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

一种生物可吸收皮下植入物，用于持续输送新型成熟抑制剂以预防 HIV 感染

基本信息

批准号：
10458685
负责人：
John A Moss
金额：
$ 90.42万
依托单位：
OAK CREST INSTITUTE OF SCIENCE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-28 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458685
关键词：
AIDS prevention Academia Address Adherence Animal Model Anti-Retroviral Agents Area Automobile Driving Biodegradation Biological Markers Clinical Clinical Trials Collaborations Complex Coupled Dapivirine Development Devices Digit structure Dose Drug Delivery Systems Drug Kinetics Evaluation Excision Formulation Frequencies Fumarates Generations Goals HIV HIV Infections Histology Human Image Implant In Vitro Individual Industry Infection Inflammation Injectable Integrase Inhibitors Intervention Kinetics Knowledge Longitudinal Studies Macaca Macaca mulatta Mass Spectrum Analysis Measures Medical Methodology Methods Modeling Nucleosides Oral Participant Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase I Clinical Trials Plasma Prevention Process Public Health RNA-Directed DNA Polymerase Rattus Recording of previous events Regimen Research Resistance profile Reverse Transcriptase Inhibitors Risk Route Safety Scientific Advances and Accomplishments Sheep Techniques Technology Tenofovir Topical application Ultrasonography Vagina Vaginal Ring Water Woman design efficacy study emtricitabine experience implant design improved in vivo in vivo Model inhibitor innovation lead candidate men metabolomics nanomolar non-nucleoside reverse transcriptase inhibitors nonhuman primate novel pharmacokinetics and pharmacodynamics pill pre-clinical pre-exposure prophylaxis preclinical development prevent programs prophylactic rectal safety study sheep model simian human immunodeficiency virus subcutaneous success transmission process truvada ultrasound uptake

项目摘要

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.

项目概要使用口服或局部抗逆转录病毒 (ARV) 药物进行暴露前预防 (PrEP) 可预防 HIV 然而，易感、未感染个体的感染。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。一些人的依从性较差。阴道环 (IVR) 提供非核苷逆转的 ASPIRE 试验中的参与者组转录酶抑制剂 (NNRTI) 达匹韦林 (DPV) 表明存在多种依从障碍，并且为了成功实施有效的治疗方案，还需要采取除减少给药频率以外的策略非疫苗，预防艾滋病毒感染的方法，可维持维持的“长效”皮下植入抗逆转录病毒制剂。为期 6 个月、最好是 1 年或更长时间的保护可以通过最大限度地减少一旦做出最初的产品采用决定，就可以确定产品的使用需求。我们提出了一种可吸收皮下植入物持续/缓释药物输送系统（SER-DDS）将开发一种成熟抑制剂机械类的新型抗逆转录病毒药物。通过采用设计、制造和体外研究的三层配方开发流程该药物在三种动物模型中反复进行体内 PK、降解、安全性和功效研究。 DFH-1160005，一种新型桦木醇衍生的第二代成熟抑制剂 (MI)，具有个位数纳摩尔浓度对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且可靠的药物。有效预防 HIV 的 SER-DDS；了解持续、系统性治疗的基本药理学； DFH-1160005 在阴道和直肠 HIV 感染的情况下给药，并应用严格的方法在目标 1 中，我们在临床前体内模型中表征植入物降解并评估安全性和有效性。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 研究在目标 2 中，我们将研究 SER-DDS 的体外降解和再吸收动力学和机制。在目标 3 中，我们将评估主要候选 SER-DDS 在绵羊中的安全性并探索功效和 PK- 非人类灵长类动物直肠和阴道挑战 SHIV 感染模型中的药效关系。