Lenacapavir - The HIV 'Vaccine'

The topic of this report is a long-acting HIV "vaccine" called Lenacapavir, developed by Gilead Sciences in the United States. You may have noticed that when we talk about Lenacapavir, we put quotation marks around the word vaccine. This is because, strictly speaking, Lenacapavir is a drug that prevents infection by interfering with HIV replication, rather than a traditional vaccine that prevents disease by stimulating immune memory.

First, let's briefly introduce the pair of concepts: HIV and AIDS.

HIV, commonly known as the AIDS virus, officially called Human Immunodeficiency Virus, is a virus that specifically infects certain immune cells in the human body. This virus likely originated from primates living in Africa and gained the ability to spread among humans about 100 years ago [1]. In the 1980s, American and French scientists finally unveiled its mysterious nature, discovering and describing HIV for the first time. In fact, an HIV viral particle is an icosahedron approximately 120 nanometers in diameter, divided into three layers from outside to inside: the outermost layer is the viral envelope, derived from the host cell membrane; the middle layer is a dense capsid formed by viral proteins; and the viral genomic RNA molecules are hidden inside the capsid [2]. 

AIDS, on the other hand, stands for Acquired Immune Deficiency Syndrome, which is the disease caused by HIV infection. Let's briefly explain how HIV leads to AIDS: After HIV enters the body, it uses special protein molecules on its envelope to precisely target and invade immune cells. Then, the virus releases its RNA genome into the immune cells, converts it to DNA through reverse transcription, and integrates it into the host cell's genome. Inside the immune cells, the virus continuously replicates and reproduces, ultimately leading to the death of immune cells, severely weakening the immune system. It's important to note that there is often a latency period of several years or even decades between HIV infection and the onset of AIDS. During this time, the virus continuously replicates in the body, steadily destroying immune cells, eventually leading to the complete collapse of the body's immune system (Read more on HIV's life cycle). At this stage, various pathogens that once seemed harmless, from bacteria to fungi, from parasites to viruses, demonstrate shocking destructive power in the body, ultimately leading to the patient's death.

In the journey of fighting HIV, despite scientists' continuous attempts at breakthrough, the challenges remain significant.

Currently, the most effective way to block viral infection is to develop vaccines. This approach has successful precedents. For instance, humans have successfully eliminated the threat of smallpox through vaccines and significantly reduced the spread of poliovirus globally, with its eradication now within reach. However, unfortunately, vaccine development against HIV has been struggling and repeatedly failing. In 2009, a highly anticipated vaccine showed partial preventive effects in the RV144 trial in Thailand, causing a momentary surge of public attention [3], but subsequent data analysis showed its effects were not as good as hoped; by 2020, another vaccine with a similar design approach met with failure in the HVTN702 trial in South Africa [4]. In retrospect, researchers believe that many biological characteristics of HIV, such as its surface structure, replication, and infection methods, naturally make it resistant to vaccines.

Since the vaccine path is not viable, drugs are the only option left. Objectively speaking, over the past three to four decades, humans have developed many drugs targeting HIV, some of which prevent viral spread by inhibiting HIV genomic RNA replication (reverse transcriptase inhibitors, such as zidovudine); some inhibit HIV protease activity, thus interfering with HIV assembly (protease inhibitors, such as ritonavir); and some can prevent HIV from entering immune cells (such as enfuvirtide). It was based on the combination of these drugs that the famous "cocktail therapy" was born. This therapy was proposed by Chinese-American scientist David Ho in the 1990s, combining several HIV drugs with different mechanisms to maximally suppress viral activity and protect immune function [5].

With the support of cocktail therapy, HIV-infected individuals who receive proper continuous treatment can achieve quality of life and life expectancy not significantly different from the general population. However, the drugs have prominent issues: unlike vaccines that work for a long time with one shot, drugs cannot completely eliminate HIV and require lifelong adherence to precise dosing schedules. Meanwhile, patients need to regularly adjust their drug combinations based on drug resistance and side effects. For patients, this is undoubtedly a huge economic and lifestyle burden, especially in underdeveloped countries.

