Research Project
9870875
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.
