CROI 2023 – GSK and Gilead’s long-acting HIV battle intensifies

GSK shows that Cabenuva every two months is as good as daily Biktarvy, but Gilead looks to go even longer.

GSK has long been the trailblazer in long-acting HIV therapies, and at last week’s Conference on Retroviruses and Opportunistic Infections (CROI) the group touted data with its doublet Cabenuva, which can be given as infrequently as every two months.

The head-to-head Solar trial showed Cabenuva had non-inferior efficacy to Gilead’s rival daily HIV therapy Biktarvy – and that 90% of patients who switched preferred the long-acting regimen. But Gilead has its own long-acting HIV ambitions, and presented early data on lenacapavir in combination with broadly neutralising antibodies, designed to be given just once every six months.

Lena combos

Lenacapavir, injected twice yearly, is already approved as Sunlenca for multidrug-resistant HIV, a small niche. Expanding into the broader HIV population will depend on combining it with other therapies.

The most advanced combo is lenacapavir plus Merck & Co’s islatravir; a phase 2 study of a once-weekly oral regimen recently restarted after a clinical hold on islatravir.

Gilead has long sought to keep its options open, however, and other efforts might be starting to bear fruit. CROI saw results from a phase 1 study of lenacapavir plus the broadly neutralising antibodies (bNAbs) teropavimab and zinlirvimab.

The uncontrolled study tested the combo in virologically suppressed HIV patients, whose baseline antiretroviral therapy was replaced by a single subcutaneous dose of lenacapavir (plus an oral loading dose) and single intravenous doses of teropavimab and zinlirvimab. The primary endpoint was safety, but the study also looked at whether patients maintained virologic suppression at six months.

Of the 20 evaluable patients, 18 were still virologically suppressed at six months.

On safety, there were no grade 4 or 5 adverse events, or any events that led to discontinuations. There were two grade 3 adverse events of injection site reactions.

This was enough for Gilead to push into phase 2, but there are reasons to be cautious. One is practicality, with the bNAb infusions taking one hour apiece, with monitoring periods of 15 minutes between infusions and 30 minutes post-infusion.

A spokesperson for Gilead told Evaluate Vantage that the company was evaluating whether shorter administration and observation periods might be possible. He stressed that the group’s ultimate aim was to have several long-acting options available, to suit different patients’ preferences.

Rebound

Potentially more worrying is that one of 20 patients receiving lenacapavir plus the bNAbs experienced viral rebound at week 16. Another patient withdrew from the study, but showed viral suppression at week 12, the last available measurement.

The Gilead spokesperson did not have an explanation for the rebound, saying the patient in question had lenacapavir and bNAb concentrations “consistent with others in the same dosing group”. Investigations continue, but this will be something to keep an eye on in future trials in larger numbers of patients. The affected patient was re-suppressed using oral antiretrovirals.

Virologic rebound can be caused by resistance to therapy, something that has long been a concern with doublets.

And the spectre of resistance was raised again with results from Solar, the head-to-head study of Cabenuva and Biktarvy. The phase 3 trial enrolled 670 patients already virally suppressed on Biktarvy, and randomised them either to continue therapy or to switch to Cabenuva. The primary endpoint was non-inferior virologic efficacy at one year, measured via the proportion of patients with HIV-1 RNA of 50c/ml or over, and rates were similar between the two arms.

However, three Cabenuva-treated patients had confirmed virologic failure with resistance-associated mutations, versus none in the Biktarvy arm.

A spokesperson for Viiv, GSK’s HIV joint venture with Pfizer and Shionogi, contended that Cabenuva’s benefits, including its less frequent administration, “outweigh the low risk of failure with resistance development”, which she noted was less than 1%.

She added that the lack of confirmed virologic failure in the Biktarvy arm “should be balanced with the fact that participants were stably suppressed on Biktarvy for over two years when they entered the study, representing those that were already successful on Biktarvy”.

GSK has a long way to go to dislodge Biktarvy: the Gilead once-daily is forecast to sell over $12bn by 2028, according to sellside consensus compiled by Evaluate Pharma, while Jefferies analysts predict worldwide peak Cabenuva sales of $3bn.

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