Lenacapavir plus broadly neutralising antibodies could be twice-yearly HIV treatment

Two broadly neutralising antibodies, teropavimab and zinlirvimab, might be good partners for lenacapavir (Sunlenca) in a long-acting HIV treatment regimen, according to study results presented yesterday at the Conference on Retroviruses and Opportunistic Infections (CROI 2025) in San Francisco.

“We believe that the high efficacy of viral suppression and the safety data support continuing our study and support the clinical development of what we think is an exciting six-monthly HIV regimen,” Dr Onyema Ogbuagu of Yale University said at a conference media briefing.

Lenacapavir, which is administered by injection every six months, is approved for heavily treatment-experienced people with multidrug-resistant HIV. But it currently does not have equally durable partners to build a complete twice-yearly regimen, so for now it must be used with daily oral antiretrovirals. Broadly neutralising antibodies (bnAbs) have the potential to fill that gap.

People living with HIV normally produce HIV-specific antibodies, but these mostly target parts of the virus that are hidden or highly variable. However, a small proportion of people naturally make bnAbs that target conserved parts of the virus that do not change much. These specialised antibodies are being explored for HIV prevention, treatment and cure research. As with antiretroviral drugs, though, the virus can develop resistance to bnAbs, so they are best used in combination therapy.

Lenacapavir plus two bnAbs

Ogbuago and colleagues conducted a phase II clinical trial (NCT05729568) of the triple combination of lenacapavir, teropavimab and zinlirvimab, all from Gilead Sciences, in people with viral suppression.

Lenacapavir is the only approved HIV capsid inhibitor. Teropavimab (GS-5423) is derived from a bnAb called 3BNC117 that targets the CD4 binding site, 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 envelope. Both bnAbs were modified to extend their half-life in the body and enable less frequent dosing. Prior research found that around half of subtype B HIV (the most common type in Europe and the US) is highly susceptible to both antibodies and over 90% is sensitive to at least one of them.

At CROI 2023 and in The Lancet HIV, researchers reported results from a small phase I trial (NCT04811040) showing that the triple combination – dubbed LTZ – maintained viral suppression for six months in people highly susceptible to both bnAbs. Further data reported at CROI 2024 and at the HIV Drug Therapy Glasgow meeting in November showed that the combination could be effective for people who were highly sensitive to at least one of the antibodies if they received a high enough dose of zinlirvimab. Those results underscore the importance of screening for viral sensitivity to the antibodies prior to treatment.

These findings set the stage for the phase II study, which enrolled 80 participants who were highly susceptible to both teropavimab and zinlirvimab according to a phenotypic resistance assay. About half of those screened were sensitive to both bnAbs, Ogbuagu reported; 24% were sensitive to teropavimab only, 16% to zinlirvimab only and 12% to neither antibody. The participants had viral suppression (viral load below 50 copies) on a standard daily oral antiretroviral regimen for at least a year and had a CD4 cell count of at least 200.

Compared with the phase I trial, the phase II study enrolled a more diverse population, Ogbuago said. About 80% were in the United States. Although most (85%) were men, more than a third were Black and a quarter were Latino. The median age was approximately 51 years. They had well preserved immune function with a mean baseline CD4 count of 749.

After antibody sensitivity screening, 53 people were randomly assigned to switch to lenacapavir plus the two bnAbs while 27 stayed on their daily oral regimen. The group that switched received a loading dose of oral lenacapavir on the first two days, subcutaneous injections of lenacapavir (927mg) every six months and intravenous infusions of teropavimab (2550mg) and zinlirvimab (2550mg) every six months. The 2550mg fixed doses are comparable to the 30 mg/kg weight-based doses used in the phase I study.

The primary study endpoint was the proportion of participants with an undetectable viral load at week 26. The response rate was high overall: 96% of people in both treatment groups maintained viral suppression. Lenacapavir, teropavimab and zinlirvimab remained well above therapeutic levels over time. Average CD4 counts increased, with no significant difference between the groups.

One person in the LTZ group experienced virological failure. This individual had a viral blip at week 12 and higher viral rebound around week 24, after which they resumed Biktarvy (bictegravir / tenofovir alafenamide / emtricitabine) and regained viral suppression. While this participant maintained average levels of the two bnAbs, the lenacapavir concentration fell below the mean. The person developed resistance to lenacapavir (Q67H mutation) and loss of susceptibility to zinlirvimab when tested at 24 weeks.

The LTZ regimen was safe and generally well tolerated with no severe drug-related adverse events, serious treatment-emergent adverse events or withdrawals due to adverse events. The most common side effect in the LTZ group was mild lenacapavir injection site reactions. About 40% developed nodules due to the formation of a ‘depot’ of lenacapavir under the skin. Pain and other injection site reactions were less common and usually mild. No one in this group experienced infusion-related reactions to teropavimab or zinlirvimab. One person in the oral treatment group withdrew due to a serious event (metastatic pancreatic cancer).

These findings show that the efficacy of the twice-yearly LTZ triple combination was comparable to continued daily oral treatment at 26 weeks, the researchers concluded. The study is ongoing with plans for an extension to 52 weeks, according to Ogbuagu.

Earlier this year, the US Food and Drug Administration granted a Breakthrough Therapy Designation for the LTZ regimen, which is intended to speed up the development of new drugs that may demonstrate substantial improvement over available therapy.

Twice-yearly LTZ is a “huge advance” and is “the longest-acting complete regimen in advanced development,” Ogbuago told reporters. “The beauty of it is that you can administer them together, which would improve the logistics of therapy.”