[Update: Results from this study were published in The Lancet HIV on January 30, 2024.]

Sunlenca (lenacapavir), a new injectable antiretroviral medication that can be taken once every six months, has the potential to be paired with two broadly neutralizing antibodies (bnAbs) to construct a complete twice-yearly regimen, according to an early study presented at the 30th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

In a small Phase Ib study, 21 participants with an undetectable viral load stopped their existing antiretrovirals and received Sunlenca injections plus infusions of the antibodies, dubbed teropavimab and zinlirvimab. Six months later, 90% maintained viral suppression.

These findings “demonstrate that we can offer long-acting [viral] suppression, but there is a lot more to do,” said presenter Joseph Eron, MD, of the University of North Carolina at Chapel Hill.

Sunlenca (formerly GS-6207), from Gilead Sciences, is an HIV capsid inhibitor that disrupts the cone-shaped shell that surrounds the viral genetic material and essential enzymes. Because it works differently than existing antiretrovirals, it remains active against HIV that has developed resistance to other drugs, and its long half-life means it can be taken just twice yearly.

The Food and Drug Administration approved Sunlenca in December but only for heavily treatment-experienced people with multidrug-resistant HIV who are unable to maintain viral suppression on their current regimen. However, studies show that it also works well for first-line treatment.

The Phase II/III CAPELLA trial (NCT04150068) evaluated twice-yearly Sunlenca injections plus an optimized background regimen for 72 people with extensive treatment experience and highly resistant HIV. At last year’s CROI, researchers reported results from the study’s randomized cohort, showing that 83% had an undetectable viral load at 52 weeks, rising to 94% for those with two or more active agents in their background regimen.

In the Phase II CALIBRATE trial (NCT04143594), 183 previously untreated people were randomly allocated to receive daily Sunlenca pills or twice-yearly Sunlenca injections in combination with daily oral antiretrovirals, or else a standard oral regimen (Biktarvy). As reported at CROI 2022 and in a recent edition of The Lancet HIV, 85% to 90% of people who received Sunlenca injections plus tenofovir alafenamide or bictegravir had an undetectable viral load at 54 weeks.

Sunlenca Plus Broadly Neutralizing Antibodies
These two studies showed that Sunlenca has the potential to be used as a component of a long-acting treatment regimen, but so far there are no other drugs that can be given at such a long interval, so it still must be taken with daily pills. The approved regimen with the longest duration, ViiV Healthcare’s Cabenuva (injectable cabotegravir and rilpivirine), is administered once monthly or every other month.

One potential partner might be islatravir, Merck’s experimental nucleoside reverse transcriptase translocation inhibitor. A clinical trial of Sunlenca plus islatravir was put on hold in December 2021 due to unexplained islatravir side effects, but the companies recently announced that the study will resume using a lower islatravir dose.

Combining Sunlenca with long-acting broadly neutralizing antibodies could be another path forward. These specialized antibodies, derived from people with a strong natural immune response to HIV, bind to parts of the virus that do not change very much as it evolves. Early research suggests that bnAbs might have potential for HIV pre-exposure prophylaxis (PrEP) and long-term remission. However, they are prone to resistance as the virus mutates, so they likely will work best in combination regimens.

Eron and colleagues evaluated a regimen of Sunlenca plus two bnAbs administered every six months. Teropavimab (GS-5423) is derived from a bnAb dubbed 3BNC117 that targets the CD4 binding site on HIV’s spike, which the virus uses to enter cells. Zinlirvimab (GS-2872) is derived from a bnAb called 10-1074 that binds to the V3 loop of HIV’s gp120 protein. Both bnAbs were modified to extend their half-life and allow less frequent dosing. More than half of clade B HIV—the predominant type in the United States and Europe—is highly susceptible to both antibodies, and more than 90% is highly susceptible to one or the other at a feasible dose, Eron noted as background.

This clinical trial (NCT04811040) enrolled people who were on antiretroviral therapy with an undetectable viral load for at least 18 months. The participants were tested to ensure that their HIV was sensitive to both antibodies. Among 124 people initially screened, 55 met the susceptibility criteria. Of these, 34 were not enrolled because of a temporary clinical hold on Sunlenca (due to a problem with the original glass vial) or for other reasons.

Of the remaining 21 people, all but three were men, a majority were white and one third were Latino. The median age was 44 years, and they had been diagnosed with HIV for a median of 8.2 years and on treatment for a median of 2.6 years. All had a current CD4 count above 500, with a median of approximately 900, and their CD4 count had never fallen below 350.

On the first day of the study, after discontinuing their existing antiretrovirals, everyone received a loading dose of oral Sunlenca (repeated on the second day), two subcutaneous Sunlenca injections and an intravenous infusion of teropavimab (30 milligrams per kilogram). In addition, they were randomly assigned to receive either 10 mg/kg or 30 mg/kg of zinlirvimab. Ten people in each group received the full treatment regimen and were included in the efficacy analysis.

The study was originally designed to run for 52 weeks, at which point participants would restart their prior antiretroviral regimen. However, when Sunlenca became unavailable due to the clinical hold, the study was halted at 26 weeks, after just one dose, Eron explained.

Sunlenca, teropavimab and zinlirvimab (using either dose) all remained well above therapeutic levels through 26 weeks. At that point, 90% of participants in both groups maintained an undetectable viral load. One person who received the higher dose of zinlirvimab decided he preferred pills and withdrew from the study. One person in the lower-dose group experienced viral rebound, resumed their baseline regimen and again achieved viral suppression. CD4 counts remained stable in both groups.

Treatment was safe and generally well tolerated. There were no serious adverse events or clinically meaningful laboratory abnormalities, and no one withdrew due to adverse events, Eron reported. The most common side effect was injection site reactions, such as pain, redness, swelling or nodules. Most reactions were mild to moderate, though one person developed cellulitis and one had severe redness.

“This study demonstrates that a combination of the bNAbs teropavimab and zinlirvimab together with lenacapavir can sustain viral suppression for six months in selected people with HIV,” the investigators concluded.

A Phase II clinical trial (NCT05729568) will start this year to test whether viral suppression can be maintained when the regimen is administered every six months for a longer duration.

Commenting on advances in HIV treatment over the past four decades, Eron told reporters: “We’ve gone from asking patients to wake up every four hours to take zidovudine [AZT], to combination treatment with 15 to 20 pills a day, to now having the opportunity to give therapy every six months.”

“Novel long-acting HIV treatment options will drive the next chapter in care and may help meet the therapy needs and preferences of people living with HIV,” he added in a Gilead press release.

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