PROJECT SUMMARY The long-term goal of this proposed project is to deliver an innovative, end-user-informed HIV pre-exposure prophylaxis (PrEP) product in the form of a Long-Acting Prevention Implantable System (LAPIS). LAPIS offers a combination of attributes that surpass existing delivery systems for PrEP and align with young men and women's preferences: user independence, discretion, long-term protection (1 year), as well as favorable zero- order release kinetics of drugs, reversibility over the therapeutic window, delivery of multiple antiretrovirals (ARVs), and bioerosion of the spent implant to bypass obligatory removal. The implant is uniquely retrievable, if needed, for the duration of drug delivery, but otherwise remains stationary and biodegrades after depletion of the drug. In this manner, reversal of drug delivery is possible in the case of adverse reactions or a user's desire for discontinuation. The implant technology also decouples drug delivery characteristics from biodegradation properties and can achieve zero-order kinetics of drug release. The LAPIS platform can accommodate different classes of active pharmaceutical ingredients (APIs) and also enables the delivery of combination ARVs for PrEP, thereby addressing the potential for increased efficacy (as demonstrated for oral dosing) and providing a higher barrier for ARV-resistant HIV strains. The proposed specific aims are: (1) To develop an implant system for delivery of ARVs for HIV PrEP, subcutaneously inserted and lasting 1 year to support adherence, safety, and effectiveness; (2) To evaluate safety, pharmacokinetics (PK), and in vivo drug depletion profiles of LAPIS in preclinical studies; and (3) To test the prophylactic efficacy of LAPIS in preventing wild-type and ARV- resistant simian-human immunodeficiency virus (SHIV) transmission via the penile route within nonhuman primates (NHPs). Importantly, the proposed work will leverage achievements made during earlier programs in developing the implant platform and will build upon this work in the following key aspects: long-term active pharmaceutical ingredient (API) delivery (up to 1 year), delivery of dual APIs, characterization of drug depletion profiles, and evaluation of prophylactic efficacy in NHPs. Our established and complementary team will use a Research Strategy that is milestone-driven, with clear expected deliverables guiding progress of product development and clinical translation.

PROJECT NARRATIVE The overarching goal of this proposed project is to develop an innovative end-user informed HIV pre- exposure prophylaxis (PrEP) technology in the form of a Long-Acting Prevention Implantable System (LAPIS). The implant system addresses barriers to adherence and offers the following unique attributes for PrEP delivery: user independence, biodegradation, long-term protection (1 year), and discretion of use and retrievability, if needed, for the duration of drug delivery.