Abstract Body

A program building on prior extensive structural and functional characterization of HIV capsid and spanning a decade of drug discovery work yielded lenacapavir (LEN; GS-6207), a small molecule inhibitor targeting several critical functions of HIV capsid. LEN binds at a conserved interface between capsid monomers and interferes with protein interactions essential for multiple phases of the HIV replication cycle, including both the assembly and disassembly of capsid core as well as capsid nuclear trafficking. LEN exhibits in vitro antiviral activity at picomolar concentrations against all subtypes of HIV, including strains resistant to other antiretroviral classes. A potent antiretroviral activity of a single dose LEN has been demonstrated in phase 1b viral dynamics study conducted in treatment-naive people living with HIV, and several ongoing clinical studies are evaluating the efficacy of LEN administered once every 6 months subcutaneously in combination with other antiretroviral agents. In addition, emerging efficacy data from non-human primates support further investigation of LEN as a long-acting agent for pre-exposure prophylaxis.