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Lenacapavir: a first-in-class HIV-1 capsid inhibitor
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Dvory-Sobol, Hadas; Shaik, Naveed; Callebaut, Christian; Rhee, Martin S.
Jan 2022
Abstract
Purpose of review
This review summarizes available data for lenacapavir, an investigational first-in-class agent that disrupts functioning of HIV capsid protein across multiple steps in the viral life cycle.
Recent findings
Lenacapavir demonstrated picomolar potency in vitro with no cross resistance to existing antiretroviral classes and potent antiviral activity in persons with HIV-1. In persons with HIV-1, there was no preexisting resistance to lenacapavir regardless of treatment history. Lenacapavir can be administered orally either daily or weekly and subcutaneously up to every 6 months. In heavily treatment-experienced persons with multidrug-resistant HIV-1 and in treatment-naive persons with HIV-1, lenacapavir in combination with other antiretroviral agents led to high rates of virologic suppression and was well tolerated.
Summary
Ongoing studies are evaluating long-acting dosing of lenacapavir for treating HIV-1 in combination with other antiretrovirals and preventing HIV-1 as a single agent.
INTRODUCTION
Combination antiretroviral therapy (cART) suppresses HIV-1 replication and increases CD4+ cell counts. Persons on cART are projected to have lifespans equivalent to those without HIV-1 and do not transmit the virus to sexual partners if viral load is below detectable levels [1,2]. In addition, preexposure prophylaxis (PrEP) is highly effective in preventing new infections among individuals at risk. However, oral cART and PrEP regimens need to be taken every day and require near-perfect adherence to minimize the emergence of drug resistant variants and prevent new infection, respectively.
Suboptimal adherence is a major cause of incomplete viral suppression, and there are multiple barriers to adherence, such as inconvenience, side effects, stigma and discrimination [3]. Some persons with HIV-1 (PWH) eventually lose virologic, immunologic or clinical benefit from individual regimens, and PWH with multiple prior regimen failures and significant drug resistance have limited treatment options. Therefore, developing well tolerated and effective therapies for heavily treatment-experienced (HTE) individuals with multidrug-resistant HIV-1 is a priority.
Lenacapavir is a novel, first-in-class, multistage, selective inhibitor of HIV capsid protein. In clinical studies, lenacapavir has demonstrated successful antiviral activity and adequate pharmacokinetic exposure for up to 6 months after a single subcutaneous injection. As described in the following section, existing Phase 1, 2 and 2/3 data support lenacapavir use in both HTE and treatment-naive PWH in combination with antiretroviral agents.
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