Originally published by our sister publication Infectious Disease Special Edition
The FDA approved lenacapavir (Sunlenca, Gilead), in combination with other antiretroviral(s) (ARV) for the treatment of HIV-1 in heavily treatment-experienced adults with multidrug-resistant (MDR) infection.
The approval for lenacapavir, a first-in-class, long-acting HIV capsid inhibitor that is injected twice yearly, is supported by data from the phase 2/3 CAPELLA trial. The study evaluated lenacapavir with an optimized background regimen in people with MDR HIV who are heavily treatment experienced. Study participants had received previous treatment with a median of nine ARV medications.
CAPELLA is an international, multicenter, double-blind, placebo-controlled study designed to evaluate the antiviral activity of lenacapavir administered every six months as a subcutaneous injection in heavily treatment-experienced people with MDR HIV. The trial includes men and women with HIV-1 and is being conducted at research centers in North America, Europe and Asia.
In CAPELLA, 36 participants resistant to multiple classes of ARV and who had a detectable viral load while not responding to a regimen were randomly assigned to receive oral lenacapavir or placebo in a 2:1 ratio for 14 days, in addition to continuing their failing regimen (functional monotherapy). An additional 36 participants were enrolled in a separate treatment cohort.
The primary end point was the proportion of participants randomly allocated to receive lenacapavir or placebo for 14 days, in addition to continuing their failing regimen, achieving a 0.5 log10 copies/mL or greater reduction from baseline in HIV-1 RNA at the end of the functional monotherapy period.
The study found that 88% of participants receiving lenacapavir (21/24) experienced at least a 0.5 log10 reduction in HIV-1 viral load by the end of 14 days of functional monotherapy compared with 17% of those receiving placebo (2/12).
Following the 14-day functional monotherapy period, participants randomly allocated to receive lenacapavir or placebo, in addition to continuing their failing regimen, started open-label lenacapavir and an optimized background regimen, while those enrolled in the separate treatment cohort received open-label lenacapavir and an optimized background regimen on day 1. This ongoing maintenance period is evaluating the additional study end points of safety and efficacy of subcutaneous lenacapavir administered every six months in combination with an optimized background regimen (N Engl J Med 2022;386:1793-1803. doi:10.1056/NEJMoa2115542).
Both cohorts are part of the ongoing maintenance period of the study, evaluating the safety and efficacy of subcutaneous lenacapavir administered every six months with an optimized background regimen.
Lenacapavir tablets are approved for oral loading during initiation of the long-term treatment, prior to or at the time of the first long-acting lenacapavir injection depending on initiation option.
The most common adverse reactions (incidence ≥3%, all grades) were injection site reactions (65%) and nausea (4%). Concomitant administration of Sunlenca is contraindicated with strong CYP3A inducers. For more information, see the package insert.
Lenacapavir has a multistage mechanism of action distinguishable from other classes of antiviral agents and no known cross-resistance exhibited in vitro to other existing drug classes.
“An effective antiretroviral regimen can be devised for most people living with the virus. However, some people living with HIV no longer have durable viral suppression due to resistance to multiple classes of antiretroviral therapies,” said Sorana Segal-Maurer, MD, the director of the Dr. James J. Rahal Jr. Division of Infectious Diseases at NewYork-Presbyterian Queens, and a Pprofessor of clinical medicine at Weill Cornell Medicine, both in New York City, and the site principal investigator for the CAPELLA trial.
“The availability of new classes of antiretroviral drugs is critical for heavily treatment-experienced people with multidrug-resistant HIV. Following today’s decision from the FDA, lenacapavir helps to fill a critical unmet need for people with complex prior treatment histories, and offers physicians a long-awaited twice-yearly option for these patients who otherwise have limited therapy choices."
Despite the significant advances in ARV therapy, there remain numerous critical and pressing unmet needs for people living with HIV, according to Gilead. This is particularly true for individuals who are heavily treatment experienced, who account for an estimated 2% of adults living with HIV who are on treatment globally, and are unable to maintain virologic suppression due to resistance, intolerance or safety considerations. This type of complexity further increases the chance of treatment failure, underscoring the need for new treatment options that are active against resistant variants of the virus with a novel mechanism of action.
Lenacapavir is also being studied for pre-exposure prophylaxis (PrEP).
“This news is an important milestone in the work to help end the HIV epidemic, as Sunlenca is now the only FDA-approved, twice-yearly treatment for people with multidrug-resistant HIV,” said Daniel O’Day, the chair and CEO at Gilead. “Our goal is to deliver multiple long-acting options for treatment and prevention that are tailored to the needs of people living with HIV and people who could benefit from PrEP medicines.”
The FDA granted lenacapavir a breakthrough therapy designation.
—From company press materials