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.
