PROJECT SUMMARY/ABSTRACT
There is a need to develop next-generation multipurpose prevention technologies (MPTs) that provide
long-acting (LA), simultaneous systemic delivery of products for the prevention of HIV acquisition and
unintended pregnancy. We propose to develop a novel silica hydrogel-based LA injectable depot system
delivering dolutegravir (DTG), a proven and potent HIV integrase strand-transfer inhibitor (INSTI), and
levonorgestrel (LNG), a licensed contraceptive agent. In the first (R61) phase of the project (Specific Aims 1-3),
the main objective is to achieve milestones demonstrating feasibility of developing a particle-based hydrogel
depot system capable of providing at least 3 months duration for both drugs, shorter tail pharmacokinetic (PK)
profiles, and no drug-drug interaction (DDI). In Specific Aim 1, we will conduct iterative formulation
development to produce and screen prototype combinations for initial feasibility, which will then be evaluated
preclinically in Specific Aim 2 in rat and non-human primate models to determine optimal
PK/pharmacodynamics (PD) profiles and characterize safety and DDI, to support selection of a lead MPT
formulation. In Specific Aim 3, we will engage with potential end-users in a US region with high HIV incidence
to gain a more in-depth understanding of user preferences of product attributes. In the second (R33) phase
(Specific Aims 4-6), the main objectives will be to expand product development efforts to characterize the lead
formulation and obtain IND-enabling feedback from the FDA in a pre-IND meeting, conduct POC contraceptive
efficacy and HIV prophylactic efficacy in animal studies, and define the optimal dosing regimen and target
product profile (TPP) based on end-user input. In Specific Aim 4, formulation optimization activities will be
performed to improve the harmonized PK profile and duration for each drug and to better meet the product
attribute preferences prioritized by end users. Preclinical proof-of-concept data will be generated using a rat
contraceptive efficacy model and the well-established repeated, low dose SHIV challenge models using pigtail
(intravaginal) and rhesus (intrarectal) macaques at CDC. Upon identification of the lead formulation, we will
also draft a toxicology testing plan, clinical study design and clinical development plan to support a pre-IND
meeting with the FDA (Specific Aim 5). Finally, in Specific Aim 6, we will build upon the formative work of SA3
with a discrete choice experiment to understand user and provider preferred product attributes for the LA MPT
injectable, in order to refine the TPP and guide on-going product development efforts. In summary, this project
proposes to develop, through preclinical proof-of-concept, a LA MPT injectable with a strong regulatory path for
future clinical advancement, providing a significant advancement of a next-generation HIV prevention and
contraceptive product that may fit into the lifestyles of at-risk women most in need.
