed “drugamer”, to achieve this innovative product candidate that delivers ultra-long acting ENG+ISL drug dosing durations. The NanoMPI leverages a nanofluidic membrane with nanochannels and a single drugamer reservoir to achieve zero-order release kinetics through passive diffusion without pumping mechanisms, permitting discreet, user-independent dosing. Key product attributes will include drug stabilization on the multi-year timeframe, minimized early- and late-stage burst release and pharmacokinetic (PK) tailing, zero-order drug release kinetics tailored to the individual drug PK/PD (pharmacodynamic) requirements, user-independent dosing, and retrievability. The project is structured around 3 specific aims: 1) to develop optimized ENG-ISL drugamer formulations that stabilize the drugs and exhibit the desired zero order release profiles, in concert with the optimization of the NanoMPI device for 2-year sustained release; 2) to assess pharmacokinetics, tolerability, and safety of the lead ENG-ISL NanoMPI device for 2 years in pigtail macaques; and 3) to evaluate contraception and HIV PrEP efficacy of ENG-ISL NanoMPI in pigtail macaques via repeated low-dose vaginal challenge and develop a PK/PD model. We will use a milestone-driven research approach to advance the ENG-ISL NanoMPI technology towards the ultimate goal of clinical translation, leveraging the interdisciplinary team’s experience in drugamer technology, drug delivery, pre-clinical and clinical HIV prevention studies, and hormonal contraceptive and antiretroviral pharmacology. Importantly, the NanoMPI addresses user preferences for a dual prevention product, discretion and longer dosing duration. Successful completion will generate a versatile MPT platform that could be adopted for other drug combinations and preventative strategies.

项目总结/摘要 孕产妇死亡率和艾滋病是全球育龄妇女死亡的主要原因， 意外怀孕和不成比例的艾滋病毒感染负担。虽然有效的预防方法 只有21%的妇女能够获得现代避孕药具，而且艾滋病毒PrEP方案的依从性很差 在许多艾滋病流行地区。多用途预防技术（MPT）旨在同步避孕 提供艾滋病毒PrEP，提供以患者为中心的方法，为性活跃的女性提供双重覆盖 在一个单一的产品。一种可以谨慎管理的长效统一交付产品可以 减少对避孕药具和艾滋病毒PrEP的污名化，从而提高对联合用药的接受和坚持 预防产品。我们的目标是开发一种长效依托孕烯（ENG）和islatravir的植入物 (ISL)drugamer与前所未有的2年释放持续时间为怀孕和艾滋病毒预防，消除 进一步需要坚持。一种新的皮下纳米流体多用途植入物（NanoMPI）将被带来 与称为“drugamer”的新聚合物前药技术一起， 候选人，提供超长作用的ENG+ISL药物给药持续时间。NanoMPI利用纳米流体 膜与纳米通道和一个单一的drugamer水库实现零级释放动力学，通过 无泵送机制的被动扩散，允许谨慎的、用户独立的剂量。关键产品 属性将包括多年时间框架内的药物稳定性、最小化的早期和后期突释 和药代动力学（PK）拖尾，针对单个药物PK/PD定制的零级药物释放动力学 （药效学）要求、用户独立给药和可检索性。该项目的结构围绕 3个具体目标：1）开发优化的ENG-ISL drugamer制剂，使药物稳定并表现出 所需的零级释放曲线，与NanoMPI装置的2年持续优化一致 放行; 2）评估电极导线ENG-ISL NanoMPI器械2年的药代动力学、耐受性和安全性 在猪尾猕猴中;和3）评价ENG-ISL NanoMPI在猪尾中的避孕和HIV PrEP功效 通过重复的低剂量阴道攻击，对猕猴进行体内试验，并建立PK/PD模型。我们将使用里程碑驱动 研究方法，以推进ENG-ISL NanoMPI技术实现临床转化的最终目标， 利用跨学科团队在drugamer技术，药物输送，临床前和临床 艾滋病毒预防研究以及激素避孕药和抗逆转录病毒药物学。重要的是，NanoMPI 解决了用户对双重预防产品的偏好，自由裁量权和更长的给药持续时间。成功 完成后将产生一个多功能的MPT平台，可用于其他药物组合， 预防策略。