Ultra-long-acting cabotegravir could be taken three times a year for HIV PrEP and treatment

A longer-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).

A small phase I trial showed that the new ultra-long-acting formulation given by subcutaneous or intramuscular injection every four months achieves comparable drug exposure but lasts longer in the body than the approved formulation administered every two months, reported Dr Kelong Han of GSK, the parent company of ViiV Healthcare.

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 news release.

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

The approved formulation of cabotegravir for PrEP (sold as Apretude) is now the longest-acting HIV prevention method, and long-acting cabotegravir plus rilpivirine (Vocabria and Rekambys) is the longest-acting complete HIV treatment regimen. (In North America and Australia, the two drugs are packaged together and sold as Cabenuva.) Both PrEP and treatment involve intramuscular injections in the buttocks administered by a health care provider every other month. (A once-monthly dosing schedule for injectable cabotegravir and rilpivirine is approved in the US and Australia, but is not available in Europe.)

One strategy to achieve less frequent dosing is to increase injection volume or the concentration of the formulation. (ViiV researchers presented an analysis of one high-concentration formulation of cabotegravir at the 2022 International AIDS Conference.) Another approach is to develop a longer-acting formulation that is absorbed more slowly and has a longer half-life in the body (the time it takes for the drug concentration to fall to half its original level).

Han and colleagues evaluated the safety and pharmacokinetics of different cabotegravir formulations and administration methods. They tested both the approved 200 mg/ml 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 (dubbed 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 years and they were racially diverse. The median body mass index fell within the overweight range. Some studies have suggested that people with obesity or who are overweight may not respond as well to injectable cabotegravir, but data are inconsistent.

In the first part of the study, volunteers received various doses (800mg/4ml, 1600mg/8ml or 3200mg/16ml) of CAB200 administered subcutaneously in the abdomen along with rHuPH20 (10,000 IU). In a subsequent part, they received a different dose of CAB-ULA (800mg/2ml, 1200mg/3ml or 1600mg/3ml) 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, however, indicating a similar absorption rate.

Find out more: Injectable and long-acting PrEP

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 redness and necrosis (tissue death) that required wound care. Given the unfavourable tolerability profile, the company decided not to continue this dosing strategy, Han reported.

Turning to 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. Further, 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 as that of CAB200, while the expected half-life of subcutaneous CAB-ULA was over six times higher.

Fortunately, CAB-ULA without rHuPH20 was better tolerated, especially with intramuscular injection. All 16 participants who received subcutaneous injections experienced injection site reactions (redness, nodules or pain), as did 22 of 32 who received intramuscular injections, but most were mild. Other types of adverse events were rare. The tolerability of intramuscular CAB-ULA was comparable to that of approved CAB200 even though doses were higher, Han noted.

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. But the new ultra-long-acting cabotegravir formulation has a favourable 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 upcoming late-stage PrEP and treatment trials, and additional evaluation of subcutaneous administration is planned, Han said. Unlike intramuscular injections, subcutaneous jabs 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 release. “As we look to the future, further advancements in longer acting medicines have the potential to revolutionise how HIV is treated and prevented.”

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