An ultra-long-acting formulation of cabotegravir may offer an HIV pre-exposure prophylaxis (PrEP) and treatment option that could be administered once every four months, according to early study results presented last week at the Conference on Retroviruses and Opportunistic Infections (CROI 2024) in Denver.

In a small Phase I trial, the new formulation given by subcutaneous or intramuscular injection achieved comparable drug exposure but lasted longer in the body than the approved cabotegravir formulation administered every two months.

This research is the “first step towards delivering ultra-long-acting injectable HIV treatment and prevention medicines that would potentially enable people to have at least four months between visits to the clinic,” according to a ViiV Healthcare news release.

Daily oral PrEP and combination antiretroviral therapy are highly effective, but some people find it difficult to take pills every day. A key theme of the conference was the importance of choice in HIV prevention and treatment options.

Cabotegravir (Apretude) is currently the longest-acting HIV prevention method, while cabotegravir plus rilpivirine (Cabenuva) is the longest-acting complete antiretroviral treatment regimen. Apretude involves intramuscular injections in the buttocks administered by a health care provider every other month; the cabotegravir plus rilpivirine regimen may be administered either monthly or every other month.

One way to achieve less frequent dosing would be to increase the volume of injections or use a more concentrated formulation. Another approach would be to develop a new formulation that is absorbed more slowly and has a longer half-life in the body, meaning the time it takes for the drug concentration to fall to half its original level.

Kelong Han, PhD, of GSK (ViiV’s parent company), and colleagues evaluated the safety and pharmacokinetics of different cabotegravir formulations and administration methods. They tested both the approved 200 milligrams per milliliter version of cabotegravir (CAB200) administered with recombinant human hyaluronidase PH20 (rHuPH20), which allows for a larger injection volume, and a new ultra-long-acting formulation (CAB-ULA) without rHuPH20.

This open-label trial (NCT05418868) enrolled 70 healthy HIV-negative adults. About 60% were men, the median age was approximately 40, they were racially diverse and the median body mass index fell within the overweight range. (Some studies suggest that people with overweight or obesity may not respond as well to injectable cabotegravir, but data are inconsistent.)

In the first part of the study, volunteers received various doses (800 mg/4 ml, 1600 mg/8 ml or 3200 mg/16 ml) of CAB200 administered subcutaneously in the abdomen along with rHuPH20. In a subsequent part, they received different doses of CAB-ULA (800 mg/2 ml, 1200 mg/3 ml or 1600 mg/3 ml), without rHuPH20, given by either subcutaneous injection in the abdomen or intramuscular injection in the buttocks.

People who received subcutaneous CAB200 plus rHuPH20 had a maximum plasma drug concentration and area under the curve (a measure of total drug exposure) higher than that of the approved intramuscular CAB200 without rHuPH20, indicating potentially increased bioavailability. The half-life was comparable, indicating a similar absorption rate.

But subcutaneous injections of CAB200 with rHuPH20 were not very well tolerated. All 22 participants who received this formulation experienced injection site reactions, which were worse at higher doses. Eight had severe reactions, including one in the highest dose group who experienced a serious reaction with tissue necrosis that required wound care. Given the unfavorable tolerability profile, this dosing strategy was discontinued, Han reported.

Looking at the new ultra-long-acting formulation, the maximum concentration of CAB-ULA administered by subcutaneous injection was lower than that of intramuscular CAB-ULA, and both were lower than the approved intramuscular CAB200. Pharmacokinetic profiles were flatter, indicating slower absorption, according to Han. The half-life of subcutaneous CAB-ULA was longer than intramuscular CAB-ULA, and both were longer than intramuscular CAB200. The predicted half-life of intramuscular CAB-ULA was more than twice as high, and the expected half-life of subcutaneous CAB-ULA was over six times higher, compared with CAB200.

What’s more, CAB-ULA without rHuPH20 was better tolerated. All 16 participants who received subcutaneous injections experienced injection site reactions, as did 22 of 32 who received intramuscular injections, but most were mild and none were severe. Other types of adverse events were rare. The tolerability of intramuscular CAB-ULA was comparable to that of approved intramuscular CAB200, even though doses were higher, Han said.

Pharmacokinetic modelling predicted that intramuscular CAB-ULA at a dose interval of at least four months would achieve higher drug exposure than intramuscular CAB200 given every two months, and this was the case for both men and women.

Based on these findings, the researchers concluded that CAB200 with rHuPH20 has “low potential” for less frequent dosing, and it will not move forward. But the new ultra-long-acting formulation has a favorable tolerability and safety profile with a pharmacokinetic profile that supports dose intervals of four months or more.

Intramuscular CAB-ULA given every four months will now progress to late-stage PrEP and treatment trials, and additional evaluation of subcutaneous administration is planned. Unlike intramuscular injections, subcutaneous shots could potentially allow for self-administration.

“These findings suggest CAB-ULA has a pharmacokinetic profile with the potential for a dosing interval of at least four months, which is longer than any currently approved HIV prevention option,” Han said in the ViiV news release. “As we look to the future, further advancements in longer acting medicines have the potential to revolutionize how HIV is treated and prevented.”

But as it moves through the pipeline, CAB-ULA will face competition from Gilead Sciences’ long-acting capsid inhibitor, lenacapavir (Sunlenca), which is administered by subcutaneous injection every six months. Lenacapavir is already approved for treatment-experienced people with multidrug-resistant HIV, and it is being evaluated as a twice-yearly PrEP option.

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