Science magazine has named twice-yearly lenacapavir pre-exposure prophylaxis (PrEP) as its 2024 Breakthrough of the Year, recognizing it as a game-changer in the fight to end the HIV epidemic worldwide.

Lenacapavir, from Gilead Sciences, is an HIV capsid inhibitor that can be injected every six months. Phase III studies showed that it significantly reduced the risk of HIV acquisition both for women and for gay and bisexual men and gender-diverse people. Gilead is now working on new formulations of injectable lenacapavir that could potentially be administered just once a year.

Lenacapavir is an antiretroviral drug that blocks HIV replication—not a vaccine that trains the immune system to fight the virus. All traditional HIV vaccine candidates have failed in large trials, and more sophisticated approaches have a long road ahead, so long-acting PrEP is the next best thing.

In making the designation, “Science acknowledges the next, but by no means final, step in the drive to fight AIDS, where the rigors of the laboratory and the needs of humanity are inseparable,” wrote editor-in-chief Holden Thorp.

Science’s 2024 Breakthrough of the Year is lenacapavir, an injectable drug that demonstrated remarkable success at preventing HIV infection with one shot every 6 months. Learn more about this year’s #BOTY and other big advances in science: scim.ag/3BrCtUn

[image or embed]

— Science Magazine (@science.org) December 12, 2024 at 11:02 AM

This is the third time Science has chosen an HIV/AIDS intervention as its top breakthrough. In 1996, it cited protease inhibitors, a new class of drugs that ushered in effective combination antiretroviral therapy. In 2011, it recognized the groundbreaking HPTN 052 trial, which showed that effective treatment dramatically reduces sexual transmission of HIV—the basis for Undetectable Equals Untransmittable, or U=U.

The Science article about the breakthrough notes that the basic science underlying long-acting PrEP could have broader applications. Other viruses have their own capsid proteins, which form the shell around their genetic material, and capsid inhibitors might help fight other viral diseases. Similarly—while there is still no HIV vaccine—investments in HIV vaccine research over the years paved the way for COVID-19 vaccines.

“The drive to get [HIV] treatments to the world has ebbed and flowed,” Thorp wrote in his editorial. “George W. Bush was a great champion of the President’s Emergency Plan for AIDS Relief [PEPFAR], but other U.S. politicians have not been as motivated. And the long-since debunked contention that HIV does not cause AIDS never seems to go away completely.”

Referring to the 1991 play Angels in America, Thorp continued, “A better place to seek angels, however imperfect they may be, is among the scientists who have advanced against the scourge of AIDS. Like angels, they have persisted in spite of the political and economic constraints…More than three decades later, the work to fight HIV/AIDS is far from over.”

 

PURPOSE 1 and 2

PrEP was first approved in 2012, but it has still not reached its full potential, and only around a third of the 1.2 million people who could benefit are using it. While daily oral Truvada (tenofovir disoproxil fumarate/emtricitabine) PrEP is around 99% effective when taken consistently, other options are still needed. Some people may have trouble remembering to take a pill every day, may feel stigma around using antiretrovirals that are also used to treat HIV or may be hesitant to have pill bottles that could be lost or stolen. Currently, ViiV Healthcare’s Apretude (injectable cabotegravir), which is administered every other month, is the longest-acting approved PrEP option.


Results from the PURPOSE 1 trial, first presented at the 2024 International AIDS Conference this summer and published in The New England Journal of Medicine, showed that twice-yearly lenacapavir PrEP was 100% effective for young cisgender women in Africa. The injections significantly reduced HIV incidence compared with the background rate and were superior to daily Truvada pills. Several studies have found that injectable antiretrovirals can encourage better adherence among women.


Findings from PURPOSE 2, presented at the HIV Research for Prevention Conference in October and also published in The New England Journal of Medicine, showed that lenacapavir injections every six months reduced the risk of HIV acquisition by 96% relative to background incidence and by 89% compared to Truvada for gay and bisexual men and transgender and nonbinary people in the United States and six other countries. In both trials, lenacapavir injections were safe and generally well-tolerated.

While these results are groundbreaking, researchers, advocates and global health officials stress that the promise of twice-yearly PrEP can only be realized if it is widely accessible and affordable to everyone who needs it worldwide.

Lenacapavir for HIV treatment costs around $4,000 per month, but a study presented at the International AIDS Conference showed that the price could be brought down to around $40 per year with voluntary licensing and competition between generic suppliers. Gilead has announced that it will work with pharmaceutical manufacturers to produce and sell generic lenacapavir for PrEP in more than 100 resource-limited countries with high HIV incidence.

Longer-Acting PrEP

The Food and Drug Administration (FDA) approved lenacapavir (sold as Sunlenca) in 2022 for heavily treatment-experienced people with multidrug-resistant HIV. Lenacapavir currently has no equally long-acting partner drugs to make up a complete treatment regimen, but a single antiretroviral is adequate for HIV prevention.

Lenacapavir is not yet approved for HIV prevention, but the PURPOSE 1 and 2 data have been submitted to the FDA, and twice-yearly PrEP could get the green light next year. Aiming to further push the envelope, Gilead is now studying even longer-acting PrEP candidates.

At an investors meeting this week, Moupali Das, MD, MPH, Gilead’s vice president of clinical development for HIV prevention and pediatrics, noted that the company is working on injectable lenacapavir formulations that could potentially be given annually, as well as a monthly oral lenacapavir prodrug (GS-3107) that could be the longest-acting PrEP pill. A recently completed pharmacokinetics study suggests that a once-yearly injectable formulation is feasible, STAT reported. Phase III testing will begin soon, and data may be available for FDA review in 2027.

“At Gilead, we will not stop innovating until HIV is conquered,” Jared Baeten, MD, PhD, Gilead’s senior vice president for clinical development and virology therapeutic area head, told POZ. “By developing additional modalities and durations of PrEP, Gilead seeks to empower more individuals to choose, initiate and stay on the PrEP regimen that fits best into their lives.”

Click here for more news about HIV prevention.