PROJECT SUMMARY While there are now successful treatment regimens and prevention strategies for people living with HIV/AIDS, the HIV pandemic remains a public health crisis in the United States and worldwide, with nearly 40,000 new infections each year in the US alone. To prevent the spread of HIV in vulnerable populations, the US Preventive Services Task Force has recommended HIV pre-exposure prophylaxis (PrEP) for all adults and adolescents at risk of HIV acquisition. Although current antiretroviral drug regimens are potent and well-tolerated, enabling the life-long suppression of HIV-1 infection and the prevention of HIV-1 infection in individuals at high risk, compliance rates are low. Long-acting antiretroviral drugs (ARVs) have the potential to improve drug adherence, reduce viral transmission, prevent new infections, and limit the emergence of viral drug resistance and systemic toxicities. However, the key challenge for using long-acting ARVs is to extend the dosing interval to reduce the pressure on the healthcare facilities, which are set up for every six-month clinic visits. This challenge likely reduces compliance, particularly in the PrEP setting. Poor compliance has been shown to increase infection rates and the possibility of developing drug resistance. Exavir Therapeutics, Inc has created an “ultra” long- acting ARV by developing an ultra-long-acting, nanoformulated injectable prodrug to overcome this challenge. Building upon our Phase I equivalent data, we proposed in this Direct-to-Phase II SBIR project to further develop our drug by 1) completing the Chemistry, Manufacturing, and Controls development of the drug substance and drug product, 2) completing IND-enabling studies, and 3) obtaining FDA IND approval. Upon completion, this Direct-to-Phase II SBIR project will enable the submission of an IND to the FDA for approval and preparation of our Phase I first-in-human clinical trial. If successful, the impact of our novel “ultra” long-acting ARV on HIV-1 prevention and quality of life for individuals already infected with HIV-1 will be far-reaching in real-world settings.