Lenacapavir: Can Gilead’s drug end the HIV pandemic?

Officially discovered in the 1980s, human immunodeficiency virus (HIV) was once considered a death sentence for anyone who was diagnosed with it. As research into the virus advanced, the scientific community was able to come up with antiretroviral medicines to suppress the viral load, in turn improving immune function and reducing the risk of infections and cancers commonly associated with HIV. Now, in the most recent development, we could be on our way to preventing HIV altogether, as Gilead’s drug, lenacapavir, has demonstrated complete protection against infection. 

Lenacapivir: 100% efficacy for HIV prevention

On June 20, 2024, Gilead announced that lenacapavir had demonstrated 100% efficacy for HIV prevention, making it the first-ever HIV PrEP drug candidate to show zero infections in a phase 3 trial. 

The trial, named PURPOSE 1, was designed to evaluate the twice-yearly injection in more than 5,300 cisgender women and adolescent girls aged 16 to 25 across multiple sites in South Africa and Uganda. One group of participants received lenacapavir, while another group received Gilead’s daily oral PrEP drug Descovy, as the two were being tested in parallel. Additionally, a third group was assigned Gilead’s other daily oral PrEP drug Truvada, which acted as a secondary comparator. 

While no infections occurred among the 2,134 women in the lenacapavir group, the Descovy group recorded 39 incident cases among 2,136 women, and the Truvada group saw 16 incident cases occur among 1,068 women. With regards to the trial’s primary endpoint, which pitted lenacapavir against a background incidence rate of 2.41 per 100 person-years, lenacapivir was found to be significantly superior. It was also found to be generally well-tolerated and no significant or new safety concerns were identified.

Based on these results, the independent Data Monitoring Committee (DMC) recommended that Gilead stop the blinded phase of the trial and offer open-label lenacapavir to all participants.

Lenacapavir mechanism of action

But what is it that makes lenacapivir so effective? 

A lot has to be said for its multi-stage mechanism of action. As an HIV-1 capsid inhibitor, it is designed to inhibit HIV at multiple stages of its lifecycle. It works by interfering with three essential steps of HIV-1 viral replication: nuclear transport, virus assembly and release, and capsid core formation. The capsid core contains and protects viral RNA and enzymes, all of which play essential roles in HIV-1 replication. The HIV-1 viral lifecycle is dependent on the function of the capsid at these stages of replication.  

This mechanism of action is distinguishable from other currently approved classes of antiviral agents, most of which act on just one stage of viral replication. Lenacapivir also has no known cross-resistance exhibited in vitro to other existing antiretroviral classes. Essentially, this means that it is fully active against variants with select gene mutations that are known to cause antiretroviral resistance. 

For this reason, the drug has already been approved by the FDA for the treatment of multi-drug resistant HIV under the brand name Sunleca, to be used in combination with other antiretrovirals. 

When could lenacapivir receive FDA approval for HIV prevention?

With such impressive phase 3 trial results, it is worth considering when we might see a potential U.S. Food and Drug Administration (FDA) approval for lenacapavir. 

At the minute, Gilead is also conducting another trial, called PURPOSE 2, to assess lenacapavir for PrEP among cisgender men who have sex with men, transgender men, transgender women, and gender non-binary individuals who have sex with partners assigned male at birth in Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the U.S. Results from this study are expected to be announced in late 2024 or early 2025. If positive, Gilead then plans to combine the results from both PURPOSE trials in order to seek FDA approval. Doing so means that lenacapavir for PrEP can be approved for multiple populations and communities most in need of additional HIV prevention options. 

In an article in Fierce Biotech, Salim Syed, an analyst at William Blair, said that with the data from the PURPOSE 1 trial (and assuming PURPOSE 2 holds) lenacapavir – if approved – is “probably well situated to garner a significant share” of the PrEP market, which is currently expected to hit around $48.8 million by 2033, expanding at a compound annual growth rate (CAGR) of 4.1% between 2023 and 2033. 

Syed also noted that Wall Street’s consensus estimate has put lenacapavir’s global peak sales at around $3 billion across HIV prevention and treatment, and suggested the drug could reach $4 billion without adjusting for any development risks. 

Lenacapavir also being tested as a long-acting HIV treatment

Although lenacapavir has already been approved to treat multi-drug resistant HIV, Gilead is not stopping there, and is currently working on creating multiple ultra-long-acting regimens for HIV treatment. The company intends to provide a phase 2 update later this year for lenacapavir in combination with the company’s broadly neutralizing antibodies, plus lenacapavir is also being paired with Merck & Co.’s islatravir as a once-weekly oral candidate.

In fact, the lenacapavir-islatravir combination has recently shown great promise as a long-acting treatment. In March, Gilead and Merck announced data from a phase 2 trial, in which the novel combination maintained a high rate (94.2%) of viral suppression in people who switched to weekly islatravir and lenacapavir pills. This matched the viral suppression rate of those who stayed on daily Biktarvy, which is a combination of three separate antiretroviral drugs in one pill.

If further data continue to show promise, the combination could become the longest-acting regimen that does not involve injections. While single-tablet daily oral therapies have helped to transform HIV care, options that allow for less frequent dosing have the potential to address adherence, stigma, and other challenges faced by some individuals taking daily oral antiretroviral therapy.

The situation is similar when it comes to PrEP, too. In a comment to the New York Times, Lillian Mworeko, who leads a group called the International Community of Women Living With H.I.V. Eastern Africa, said: “For a young woman who can’t get to an appointment at a clinic in a town, a young woman who can’t keep pills without facing stigma or violence — an injection just twice a year is the option that could keep her free of HIV.”

Making lenacapavir affordable: A promising step forward in combating HIV at an accessible price

Globally, 4,000 adolescent girls and young women were infected with HIV every week in 2022. Of these, 3,100 infections were in sub-Saharan Africa. This means that 82% of adolescent girls and young women who acquired HIV in 2022 live in sub-Saharan Africa, including two-thirds in eastern and southern Africa, making it a high-risk region for HIV.

Naturally, there are questions surrounding whether Gilead – a biopharma giant – is going to make Lenacapavir affordable to those who need it the most. The company has said that is committed to making large volumes of the drug available “at prices that enable widespread availability” as quickly as possible in low-income countries with high HIV incidence rates. Janet Dorling, Gilead’s senior vice president for global patient solutions, told the New York Times that the company plans to sign voluntary licenses with generic drug makers to produce cheaper versions of lenacapavir, sharing its intellectual property in exchange for a licensing fee. This means that a cheaper generic product could then become available in low- and middle-income countries. 

However, Dorling added that it can take generic makers years to produce a drug, and they need to have a sense of the potential market in order to commit to investing in production. Therefore, in the meantime, Gilead will aim to ship “sufficient volumes” of lenacapavir to low-income countries as soon as it has regulatory approval. 

Nevertheless, if Lenacapavir receives approval and this can be achieved, the HIV drug could be a significant step forward in our ability to combat a virus that has so far eluded our efforts to wipe it out entirely.