If Twice-Yearly Lenacapavir Could Be a HIV PrEP Game Changer, Would a Once-Yearly Version Be a HIV Epidemic Ender?

Gilead has reported results for a once-yearly intramuscular injection that show blood concentrations of lenacapavir exceed those from the twice-yearly dosing

Early results indicate a yearly intramuscular injection of lenacapavir could be more effective at preventing HIV infection than a twice-yearly dose given subcutaneously, according to new clinical data presented at the Conference on Retroviruses and Opportunistic Infections (CORI) and simultaneously published in The Lancet.

The positive results for the twice-yearly dose for the preexposure prophylaxis (PrEP) version of lenacapavir were hailed as a major breakthrough when Gilead Sciences reported them last year, and now the company is pushing the timing of the preventive injections out further to once a year.

“By decreasing dosing frequency and providing an additional PrEP option for people who want or need PrEP, yearly dosing of lenacapavir has the potential to further decrease current barriers to PrEP by increasing the uptake of, persistence on and, therefore, scalability of PrEP,” wrote corresponding author Renu Singh, Ph.D., senior director of clinical pharmacology at Gilead Sciences, and co-authors in The Lancet article.

Gilead has submitted an application for approval of the twice-yearly shot, and the company says the FDA has indicated it will make a decision — the so-called Prescription Drug User Fee Act, or PDUFA date — June 19.

The phase 1 results reported at the CROI meeting in San Francisco showed that the concentrations of lenacapavir in the blood stayed higher after the yearly dose than after the twice-yearly dose, suggesting that the yearly dose could be more protective against HIV infection. None of the 40 participants enrolled in the trial experienced serious side effects. Most (31) of the participants experienced injection-site pain, but it was gone after 15 days. Putting ice on the ventrogluteal injection site — the upper part of the buttock — before the injection reduced the pain and made it go away faster.

The twice-year dose of lenacapavir consists of 927 milligrams (mg) of lenacapavir delivered as two, 1.5 milliliter (mL) subcutaneous injections accompanied by two oral doses of 600 mg. The once-yearly dose is 5,000 milligrams of the drug delivered as two, 5 mL intramuscular injections. In this phase 1 trial, the Gilead researchers tested two formulations, with one having more ethanol than the other. The ethanol decreases viscosity.

They calculated plasma concentrations of lenacapavir in several ways: peak plasma concentration, time to reach peak plasma concentration, and trough, or the lowest, concentration. The peak concentration for the two formulations of the yearly dose was four to five times higher than the peak concentration of the twice-yearly dose. The measurement of the trough concentration at 52 weeks for the two formulations of the yearly dose was more than twice as high as the trough concentration for the twice-yearly dose at 26 weeks when another dose would be given.

Efforts to develop a vaccine against HIV have failed, so currently, hopes for preventing HIV are pinned on PrEP, which consists of the same antiviral medication used to treat HIV but at lower doses and taken preventively. There are formulations of PrEP taken as pills, but that leads to adherence problems. Injections given relatively infrequently are seen as more promising than pills for widespread, effective PrEP. So far, the FDA has approved only one injectable PrEP, Apretude (cabotegravir), which is injected intramuscularly and on an every-other-month schedule.

The 2019 Ending the HIV Epidemic in the U.S. initiative, launched during President Donald Trump’s first administration, had a goal of reducing new HIV infections by 75% by 2025 and by 90% by 2030. According to a March 2024 report about progress toward meeting the initiative’s goals, there were an estimated 32,100 new HIV infections in 2021, 12% fewer compared with 2017 (36,500 infections), but a far cry from the 75% reduction target for this year. In 2022, preliminary data showed 36% of people who could benefit from PrEP were prescribed it. The report says the goal is to increase that proportion to 50% by this year.