A Bioresorbable Subdermal Implant for Sustained Delivery of a Novel Maturation Inhibitor to Prevent HIV Infection

项目总结 暴露前预防(PrEP)使用口服或局部给药的抗逆转录病毒(ARV)药物可以预防艾滋病毒 易感人群感染，未感染人群感染。然而，坚持每天或每月给药方案， 已经成为推动艾滋病毒PrEP临床成功的关键因素。一些人的坚持性很差 ASPIRE阴道内环(IVR)递送非核苷反转试验的参与者组 转录酶抑制剂(NNRTI)达匹韦林(DPV)表明存在多个障碍， 要成功实施有效的 非疫苗，预防艾滋病毒感染的方法。“长效”皮下植入抗逆转录病毒制剂 保护期为6个月，最好是1年或更长时间，通过最大限度地减少 一旦做出最初的产品吸收决策，产品的使用需求。 我们提出了一种可吸收皮下埋植剂缓释/缓释给药系统(SER-DDS) 提供一种成熟抑制机制类的新型抗逆转录病毒药物。植入物将被开发出来 通过使用设计、制造和体外研究的三层配方开发过程 迭代结合体内PK，在三个动物模型中进行降解、安全性和有效性研究。这药是 DFH-1160005，一种新型白桦醇类第二代成熟抑制因子(MI)，具有一位数纳米分子 抗艾滋病毒的效力和强大的耐药性。该计划的目标是开发一种安全和 有效预防艾滋病毒的SER-DDS；了解持续、全身性 DFH-1160005分娩在阴道和直肠艾滋病毒感染的背景下，并应用严格的方法来 在临床前的活体模型中表征植入物的降解，并评估安全性和有效性。在目标1中，我们 将在大鼠、绵羊和恒河猴身上配制植入物，测量体外药物释放，并进行PK研究 猕猴。在目标2中，我们将研究SER-DDS在体外的降解和再吸收动力学和机制 在活体内。在目标3中，我们将评估主要候选SER-DDS在绵羊身上的安全性，并探索其有效性和PK-2。 非人灵长类动物直肠和阴道感染SHV感染模型的药效学关系。

PROJECT SUMMARY Pre-exposure prophylaxis (PrEP) using orally or topically delivered antiretroviral (ARV) drugs can prevent HIV infection in susceptible, uninfected individuals. Adherence to the daily or monthly dosing regimens, however, has emerged as a critical factor driving the clinical success of HIV PrEP. The poor adherence of some participant groups in the ASPIRE trial of an intravaginal ring (IVR) delivering the non-nucleoside reverse transcriptase inhibitor (NNRTI) dapivirine (DPV) indicates that multiple barriers to adherence exist, and strategies beyond decreased dosing frequency will be required for successful implementation of an effective non-vaccine, method to prevent HIV infection. “Long-acting” subdermal implant ARV formulations that maintain protection for periods of 6 months, and preferably 1 year, or more may increase adherence by minimizing a product's use demands once the initial product uptake decision is made. We propose a resorbable subdermal implant Sustained/Extended Release Drug Delivery System (SER-DDS) delivering a novel ARV agent from the maturation inhibitor mechanistic class. The implant will be developed through a three-tiered formulation development process employing design, fabrication, and in vitro studies iteratively coupled with in vivo PK, degradation, safety, and efficacy studies in three animal models. The drug is DFH-1160005, a novel betulin-derived, 2nd generation maturation inhibitor (MI) with single-digit nanomolar potency against HIV and a robust resistance profile. The program objectives are to develop a safe and effective SER-DDS for HIV prevention; understand the fundamental pharmacology of sustained, systemic DFH-1160005 delivery in the context of vaginal and rectal HIV infection, and apply rigorous methodologies to characterize implant degradation and evaluate safety and efficacy in preclinical in vivo models. In Aim 1, we will formulate implants, measure drug release in vitro, and conduct PK studies in rats, sheep, and rhesus macaques. In Aim 2, we will investigate SER-DDS degradation and resorption kinetics and mechanisms in vitro and in vivo. In Aim 3, we will evaluate lead candidate SER-DDS safety in sheep and explore efficacy and PK- pharmacodynamic relationships in a non-human primate rectal and vaginal challenge SHIV infection model.