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

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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.