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

项目摘要 使用口服或局部给予抗逆转录病毒（ARV）药物的暴露前预防（PrEP）可以预防艾滋病毒 感染易感的未感染个体。然而，坚持每日或每月给药方案， 已成为推动HIV PrEP临床成功的关键因素。 ASPIRE试验的参与者组， 转录酶抑制剂（NNRTI）达匹韦林（DPV）表明存在多种依从性障碍， 为了成功实施有效的治疗方案，需要采取降低给药频率以外的策略。 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， 6个月、优选1年或更长时间的保护可以通过最小化 产品的使用需求，一旦最初的产品摄取决定作出。 我们提出了一种可吸收的皮下埋植型缓释/缓释给药系统（SER-DDS） 递送来自成熟抑制剂机制类别的新型ARV剂。植入物将被开发 通过采用设计、制造和体外研究的三层配方开发过程 在三种动物模型中进行的体内PK、降解、安全性和有效性研究迭代结合。述药物是 DFH-1160005，一种新的白桦脂衍生的第二代成熟抑制剂（MI），具有个位数纳摩尔浓度 抗HIV的效力和强大的耐药性。该计划的目标是建立一个安全和 有效的SER-DDS预防艾滋病毒;了解持续，全身 DFH-1160005在阴道和直肠HIV感染的情况下分娩，并采用严格的方法， 在临床前体内模型中表征植入物降解并评价安全性和有效性。目标1： 将配制植入物，测量体外药物释放，并在大鼠，绵羊和恒河猴中进行PK研究 猕猴目的2：研究SER-DDS体外降解和吸收动力学及机制 和体内。在目标3中，我们将评估主要候选药物SER-DDS在绵羊中的安全性，并探索其疗效和PK。 在非人灵长类动物直肠和阴道攻击SHIV感染模型中的药效学关系。

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.