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Lenacapavir + super antibodies

Super antibodies (so-called broadly neutralizing antibodies, or bNAb) have been developed that are generally highly active against HIV in experiments with cells and viruses in the lab as well as in animals. These antibodies bind to HIV and prevent it from attaching to the CD4 receptor on cells; as a result, HIV is not able to infect a cell.

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Gilead Sciences is developing the following two bNAbs:

  • teropavimab (Tab)
  • zinlirvimab (Zab)

Both antibodies persist a long time after administration (intravenously), which allows for dosing every six months.

Gilead is testing a combination of these antibodies with the antiviral drug lenacapavir (a capsid inhibitor). In lab experiments with cells, the combination of all three agents has been found to be potent. Preliminary testing in people also suggests that these drugs combined have a high level of effectiveness. In one study, 18 out of 20 people were able to maintain virological suppression for six months after dosing.

A drawback of antibody-based therapy is that participants have to be tested before using it to find out if their HIV is susceptible to the antibodies. Such testing is not yet routine.

In one study, researchers enrolled participants who were susceptible to at least one of the antibodies. Participants who were already suppressed on oral regimens (of other drugs) were randomly assigned to one of the following long-acting regimens:

  • lenacapavir + Tab 30 mg/kg of body weight + Zab 10 mg/kg – 5 people
  • lenacapavir + Tab 30 mg/kg + Zab 30 mg/kg – 6 people

They stopped their oral regimens and immediately received the study regimens.

Drugs were injected once and participants were monitored for 26 weeks. After that they would restart standard oral ART (taken daily).

Lenacapavir was given orally at a dose of 600 mg on days 1 and 2 of the study. It was also injected subcutaneously at a dose of 927 mg on day 1.

Antibodies were given intravenously on day 1.

One person taking Zab 10 mg left the study because they developed chronic hepatitis B virus infection (HBV). All other participants completed the study.

The average profile of participants upon study entry was as follows:

  • age – 49 years
  • 3 females and 8 males
  • weight – 86 kg
  • CD4+ count – 916 cells/mm3
  • duration of prior ART – 4 years
  • time since HIV diagnosis – 16 years

Results – safety

All adverse events were related to the subcutaneous injection of lenacapavir, including redness, pain, swelling and itchy skin. These were mild and temporary. No adverse events were linked to the infusion of antibodies. There were no abnormal lab test results.

Virological results

All six people taking the higher dose of Zab (30 mg/kg) maintained virological suppression throughout the study. In contrast, only two out of five people who took the lower dose of Zab (10 mg/kg) were able to maintain virological suppression.

All participants had high concentrations of antibodies in their blood.

Focus on virological rebound in two people

One participant had HIV that was partially susceptible to Tab. He maintained suppression until about week 25 of the study and then his viral load rose to 72 copies/mL. He then resumed his previous oral ART regimen and HIV became suppressed.

Another person had HIV that was susceptible to Tab but became less susceptible to Zab. She had low levels of detectable HIV from the start of the study. During the study, her viral load rose to 112 copies/mL and then subsequently fell to 55 copies/mL at week 26. She resumed oral ART but her viral load became detectable again a year later, though it was less than 100 copies/mL.

Resistance to treatments was not detected in either of these people.

Bear in mind

The combination of lenacapavir and super antibodies was generally safe, and the higher dose of Zab was more effective. Further clinical trials are planned in people who have HIV that is highly susceptible to both antibodies.

—Sean R. Hosein

REFERENCE:

Eron JJ, Cook PP, Mehrotra M, et al. Lenacapavir Plus bNAbs for People With HIV and Sensitivity to Either Teropavimab or Zinlirvimab. Conference on Retroviruses and Opportunistic Infections, March 3-6, 2024. Abstract 120.