A “significant breakthrough” in HIV prevention could be on the horizon, according to the World Health Organization. Results of an interim analysis from a Phase 3 clinical trial sponsored by Gilead Sciences, Inc., showed that lenacapavir, a twice-yearly injectable drug, is a highly promising tool for thwarting new HIV infections. We spoke to Onyema Ogbuagu, MBBCh, associate professor of medicine (AIDS) and of pharmacology at Yale School of Medicine, and the study’s principal investigator, about the trial, named PURPOSE 2, and the future of lenacapavir.
What is lenacapavir and how does it work to prevent HIV?
Lenacapavir is a first-in-class HIV drug, which means that it has a mechanism of action that has not previously been utilized for HIV treatments. It inhibits what we call the HIV capsid, a conical structure that houses both the genetic material of HIV and the proteins that [the virus] uses to make copies of itself. By interfering with the capsid, the drug prevents HIV from replicating itself into host cells.
These are the best numbers ever reported from an HIV prevention study.
Onyema Ogbuagu, MBBCh
Even if the virus evades this process, lenacapavir also prevents HIV from forming mature virions [virus particles] that propagate the infection. So, it actually has multiple mechanisms of action, and that’s why we investigated it not just for HIV prevention, but also for HIV treatment. It is currently approved for HIV treatment for people who have limited treatment options and multi-drug-resistant infections.
What are the current options for HIV prevention? What added benefits could lenacapavir offer?
There are many ways to prevent HIV. Some of them are behavioral—these include reducing one’s number of sexual partners and using condoms during intercourse. We also have surgical interventions. Male circumcision, for example, can reduce HIV uptake. We know that treating sexually transmitted infections can also prevent HIV.
That said, people don’t always follow or accept these interventions. So, for little over a decade, we’ve leaned more into biomedical HIV prevention—this means using therapeutics to prevent infection. Some oral antiretroviral therapies for HIV are taken once a day and show good efficacy for preventing HIV infection as long as there’s correct adherence. However, people tend to struggle with having to take pills every day. They often start with good intent, and then adherence drops off over time. So, while the pills are a great tool for biomedical HIV prevention, they have significant limitations in regard to adherence. There are also disparities in these pills’ availability driven by insurance status that hinders access for some of the most affected groups.
Then, in the past two or three years, a new injectable was approved. This intramuscular drug, given every two months, is called cabotegravir. Researchers had become interested in long-acting injectables as a way to address the issues with poor adherence associated with oral therapies. The efficacy of injectables is much less dependent on people having to remember to take a pill every day. Clinics can support people with adherence—they can remind people when they have their next appointment and call them if they miss an appointment to make sure they stay on track. So, it wasn’t surprising when cabotegravir did better than the oral therapies.
Lenacapavir is a new drug that’s given subcutaneously [under the skin] every six months. Subcutaneous injections tend to be much easier to administer than intramuscular injections. This is also the longest-acting PrEP [pre-exposure prophylaxis] medication we have. Because it’s a first-in-class, we do not expect that anyone exposed to HIV will be resistant to lenacapavir since it hasn’t been widely used.
You recently concluded the PURPOSE 2 clinical trial. Gilead has stated the PURPOSE clinical trials are the most comprehensive and diverse HIV prevention trial program ever conducted. Can you tell me more about the trials? And what did they mean by this?
PURPOSE 2 is the sister study to PURPOSE 1, which looked at adult women and girls in Sub-Saharan Africa, and found that lenacapavir was superior to both oral PrEP pills. It had a unique study design where we measured the background rate [rate of new cases in a given population] of HIV. So, we looked at the incident cases in a population, then we put participants on PrEP, and then we compared the number of new cases to what it would have been based on the background HIV assessments. That was the primary endpoint. In fact, nobody in the lenacapavir arm of the study contracted HIV. It provided 100% protection.
In PURPOSE 2, we used lenacapavir for four other groups around the world who have sex with men: men, trans women, trans men, and gender non-binary people. There were about 3,200 people in this study. It was a 2:1 randomization, so roughly 2,200 people received lenacapavir, and the rest received oral emtricitabine and tenofovir disopoxil fumarate, which was the first oral PrEP option that was available. And then again, we compared the incidence between both groups, as well as to the background rate of HIV infections.
We took great efforts to ensure that PURPOSE 2, for which I was a lead PI [principal investigator], had lots of diversity. We included trans and gender-diverse individuals, who are typically underrepresented groups in HIV prevention trials. The study also had geographic diversity including low-resource countries: we included countries from Southeast Asia, Africa, South America, and North America. We included age diversity as well. Adolescents tend to be left out, and we made sure that the study included individuals 16 years and above.
And we even had diversity with the study teams. We intentionally included [diverse] principal investigators and other study personnel and engaged a community advisory board to inform the study. We made sure as we were designing the study that we had input from people who have lived with HIV, or are from a racial, ethnic, or gender minority population. This set us up to make sure that the clinical trial reflected geographic, racial, and gender diversity, and we’re very proud of that.
What were the significant findings of PURPOSE 2?
Our recently reported findings were based on an interim analysis. It wasn’t the planned end of the study. An interim analysis is where the Data and Safety Monitoring Board reviews the data, and usually if they see overwhelming benefits in a study arm, they discontinue it (the study) because it is unethical to continue [not providing the more effective medication to some participants] if there are already clear benefits. In this interim analysis, they found that there were only two infections in the lenacapavir arm and nine infections in the emtricitabine and tenofovir disopoxil fumarate arm. Lenacapavir showed 96% prevention efficacy compared to background incidence rates and was 89% more effective than the oral drugs. 99.9% of participants taking the drug in the study did not acquire HIV infection.
These are the best numbers ever reported from an HIV prevention study. It supplements the results from the PURPOSE 1 study for women. We now have robust data from women, men, and gender-diverse individuals.
The World Health Organization has described lenacapavir as “a significant breakthrough” in HIV prevention. Do you agree, and why or why not?
100%. This would be the longest-acting HIV prevention modality out there. It’s user friendly, it’s very well tolerated, it’s safe, and the efficacy is amazing. One of the goals of the Ending the HIV Epidemic initiative is to increase PrEP coverage by 50%. White people have achieved that so far. But other racial groups have not—about 10% or less of Black people eligible for PrEP are on it. I think lenacapavir will be a tool to help us reach this goal.
Another reason it is a game changer is that injectables, especially if they’re long-acting, allow us to deploy HIV prevention outside of the clinic. A long-acting injectable can allow us to deliver these products in a variety of community settings, reaching groups who are typically left out. Lenacapavir has huge potential, and we all look forward to how far we can take this exciting tool, put it to work in the real world, and help those who need it the most.
The trial seems likely to pave the way to the approval of the drug for PrEP. What are the next steps, and when can we expect to see it available?
Our data now will allow Gilead to do regulatory filing for approval of the drug for the indication of HIV prevention. Obviously, we’re not in control of what the FDA does. But projections are that the drug should be deployed by the end of 2025.
Lenacapavir has a hefty price tag of $42,250 per patient per year. What needs to be done to make it accessible to those who need it?
There are many ways, but I know that there will be a contractual agreement with generic manufacturers. That is typically a mechanism to have affordable pricing for places particularly outside the U.S. Those plans are ongoing. I care for patients and do global health in Rwanda and Liberia—parts of the world that are disproportionately affected by HIV—so I care deeply about making sure that the benefits permeate to these places.
That being said, for those who participated in the study, there’s going to be an open-label extension. We will unblind people so that they know what their treatment assignments were, and we’ll give them the option to go on lenacapavir until it’s available in their home countries.