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The FDA has approved Gilead Science’s first-in-class capsid inhibitor lenacapavir, providing a new treatment option for people with multidrug-resistant HIV.
Many patients already respond well to antiretroviral regimens, built around drugs that inhibit the virus’s protease, reverse transcriptase or integrase enzymes. Lenacapavir instead takes aim at the virus’s capsid protein, which makes up the shell that protects the virus as it tries to sneak into host cells. By inhibiting the proper formation of the capsid, Gilead’s drug delivers a potent and long-lasting addition to the HIV arsenal.
The FDA approved lenacapavir on the basis of the phase II/III CAPELLA trial, in 72 heavily treatment-experienced subjects with multiclass-resistant HIV-1. In cohort 1 of this trial, 36 patients were randomized to oral lenacapavir or placebo in addition to their failing therapy for 14 days, followed by subcutaneous lenacapavir once every six months for those already on the new drug, and by oral and then subcutaneous lenacapavir for those initially on placebo. The trial met its primary endpoint, with 88% of lenacapavir recipients having a decrease of at least 0.5 log10 copies per milliliter in the viral load at day 15, compared with 17% of placebo recipients, the company reported in the The New England Journal of Medicine. In cohort 2, all patients received open-label oral lenacapavir with optimized background therapy until day 14, followed by subcutaneous lenacapavir once every six months. At week 26, 81% of the patients in cohort 1 and 83% of those in cohort 2 had viral loads of less than 50 copies per milliliter.
No serious adverse events related to lenacapavir were identified.
Further trials of the long-acting drug in various combinations are ongoing, including two large phase III trials to see if the drug can be used to prevent HIV infection in at-risk individuals.
Academic and industry drug developers have been hunting for HIV capsid inhibitors for decades. GSK also has two HIV capsid inhibitors — VH4004280 and VH4011499 — now in phase I.