Once-Yearly Lenacapavir PrEP a Safe, Promising Alternative to Twice-Yearly Dosing

SAN FRANCISCO — A once-yearly intramuscular lenacapavir (Sunlenca) injection was safe and well-tolerated and had higher median levels of plasma concentrations compared with twice-yearly subcutaneous lenacapavir for HIV pre-exposure prophylaxis (PrEP), according to a phase I open-label study.

For 40 participants who received one of two lenacapavir free acid formulations administered by ventrogluteal intramuscular injection as a single 5,000-mg dose, the highest median concentration was 247.0 ng/mL for formulation 1 and 336.0 ng/mL for formulation 2 compared with a previously observed highest median concentration of 67.3 ng/mL for twice-yearly subcutaneous lenacapavir, reported Renu Singh, PhD, of Gilead Sciences, at the Conference on Retroviruses and Opportunistic Infections (CROI).

The median time to maximum concentration was 84.1 days for formulation 1 and 69.9 days for formulation 2, as noted in The Lancet where the study was published.

“Injections were generally well tolerated, with injection-site pain being the most common adverse event,” the authors wrote. “No clinically significant safety concerns were identified.”

Lenacapavir was previously shown to be safe and effective administered in twice-yearly subcutaneous injections in the phase III PURPOSE 1 and PURPOSE 2 trials, but once-yearly administration “could further address HIV PrEP barriers, such as stigma, adherence challenges, and the need for frequent healthcare interactions,” Singh told CROI attendees.

The drug works by forming a drug depot after injection that slowly releases the drug over time.

“Once-yearly intramuscular lenacapavir for HIV PrEP has the potential to improve PrEP uptake and persistence and thus improve the scalability and public health impact of PrEP in populations who would benefit most,” Singh added.

Dmitry Lyumkis, PhD, of the Salk Institute for Biological Studies in La Jolla, California, told MedPage Today that “with any long-acting formulation, the idea is to decrease the number of times that you must take the required therapeutic dosing, which can minimize ‘pill burden,’ improve consistency of care, and avoid HIV-related stigma, among other motivations.”

“The data look great,” he added. “However, as with all drugs, HIV-1 will eventually acquire resistance to therapy. Monitoring for lenacapavir drug resistance, and how this may differ across formulations, will ultimately be an important goal.”

The study involved two cohorts, each with 20 healthy participants ages 18-55, who had a low likelihood of acquiring HIV.

The first cohort, who received formulation 1 (5% ethanol), had a mean age of 37; 65% were male at birth, and 85% were white. The second cohort, who received formulation 2 (10% ethanol), had a mean age of 33; 65% were male at birth, and 75% were white. Half of the participants who received formulation 2 were pretreated for approximately 10 minutes with an ice pack at the sites of injection.

The evaluated pharmacokinetic parameters included the area under the concentration-time curve (AUC) for the once-yearly dosing interval calculated from days 1 to 365, peak plasma concentration, time to reach peak plasma concentration, and trough concentration. Plasma concentration data for twice-yearly subcutaneous lenacapavir were taken from PURPOSE 1 and PURPOSE 2 for comparison with once-yearly intramuscular lenacapavir formulations.

Pharmacokinetic samples were taken 5 minutes before dosing and then 2, 4, 8, 12, 24, and 36 hours post-dose. Additional pharmacokinetic samples were taken at 22-43 days, 57-141 days, and 169-393 days.

The median AUC from days 1 to 365 was 1,011.1 h*μg/mL for formulation 1 and 1,274.0 h*μg/mL for formulation 2. The median trough concentration at the end of 52 weeks was 57.0 ng/mL for formulation 1 and 65.6 ng/mL for formulation 2, exceeding the median twice-yearly subcutaneous lenacapavir trough concentration of 23.4 ng/mL at the end of 26 weeks.

The peak plasma concentration was at least threefold lower than lenacapavir concentrations previously studied, without safety concerns, Singh reported, adding that “preliminary population pharmacokinetics modeling results suggest that a dose lower than 5,000 mg could maintain target concentration for 1 year.”

Most adverse events were mild or moderate, with no grade 4 adverse events or lab abnormalities. One participant receiving formulation 2 experienced a grade 3 adverse event of injection-site pain and syncope. Most participants had no or mild pain that diminished over time and usually resolved within a week, and pretreatment with ice substantially reduced reported pain.

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