On June 18, 2025, the FDA approved lenacapavir (Yeztugo) as the first twice-yearly injectable PrEP (pre-exposure prophylaxis) for HIV. But the medicine was first approved in December 2022 to treat HIV.
In 2024, two large clinical trials, PURPOSE 1 and PURPOSE 2, showed that lenacapavir was safe and worked well to prevent HIV infection. The medicine is the fourth FDA-approved HIV option to prevent HIV and the second type of shot.
The FDA approval of any drug is the capstone of a long and thorough process that requires research, work, testing, and teamwork among scientists, doctors, and others. Here’s how lenacapavir was made and how it can help prevent new HIV infections.
Step 1: Discovery and Development
Figuring out how to make lenacapavir stretches back more than two decades. In the early years of the AIDS epidemic, after scientists discovered HIV, they quickly focused on stopping the virus from infecting T cells (a type of white blood cell).
Next, the landmark discovery to combine antiretroviral medicines drastically lowered the AIDS death rate. But researchers weren’t done looking for chinks in HIV’s armor.
In the early 2000s, a team of researchers at University of Utah Health, led by biochemist Wesley Sundquist, PhD, separated the protein shell from the genetic material for HIV. This protein shell is called the capsid.
The team studied the capsid closely to understand how it functions. Then, efforts pivoted to finding a medication to interrupt HIV infection.
Together with the pharmaceutical company Gilead Sciences, Sundquist and his team made a new class of medications. They called it capsid inhibitors.
“It’s called capsid inhibitor because it does just that — inhibits the capsid,” says Mitchell Warren, executive director of AVAC, an international nonprofit organization that helps accelerate ethical development and equitable delivery of effective HIV prevention options around the world.
Like most research at the time, early capsid inhibitor work was focused mainly on HIV treatment. Around that time, CDC researchers did studies on antiretroviral medicines to see if they could prevent HIV.
Both efforts eventually opened the door for lenacapavir to become a prevention as well. Lenacapavir is the first approved medicine to use the outer shell (capsid), blocking the virus to prevent HIV infection.
Step 2: Lab Testing
Before doctors can prescribe a medication, it goes through lab testing and animal studies. These studies tell experts if the medicine is safe and works well enough to test in human trials.
Animal studies are especially important in HIV research. “In monkeys there is an HIV-related virus called simian immunodeficiency virus (SIV),” Warren says. “Because SIV is similar to HIV, researchers can test drugs in monkeys to look for early signs of safety and effectiveness.”
The tests using medications to prevent a disease are more challenging than treatments. But animal studies can help with this.
Experts can use “challenge models,” where animals get the preventive medication first, before being exposed to the virus. If the medication protects the animals from infection, it’s a good sign.
This model has guided HIV research for years to help decide when a medicine is ready for human trials.
Animal studies with lenacapavir had positive safety results and showed strong results to prevent infection in animals. So lenacapavir moved easily into human testing.
Step 3: Clinical Trial Testing
Human trials (clinical trials) take place in phases. Each phase answers different questions.
Phase 1 for safety and dose
The first trials are the smallest (about 100 or fewer people) who aren’t at risk of an HIV infection. The focus of the study is on safety. Researchers also look at the best working dose for the medicine in this phase.
“You may give half of [the participants] the product and half a placebo [sugar pill], and you see if the drug has any negative effects,” says Warren. “Did it change your T-cell count? Did it change your cholesterol? Did it change your heart rate?”
Phase 2 tests how well the medicine works
Once medication is found to be safe, researchers test how well it works. This is called the intended purpose, or what the medicine will be used for.
The second phase will test several hundred people who have a fairly high risk for HIV. The trial also tests how well the medicine works (efficacy) in a controlled setting.
A controlled setting just means a wide range of people are monitored and take a specific amount at the same time.
Phase 3 for prevention
This is typically the longest phase of testing. The testing checks if the medicine can actually prevent infection in the real world.
For lenacapavir, there were two main studies: PURPOSE 1 and PURPOSE 2. Both tested over 2,000 people at high risk of HIV. Each trial compared the twice-yearly lenacapavir injection with other standard prevention methods.
Warren, who served on the Independent Data Safety and Monitoring Board (DSMB), reviewed both studies, particularly the PURPOSE 1 study.
“I will never forget June 18th, 2024, when we got the data report and it showed that on PURPOSE 1, there wasn't a single infection amongst people who got lenacapavir,” says Warren. “I've been on a lot of data safety monitoring boards, and I have never seen anything like that.”
PURPOSE 2 had similar results, with only two infections. Warren and his review board suggested that the company, Gilead, stop their trial and offer lenacapavir to those taking the placebo right away.
“It was working, so that was the ethical thing to do,” says Warren.
Step 4: Checking by Experts
After clinical trials succeed, companies turn in a regulatory submission to the FDA. This is a huge amount of medical information (data) which includes:
- All the study data from each clinical trial
- All the safety information from the clinical trials
- Any side effects from the clinical trials
- All the patient lab and hospital records
- Studies on potential medicine interactions
- Chemical studies on how the medicine works
- Any animal studies on the medicine
“You don't just go to the FDA to say, ‘We have no infections, you should approve our product,’” says Warren. “You have to compile this regulatory dossier [case file] about not only the efficacy, but also every possible side effect and drug-to-drug interaction.”
Warren says the case file needs to answer questions like:
- Did people get more fevers?
- Did they get the flu?
- Is this drug safe to take with contraception?
- Is this drug safe to take with tuberculosis drugs?
These files can be tens of thousands of pages long, says Warren. Once the FDA gets all this information, an entire team looks it over, including people specially trained in math (statisticians), medicine, and other sciences.
For a standard review, the FDA must give the company an answer within 10 months, or six months for a priority review. A priority review is for unique products or those that add value to public health.
Gilead did just that. Six months to the day after the submission, the FDA approved lenacapavir for HIV PrEP.
Step 5: Watching Over Time
FDA approval isn’t the end of the scientific process. After a medicine reaches the public, regulators, doctors, and researchers still keep watch.
They’ll look at the long-term safety of the medicine and how well it works. It’s called postmarketing surveillance.
“FDA approval is not the beginning of the end, it’s the end of the beginning,” says Warren. “It's important that we don't just assume that everything’s over once a drug is safe and effective and approved by the FDA. You need to see what might happen on a long-term basis.”
Any health provider who prescribes lenacapavir must also report to the FDA any problems patients have after taking the medicine. That way, the FDA can make changes to the medication label — or even pull the medicine off shelves — if they need to.
The Bottom Line
Globally, about 1.3 million people are newly infected with HIV each year, including tens of thousands of people in the U.S. But lenacapavir offers an easier-to-stick-with option that also works better to prevent HIV.
“In biomedical research you have both what's called efficacy and effectiveness,” says Warren. “Efficacy is how well the product works biologically in perfect conditions. And effectiveness is what happens in real life.”
“Oral PrEP efficacy is very effective, also in the 95% to 98% efficacy range, like lenacapavir. But the difference is that with daily oral PrEP, you have to take a pill every single day,” Warren says.
Lenacapavir offers you the ease of a twice a year PrEP shot with a similar outcome.
