SUMMARY HIV/AIDS remains a formidable global epidemic, with ~37 million people infected (including ~1.1 million in the US) and about one million AIDS-related deaths in 2017 (UNAIDS, CDC). Despite the efficacy of modern combination anti-retroviral therapy (cART), side effects and drug resistance remain serious obstacles to achieving optimal care, and poor adherence is a key factor in treatment failure. Thus, there is continued demand for well-tolerated HIV inhibitors with novel mechanisms of action and stronger barriers to resistance. HIV specialists are especially enthusiastic about the potential of long-acting therapies to minimize side effects, enhance efficacy, and delay resistance through improved compliance. Navigen has identified a novel, protease-resistant D-peptide HIV entry inhibitor, CPT31, with these desired characteristics and has advanced it through preclinical development. CPT31 addresses many of the limitations of current cART and has proven to be well tolerated and highly efficacious for both indications in non-human primates (NHPs), making it an ideal candidate for both therapy and PrEP. Additionally, CPT31’s PK makes it amenable to monthly and perhaps quarterly dosing (with depot formulation). In this grant application, we will partner with Johns Hopkins University to conduct a Phase Ia/Ib safety, tolerability, pharmacokinetics, and pharmacodynamics study of CPT31. The study will include three stages: 1) single ascending dose (SAD) in healthy volunteers, 2) multiple ascending dose (MAD) in healthy volunteers, and 3) MAD in HIV positive patients classified as Group 1 under the FDA guidance for industry. This study will enable Navigen to determine whether CPT31 has the characteristics that warrant continued clinical studies and further investment.