Notably, between preventive vaccines and therapeutic drugs, a third path has achieved tremendous breakthrough, namely using drugs for so-called Pre-Exposure Prophylaxis (PrEP). Let's first briefly explain what pre-exposure prophylaxis is. This term means using drugs to prevent infection in people who haven't been infected with the virus but live in environments where they are at risk of infection. For example, if a woman is not infected with HIV but her partner is HIV-positive, she could potentially be infected through sexual activity. If effective pre-exposure prophylaxis drugs exist, she can live safely without being infected. This term might sound complicated, but I'll give you an example you'll surely understand: the famous flu "miracle drug" Tamiflu (oseltamivir), besides being used for flu treatment, can also provide pre-exposure prophylaxis against flu. Therefore, during flu seasons, healthcare workers who frequently interact with flu patients can prevent infection by taking Tamiflu [6].

In fact, at this point you might easily imagine that if HIV treatment drugs were taken regularly before infection, they might achieve pre-exposure prophylaxis effects. Because when HIV first enters the body, the viral load is still very low, and if viral replication and spread can be effectively prevented, the body's immune system can effectively recognize and kill the limited number of viruses. This is indeed the case, for example, two approved HIV pre-exposure prophylaxis drugs, TDF and TAF, work on this principle. These two drugs are combination preparations composed of emtricitabine and different forms of tenofovir, both HIV reverse transcriptase inhibitors. Research has shown that as long as these drugs are taken on time daily, they can reduce the risk of HIV infection by 99%.

This approach sounds perfect, but upon careful consideration, it's not. Getting a healthy person to take medication every day, especially medication with numerous side effects, is inherently against human nature. It's easy to miss a dose, and laziness can lead to sporadic adherence. Moreover, living with an HIV-infected person doesn't necessarily lead to transmission—for instance, the risk of infection through vaginal intercourse between men and women is less than 0.1%. In this situation, getting healthy people who are exposed to potential risks to stick to taking medication year after year is indeed very difficult to achieve.

Fortunately, this report's protagonist, Lenacapavir, is exactly such a drug. Developed by U.S. company Gilead, it was initially designed as an HIV therapeutic drug. But unlike the several types of drugs we discussed above, its mechanism of action is quite unique, as it can precisely insert itself between HIV capsid proteins, preventing HIV particle assembly [7] (Read more on Lenacapavir's mechanism of action). In 2022, the FDA approved this drug for the treatment of HIV patients.

Meanwhile, Gilead's researchers also discovered that this drug is cleared very slowly from the body, has a long half-life, and can maintain effective doses for over 24 weeks with a single subcutaneous injection. This discovery naturally demonstrated Lenacapavir's enormous potential as a long-acting pre-exposure prophylaxis drug. Therefore, in 2021, Gilead simultaneously launched multiple Phase 3 clinical trials, Purpose 1-4, to test Lenacapavir's effectiveness as a pre-exposure prophylaxis drug.

All studies were classic randomized, double-blind, multicenter clinical trials, but targeted different high-risk HIV populations. For example, Purpose 1 targeted cisgender young women living in high-HIV-prevalence areas of Africa (meaning the subjects were women with male sexual partners), while Purpose 2 included multiple categories: cisgender gay men (males who identify as male and have male sexual partners); transgender men and women; and non-binary individuals (those who cannot define themselves within the male-female binary), while Purpose 4 targeted drug users, etc.

In July 2024, Purpose 1's clinical data was first published in The New England Journal of Medicine [8] (Read more on Purpose 1 report). Over 5,000 healthy subjects who were not infected with HIV were divided into three groups in a 2:2:1 ratio, with the first group receiving Lenacapavir subcutaneous injection every six months, and the second and third groups requiring daily oral TAF or TDF. During the one-year observation period, 39 people in the TAF group and 16 in the TDF group were found to be HIV-infected, with infection rates of 2.92/100 person-years and 1.69/100 person-years respectively, not much different from the local social baseline infection rate (2.41/100 person-years). The group receiving Lenacapavir injections achieved zero infections, with an infection rate significantly lower than both the social baseline and oral medications.

In November 2024, Purpose 2's clinical data was also published in The New England Journal of Medicine [9], achieving similarly good results. Over 3,000 healthy subjects were divided into groups in a 2:1 ratio, with the former receiving Lenacapavir injections and the latter requiring daily oral TDF. During the observation period, 2 people in the first group were infected, with an infection rate of 0.1/100 person-years, while 9 people in the second group were infected, with an infection rate of 0.93/100 person-years. As a reference, the local baseline infection rate was approximately 2.37/100 person-years.

We have succesfully developed and have been manufacturing relevant Lenacapavir intermediates at our CDMO subsidiary, these includes: