PURPOSE 1 Lenacapavir Results ‘Highly Anticipated’

The HIV community will soon get to look at data from the PURPOSE 1 clinical trial of twice-yearly lenacapavir for preexposure prophylaxis after interim results showed it was 100% effective in preventing infection.

Linda-Gail Bekker, MBChB, director of the Desmond Tutu HIV Center at the University of Cape Town, South Africa, will present the results on July 24 at the International AIDS Conference in Munich, Germany.

The PURPOSE 1 trial results are “incredibly highly anticipated,” Monica Gandhi, MD, MPH, director of the UCSF-Bay Area Center for AIDS Research in San Francisco, told Medscape Medical News. Trial sponsor Gilead Sciences’ announcement in June that it would halt the blinded phase of the trial and shift to open-label lenacapavir for all participants caught the HIV community off guard, Gandhi said. 

PURPOSE 1 is evaluating preexposure prophylaxis with the HIV-1 capsid inhibitor lenacapavir given twice yearly as a subcutaneous injection, and once-daily oral Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg). The trial enrolled 5338 girls and women aged 16-25 years at risk for HIV in South Africa and Uganda. A comparator group was given once-daily Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg).

Promising Early Results

The interim results showed no cases of HIV infection among 2134 women given lenacapavir. Sixteen cases of HIV infection were reported among 1068 women in the Truvada group, an incidence of 1.69 per 100 person-years. In the Descovy arm, 39 incident cases of HIV infection were reported in 2136 women, an incidence of 2.02 per 100 person-years. 

Those interim results have infectious disease specialists longing for more details. 

“Long-acting PrEP has the potential to be a game changer for ending the transmission of HIV,” said Jenell Stewart, DO, MPH, an infectious disease specialist at Hennepin Healthcare in Minneapolis. “Taking a daily pill works great for some, but for others a daily pill isn’t feasible or desirable. No one method is going to be right for everyone, and having the freedom to choose and change PrEP methods to fit into your life is central to individual- and community-level impact.”

Paul Sax, MD, director of infectious diseases at Brigham and Women’s Hospital in Boston, said the twice-a-year dosing for lenacapavir makes it compelling because other long-acting injectable PrEP treatments still require every-other-month dosing. “One of the challenges with currently available injectable PrEP is that the patient has to come to the clinic every 2 months; that’s six times a year as opposed to twice a year,” he said. 

As a capsid inhibitor, lenacapavir is a new class of drug for HIV, which could help fight resistance, said Matthew Spinelli, MD, PrEP medical lead at the University of California, San Francisco. ” This being in a different class than our current main treatment classes is a really exciting aspect,” he said.

Cabotegravir — another long-acting injectable PrEP option — has had some problems with resistance, which compromises the main treatment strategy, said Spinelli. “So having this prevention option not in the i ntegrase strand transfer inhibitor class and not seeing resistance is also a real exciting and unprecedented aspect of the study,” he said.

Remaining Questions

But the community still has many questions that clinicians are keen to see answered at the conference. How well were participants able to adhere to the dosing regimen is of particular interest. “How many people stay on the treatment in the study? That could be a good feasibility indicator,” Spinelli said. “It’s not real-world data, but how well people are remaining engaged in this study is another indicator of how acceptable and feasible this is.”

Side effects will also be closely scrutinized. One reported potential side effect is nodules at and around the injection site. “I would describe lenacapavir as viscous, and when it’s injected subcutaneously it can trigger nodules that can be present for weeks and sometimes over months,” Sax said. ” We’ll have to see if there were people who dropped out because of the nodules. How bothersome was that? How physically or mentally disturbing was it?”

Getting the treatment into the right hands at an affordable cost is a longer-term consideration. Injectable extended-release cabotegravir and cabotegravir-rilpivirine combination, both approved by the US Food and Drug Administration in 2021, have had limited rollouts, Stewart and Spinelli said. 

“A commitment to access and scaling up are needed,” Stewart said. “Cabotegravir has had a very limited rollout and lack of access, affordability, and clinical infrastructure have made real-world impact fall short of its potential.”

Spinelli is also concerned about access for those in greatest need. ” Is this going to be another blockbuster amazing option that’s just not available due to questions of logistics and patents and cost and generic production, lack of political will, et cetera?” he asked. “Will that all just be repeated again with lenacapavir?” 

The first step for Bekker at AIDS 2024 will be to roll out the final results of the trial in her presentation. “I am eager to hear more from the PURPOSE 1 trial team on participant experiences with injections, the details surrounding any breakthrough cases, and recommendations for next steps,” Stewart said.