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.

项目摘要/摘要 由于孕产妇死亡率和艾滋病是由于生殖年龄妇女的主要死亡原因 意外怀孕和艾滋病毒感染的不成比例。同时有效的预防方法 存在，只有21％的妇女可以使用现代避孕药，并遵守艾滋病毒准备方案很差 在许多艾滋病毒 - 内态地区。多用途预防技术（MPT）旨在同步避孕技术 使用艾滋病毒准备的交付，提供以患者为中心的方法为性活跃的女性提供双重覆盖 在单个产品中。可以以谨慎方式管理的长效统一交付产品可以 减少避孕药和艾滋病毒准备的污名，从而改善摄取和遵守 预防产品。我们的目标是开发Etonogestel（Eng）和Islatravir的长效交付植入物 （ISL）具有前所未有的2年释放持续时间的药物，以消除妊娠和艾滋病毒的预防 依从性的进一步需求。将带来新的皮下纳米富集植入物（Nanompi） 连同一种称为“药物制剂”的新聚合物前药技术，以实现这种创新的产品 提供超长表演ENG+ISL药物剂量持续时间的候选人。 Nanompi利用了纳米流体 带有纳米通道和单个药物储层的膜，通过 被动扩散而无需泵送机制，允许谨慎，与用户无关的给药。关键产品 属性将包括在多年时间内进行药物稳定，最小化早期和晚期爆发 和药代动力学（PK）尾巴，零级药物释放动力学动力学针对单个药物PK/PD量身定制 （药效）要求，与用户无关的剂量和可检索性。该项目围绕着 3个具体目的：1）开发优化的Eng-Isl Drugmer公式，以稳定药物并暴露 所需的零订单释放曲线，并与Nanompi设备的优化一起进行了2年的持续 发布; 2）评估铅英语nanompi设备的药代动力学，耐受性和安全性2年 在辫子猕猴中； 3）评估辫子中英语nanompi的避孕和艾滋病毒准备效率 猕猴通过重复的低剂量阴道挑战并发展PK/PD模型。我们将使用一个里程碑驱动的 将Eng-Isl Nanompi技术推向临床翻译的最终目标的研究方法， 利用跨学科团队在药物技术，药物交付，临床和临床方面的经验 HIV预防研究以及激素避孕药和抗逆转录病毒药理学。重要的是，nanompi 解决用户对双重预防产品，酌处权和较长剂量持续时间的偏好。成功的 完成将产生一个多功能的MPT平台，该平台可以用于其他药物组合和 预防策略。