What’s the latest on lenacapavir—the promising new treatment for multi-drug resistant HIV?

If approved by the U.S. Food and Drug Administration (FDA), lenacapavir could be a game changer for people living with HIV (PLWH) who have developed drug resistance on their current regimens and have limited treatment options available to them. The long-acting capsid inhibitor—administered as twice-yearly injections—could also be a convenient option for PLWH who are just starting therapy, and as an alternative to daily pills for pre-exposure prophylaxis (PrEP) as well.

Currently, the only other available long-acting HIV treatment is Cabenuva (cabotegravir and rilpivirine), which was approved in January and requires a monthly injection. How Cabenuva stacks up against lenacapavir is not yet known.

Manufactured by Gilead Sciences, lenacapavir is a capsid inhibitor, a class of drugs that works differently than other antiretrovirals, making it a possible alternative for PLWH who have developed resistance to current HIV treatments. Capsid inhibitors have been shown in the lab to disrupt the HIV capsid, or the shell surrounding the viral genetic material, preventing it from entering a host cell.

Multiple studies are evaluating the potential of lenacapavir (often abbreviated as LEN) as a long-acting agent to treat—and even prevent—HIV, and future trials are in the works. In an email from Gilead spokesperson Brian Plummer, he emphasized that lenacapavir is an “investigational compound and is not approved by any regulatory authority for any use” since “its safety and efficacy are not yet established.” Despite that caveat, the results of ongoing research are encouraging.

A High Barrier to Resistance

Over the past four decades of the HIV epidemic, the FDA has approved seven types of medications to combat or suppress the virus. In general, having a variety of types, or classes, of medications for treatment—whether it’s for HIV or tuberculosis or other microbes—is a good thing, because there’s no guarantee a single medication will work for everyone, nor whether it will continue being effective for a person over years or decades.

At the 2021 Conference on Retroviruses and Opportunistic Infections (CROI) in March, a researcher presented results from a phase 2/3 trial of LEN for HIV along with participants’ failing regimens and found that one injection resulted in a significant reduction in viral load. The trial, CAPELLA, evaluated 72 PLWH with resistance to at least two drugs from three major classes of antiretroviral drugs. Referring to the CAPELLA results as “clinically meaningful,” Sorana Segal-Maurer, M.D., from New York-Presbyterian Queens Hospital, explained that after two weeks, 88% of the group taking LEN achieved a decline in HIV-1 RNA, versus 17% of PLWH in the placebo group who experienced HIV-1 RNA decline. In the LEN group, 81% of participants had an undetectable level of HIV six months after receiving the treatment. LEN was also well tolerated, with no adverse events causing subjects to discontinue use.

Based on data from the phase 2/3 CAPELLA study, in late June, Gilead submitted a new drug application (NDA) to the U.S. FDA for lenacapavir for PLWH currently on failing regimens. The FDA granted Priority Review designation to the NDA, which will speed up the review process. A Prescription Drug User Fee Act action date of Feb. 28, 2022—though approval of any new medication is never guaranteed—means twice-yearly injections of lenacapavir could be available as early as next spring.

In addition, Gilead earlier this year announced it would collaborate with drugmaker Merck to study the effectiveness of lenacapavir along with islatravir, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), which is a new drug class in HIV. Researchers have observed significant potential in combining the long-acting non-oral versions of both drugs.

In response to recent criticism for a lack of diversity in its trial populations, Gilead is making a stronger effort to ensure populations most impacted by the HIV epidemic are represented in HIV clinical research studies, according to Plummer.

“In the CAPELLA trial, the proportion of Black (38%) and Hispanic or Latinx (21%) participants is higher than the average representation of Black and Hispanic or Latinx participants in HIV clinical research,” Plummer said. “Despite accounting for most new HIV infections globally, cisgender women remain underrepresented in HIV research, including the CAPELLA trial. Twenty-five percent of participants in the CAPELLA trial were [assigned] female at birth.”

LEN May Be an Option for the Treatment-Naive

Early data from another trial also suggests that LEN may benefit patients who have not yet received treatment for HIV. The trial, CALIBRATE, is evaluating the effectiveness of injectable LEN in combination with other antiretroviral agents in treatment-naive PLWH. At the International AIDS Society Conference on HIV Science (IAS 2021) in July, early phase 2 study results from CALIBRATE showed that a combination of lenacapavir, given orally and as an injection, along with Descovy (emtricitabine-tenofovir alafenamide), resulted in 94% of patients achieving viral suppression by 28 weeks, versus 100% viral suppression for those getting Biktarvy (bictegravir-emtricitabine-tenofovir alafenamide), Gilead’s once-daily oral. CALIBRATE is ongoing, with the end goal of determining the proportion of patients with undetectable viral load at 54 weeks.

“The CALIBRATE results support the ongoing evaluation and further development of lenacapavir in combination with other long-acting partner agents for the treatment of HIV-1 infection for PLWH beyond the [heavily treatment-experienced] population,” said Plummer, “and will support Gilead’s long-acting oral and injectable development program.”

Months after adding a lenacapavir arm to its oral Descovy study last year, Gilead announced two planned trials to evaluate LEN as a twice-a-year injectable for PrEP. The PURPOSE 2 trial started in June, to evaluate LEN as PrEP for cisgender men, gender nonbinary individuals, and persons of trans experience who have sex with men. It’s being conducted at sites in the U.S., South Africa, Peru, and Brazil, where there is a high incidence of HIV or prevalence of people living with HIV. And in August, the PURPOSE 1 trial started, evaluating LEN as a twice-a-year PrEP injectable for cisgender adolescent girls and young women. The trial is being conducted in Uganda and South Africa, where there is a high incidence of HIV and prevalence of people living with HIV.

By Larry Buhl

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