Lenacapavir, an injectable HIV-1 capsid inhibitor administered twice yearly, has demonstrated 100% efficacy in preventing HIV among women at high risk of infection, according to interim findings from the phase 3 PURPOSE 1 trial.
The results were so promising that the independent data monitoring committee advised Gilead Sciences to end the blinded phase of the trial and provide open-label lenacapavir to all participants.
The findings were both unexpected and thrilling. “I’ve been in the HIV field for a really long time, and there’s no other phase 3 PrEP trial that found zero infections,” stated Moupali Das, MD, PhD, executive director of clinical development at Gilead Sciences, located in Foster City, California.
PURPOSE 1 is assessing the safety and effectiveness of two treatment regimens: twice-yearly subcutaneous lenacapavir for preexposure prophylaxis and once-daily oral Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg) in women and girls aged 16-25.
The study compares these drugs to the standard once-daily oral Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg).
Among more than 2,000 women in the lenacapavir group, there were no HIV infections; in contrast, the HIV incidence was 2.02 per 100 person-years in the Descovy group and 1.69 per 100 person-years in the Truvada group.
The background incidence of HIV, one of the trial’s primary endpoints, was recorded at 2.41 per 100 person-years with lenacapavir.
All treatments were found to be safe and well-tolerated, and full interim data from the trial will be disclosed at an upcoming conference, according to Das.
The medical community is “thrilled” with these results, said Monica Gandhi, MD, director of the UCSF-Gladstone Center for AIDS Research.
“We have to wait for the full data, but so far, it has been 100% effective and far superior to other treatments.”
Gandhi expressed interest in further details regarding side effects and tolerability, as well as reasons for discontinuation in the trial.
For example, lenacapavir can cause nodules to form under the skin, which serve as depots for the drug’s release over a six-month period. She is curious if any participants found these nodules bothersome enough to discontinue treatment.
The global HIV epidemic persists, with 1.3 million new infections reported in 2022.
Existing oral PrEP options, including the long-acting injectable cabotegravir, have not significantly reduced infection rates as anticipated, Gandhi noted. “We’ve been waiting for another option.”
Lenacapavir’s twice-yearly injection offers a simple and convenient alternative to daily oral PrEP. Many individuals, particularly younger participants in the PURPOSE 1 trial, struggle to remember to take daily pills.
Many trial participants expressed discomfort with the stigma surrounding HIV PrEP, preferring not to have visible pill bottles at home or hear them rattling in their bags. An injection given only twice a year in a doctor’s office is appealing.
“This is a discrete option. People were very excited about the privacy and not having to take daily pills,” explained Das. “PrEP only works if you take it.”
Improved adherence to the treatment regimen likely contributes to lenacapavir’s superior performance compared to oral PrEP.
Moreover, lenacapavir employs a unique mechanism of action as a multistage viral capsid inhibitor, targeting the capsid both before and after the virus integrates into the host nucleus, which may enhance its efficacy.
While the results are encouraging, concerns remain regarding the accessibility of lenacapavir, especially in low- and middle-income countries where HIV prevalence is highest.
“No one has any clue how Gilead plans to make this accessible,” remarked Gandhi.
Gilead Sciences has not enrolled in the Medicines Patent Pool (MPP), which typically facilitates the manufacture of generic formulations of drugs, a necessary route for providing affordable alternatives in low-income countries.
Gandhi described the rollout of injectable cabotegravir as “disastrous,” with limited availability in poorer nations serving as a troubling precedent.
Gilead Sciences confirmed that all 5,300 participants in the PURPOSE 1 study will have the opportunity to continue receiving lenacapavir until it is available in their respective countries.
The company has pledged to ensure a dedicated supply in regions with the greatest need until licensing partners can produce high-quality, low-cost versions of lenacapavir.
Instead of utilizing the MPP, Gilead is negotiating a voluntary licensing agreement directly with partners to supply generic versions in low-income countries.
Lenacapavir is already approved for the treatment of multidrug-resistant HIV but has yet to receive approval for HIV prevention.
A related trial, PURPOSE 2, is ongoing and investigates lenacapavir in men who have sex with men, as well as transgender men, transgender women, and nonbinary individuals with male partners.
Should the results, expected by late 2024 or early 2025, be positive, the company plans to proceed with regulatory submissions for lenacapavir as PrEP.
Additionally, three other trials are in progress. PURPOSE 3 and PURPOSE 4 are smaller studies based in the U.S. involving women and people who inject drugs, while PURPOSE 5 is enrolling individuals at high risk for HIV in France and the United Kingdom to gather European data for regulators.
