FDA Approves Novel Capsid Inhibitor for Super-Refractory HIV-1 Infection

The US Food and Drug Administration (FDA) approved lenacapavir (Sunlenca^®; Gilead Sciences), in combination with other antiretroviral therapy (ART), for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection.

Lenacapavir, a first-in-class long-acting HIV capsid inhibitor, is initially administered via oral tablets (300 mg) and subcutaneous injections (463.5 mg/1.5 mL), followed by maintenance injections every 6 months. By blocking the HIV-1 virus' protein shell, or capsid, the novel therapy interferes "with multiple essential steps of the viral life cycle," according to the FDA.

"Today's approval ushers in a new class of antiretroviral drugs that may help patients with HIV who have run out of treatment options," said Debra Birnkrant, MD, director, Division of Antivirals, Center for Drug Evaluation and Research, FDA, in an agency press release. "The availability of new classes of antiretroviral medications may possibly help these patients live longer, healthier lives."

The safety and efficacy of lenacapavir were established through the multicenter phase 2/3 CAPELLA clinical trial that included 72 patients. Participants had high viral loads despite their ART regimens and had undergone previous treatment with a median of 9 antiretroviral medications.

Participants were enrolled into 1 of 2 study groups: one group was randomized to receive either lenacapavir or placebo in a double-blind fashion, and the second group received open-label lenacapavir.

The primary outcome measure was the proportion of patients in group 1 who achieved a 0.5 log₁₀ reduction in HIV-1 viral load during the initial 14 days compared to baseline.

Results showed that 87.5% of patients in group 1 who received lenacapavir achieved a 0.5 log₁₀ reduction in HIV-1 viral compared to 16.7% of those who received placebo. In addition, 81% and 83% of participants given lenacapavir in group 1 achieved undetectable levels of HIV RNA at 26 and 52 weeks, respectively.

"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 site principal investigator of CAPELLA, in a Gilead press release.

"The availability of new classes of antiretroviral drugs is critical for heavily treatment-experienced people with multi-drug resistant HIV," continued Segal-Maurer. "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."

Common adverse events with lenacapavir included nausea and injection site reactions, with some of the reactions described as nodules or indurations that proved persistent in some patients. The FDA also included warnings and precautions about the risk for developing immune reconstitution syndrome and noted that low levels of lenacapavir due to missed doses may increase the risk of viral resistance.

As residual amounts of lenacapavir can remain in the body for a year or longer, the risk of drug interactions can persist. Gilead noted that inducers of CYP3A can decrease lenacapavir concentrations; while drugs that strongly inhibit CYP3A, P-gp, and UGT1A1 can increase concentrations of the capsid inhibitor.