Novel Capsid Inhibitor Approved for Super-Refractory HIV

The FDA approved lenacapavir (Sunlenca) in combination with antiretroviral therapy (ART) for heavily pretreated HIV-1 patients with drug-resistant infections, and for those who cannot tolerate other available options.

Lenacapavir, a first-in-class long-acting HIV capsid inhibitor, is initially administered via oral tablets (300 mg) and subcutaneous shots (463.5 mg/1.5 mL), which are then followed by maintenance injections every 6 months. In 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 agency.

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

Supporting approval was the multicenter CAPELLA trial, which included 72 patients with drug-resistant HIV-1 infections. Patients enrolled in the phase II/III study had high viral loads despite their ART regimens.

During a randomized double-blind phase of the trial, 36 patients were given either oral lenacapavir or placebo, in addition to their failing regimens. At 14 days, 87.5% of patients on lenacapavir achieved a 0.5 log₁₀ reduction in HIV-1 viral load compared with 16.7% of the placebo patients.

During an open-label phase, 81% and 83% of participants on lenacapavir 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, of NewYork-Presbyterian/Weill Cornell Medicine in New York City, in a press release from drugmaker Gilead.

"The availability of new classes of antiretroviral drugs is critical for heavily treatment-experienced people with multi-drug resistant HIV," continued Segal-Maurer, who served as a site investigator in the CAPELLA trial. "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 might increase the risk of viral resistance.

As residual amounts of the drug 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 inhibit CYP3A, P-gp, and UGT1A1 can increase concentrations of the capsid inhibitor.

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