Abstract
Long-acting (LA) pre-exposure prophylactic (PrEP) strategies offer the promise of improving adherence to
therapeutic regimen for maximal HIV preventive efficacy. Key attributes of zero-order release kinetics, long-term
drug delivery, user-independent dosing, therapeutic discretion, safety for chronic use and retrievability are
desirable criteria for successful widespread clinical PrEP implementation. To date, LA PrEP strategies do not
sufficiently address the aforementioned criteria. Our goal is to address these limitations by developing an ultra-
long acting islatravir (ISL) delivery implant with an unprecedented release duration of at least 2 years
uninterrupted for durable and safe HIV prevention independent of user adherence. To achieve this goal, we
propose the NanoDDI, a transcutaneously refillable subcutaneous nanofluidic drug delivery implant for sustained
and constant ISL release. The NanoDDI comprises a newly patented nanofluidic membrane, and ports for rapid,
minimally invasive transcutaneous drug refilling. Refilling is performed manually via a syringe without any
complex pumps or equipment to extend implant use duration beyond 2 years. The nanofluidic membrane use
nanochannels to control drug release through passive diffusion without pumping mechanisms, permitting
discrete, long-term user-independent dosing. Unlike injectables or other LA polymeric strategies, NanoDDI
avoids burst and decay release. Zero-order release kinetics is achieved independent of physiological conditions,
regardless of interindividual heterogeneity. Importantly, the NanoDDI addresses user preferences for discretion
and longer dose duration.
Here we will test the hypothesis that constant and sustained ISL delivery from NanoDDI will achieve preventative
drug levels for a 2-year duration and effectively prevent SHIV infection in non-human primates (NHP). This
proposal outlines a comprehensive preclinical framework fundamental for developing NanoDDI as a HIV PrEP
platform, leveraging the team’s experience in pre-clinical and clinical HIV PrEP, long-acting drug delivery, drug
formulation, and antiretroviral pharmacology. We aim 1) to develop and optimize NanoDDI and ISL formulation
for sustained and constant release; 2) to assess pharmacokinetics (PK), tolerability, and safety of NanoDDI-ISL
for 2 years in NHP and evaluate effectiveness of transcutaneous drug refilling; and 3) to comprehensively
evaluate PrEP efficacy of NanoDDI-ISL in NHPs using 4 routes of simian HIV transmission, namely rectal, penile,
vaginal and intravenous.
Our multidisciplinary team has a solid history of collaborative HIV PrEP studies with long-acting drug delivery
implants and will receive Merck’s scientific and technical support and drug supply for this study. We will use a
milestone-driven research approach to advance the NanoDDI-ISL technology towards the ultimate goal of clinical
translation.
