A twice-yearly shot of the investigational antiretroviral medicine lenacapavir (Gilead Sciences) was associated with nearly a two-log drop in HIV viral load when paired with an optimized backbone antiretroviral regimen in people with resistance to multiple drug classes and few fully active treatment options.
This led Sharon Hillier, PhD, a researcher at the University of Pittsburgh, Pittsburgh, Pennsylvania, to call the results "small but pivotal" because they show activity. Most trials at this stage show negative results and end the program. But these suggest continuing.
"I was blown away," said Hillier, cochair of the Conference on Retroviruses and Opportunistic Infections 2021, who was not involved in the trial. And while the findings were limited by small numbers and interim analysis, Hillier added, "We need to keep our eye on the fact that this is amazing."
Lenacapavir binds to the conical capsid that encapsulates the HIV viral genome. If successful in larger phase 3 trials, it would be the first capsid inhibitor in HIV to come to market. It would also join fostemsavir (Rukobia) and ibalizumab (Trogarzo) as a new option for people with multiple drug resistance.
The phase 2/3 CAPELLA trial (NCT04150068) enrolled 72 heavily pretreated people living with HIV at trial sites in Canada, the US, the Dominican Republic, Japan, Taiwan, Thailand, France, Germany, Italy, Spain, and South Africa. Participants were a median of age 52 years and had been living with HIV for nearly half their lives — a median of 24 years. They also had access to two or fewer fully active antiretroviral agents.
One in four participants overall were assigned female at birth, 38% were Black, and 21% were Latinx.
The trial was broken down by a randomized, placebo-controlled cohort of 36 participants and a nonrandomized cohort of another 36 participants. Participants were put in the nonrandomized group if, between study enrollment and day 1 of the trial, their viral load dropped by a log RNA of 0.5 log10 copies/mL or if participants had an overall viral load of less than 400 copies/mL.
Those in the nonrandomized group received open-label access to oral lenacapavir on day 1, with dosing of 600 mg of oral lenacapavir on days 1 and 2, and 300 mg on day 8. Then, on day 15, they received two injections of 1.5 mL each of lenacapavir in the abdomen and were followed for 52 weeks. On day 1 they also started new backbone ART regimen designed to address each participant's individual drug resistance profile.
The remaining 36 participants were randomly assigned 2-to-1 to treatment vs placebo. Like the nonrandomized group, the active treatment group of the randomized trial started the trial with oral lenacapavir for 14 days and then received the same two long-acting shots of lenacapavir.
Unlike the nonrandomized group, instead of switching to an optimized backbone regimen on day 1, they did that when they received their shots of lenacapavir at day 15. This created a "functional monotherapy" period in which to test the action of lenacapavir itself. Likewise, the placebo group stayed on their previous, failing treatment regimen for 15 days and switched to an improved regimen and received shots at day 15. But in the oral lead-up, they took only placebo pills.
All participants then returned in 6 months for another double dose of the drug.
At baseline, median viral load overall was 4.5 log10 copies/mL, with 17%, 50%, and 28% of participants having viral loads of more than 75,000 copies/mL in the lenacapavir arm, the placebo arm, and the nonrandomized arm, respectively. And they were heavily pretreated. People in the randomized cohort had used a median nine different medications prior to enrolling in the trials, while members of the nonrandomized cohort had experience with 13.
People in the placebo group started out sicker — with 92% of them starting the trial with 200 or fewer CD4 cells/μL (vs 67%) and half of them with viral loads over 75,000 copies (vs 17%).
The primary goal of the study was to see if participants experienced drops in viral load from taking lenacapavir all by itself in the first 14 days of the trial. This they achieved, Sorana Segal-Maurer, MD, of NewYork-Presbyterian Hospital in New York City, told the audience in a prerecorded presentation: 88% of participants in the lenacapavir group saw their viral loads drop by at least half a log in the first 14 days of the trial, vs. 12% in the placebo arm (P = .0001). And it was quite a bit more of a viral load drop than half a log in the lenacapavir arm — nearly two logs or 1.93. By contrast, the 12% of participants in the placebo group saw a mean drop in viral load of 0.29 log10 drop in viral load (P = .0001).
Then researchers looked at how many participants experienced undetectable viral loads (<50 copies/mL) by week 26. All participants saw viral suppression increase — from about 3% at day 1 to 28% after 15 days. Once the participants received the shots and better backbone HIV regimens, viral suppression continued to increase, with 26% of the overall study participants reaching an undetectable viral load by week 26.
Meanwhile, CD4 counts rose by 72 copies/μL across all participants by week 26.
For Segal-Maurer, this data meant that lenacapavir was promising enough to move forward into additional trials. The study is still ongoing and is expected to be completed in 2022.
"Lenacapavir has the potential to become an important agent for heavily treatment-experienced persons with HIV with multidrug resistance," she said.
Side Effects and Resistance
As for side effects, the most common non-injection-site reactions included:
nausea, which occurred 14 times in the randomized lenacapavir arm
cough and diarrhea, each of which occurred 11 times in people in the randomized lenacapavir arms
headache, which occurred 8 times in the randomized lenacapavir arm
One participant died from pneumonia during the trial, but it was not considered related to the study drug.
Perhaps most surprisingly, there were 18 incidents of participants developing grade-1 nodules at the injection site, which lasted a median of 116 days.
But offering what is essentially monotherapy and then partial therapy for people with resistance to multiple drug classes has a downside: Two people who experienced an undetectable viral load both developed M66I capsid mutations with an 884-fold increased resistance or more to lenacapavir.
One participant was on a combination of darunavir/cobicistat (Prezcobix), dolutegravir (Tivicay) and rilpivirine (Edurant). The other had no fully active agents available to them as a backbone regimen, but was taking maraviroc (Selzentry), lamivudine (Epivir), Prezcobix, twice-daily Tivicay, and enfuvirtide (Fuzeon).
"It's very important to note that both [participants] resuppressed while continuing lenacapavir," Segal-Maurer said — and this was without a change in backbone regimen among the person on Prezcobix/Tivicay/Edurant. The other participant added tenofovir alafenamide (Vemlidy) back to his regimen and also resuppressed.
These findings, in such small numbers, led to several questions. For instance, no participants discontinued the trial because of the nodules, but the data led Carl Fichtenbaum, MD, of the University of Cincinnati, Cincinnati, Ohio, to point out that enfuvertide also caused the development of nodules and "that was an issue that affected use of that agent."
Following the presentation, several people asked how Segal-Maurer could say that the suppressed viral load was a result of lenacapavir and not the switch to more active backbone regimens. Segal-Maurer replied that the trial is still ongoing and that data on viral load by backbone regimen would be available in the future. But Frank Palella, MD, of Northwestern University Feinberg School of Medicine, Chicago, Illinois, was not satisfied, asking again that Segal-Maurer address outcomes by the switched backbone regimens.
The question "gets at the issue of how much of the viral suppression was due to lenacapavir vs the [optimized backbone regimen]," he noted.
These questions didn't dampen enthusiasm for the early results, however. Melanie Thompson, MD, of the AIDS Research Consortium of Atlanta, works with many people for whom available antiretroviral agents no longer work. For her, the data suggest a future where clinicians "have several options for people who are heavily treatment experienced."
"The exciting thing is that because it's a new target, a capsid inhibitor, there should be very little preexisting resistance to this drug," she told Medscape Medical News. "People who have really pan-drug resistance to currently available drugs, even to fostemsavir, should have a virus susceptible to lenacapavir. The other exciting thing is that it could be administered every 6 months, which means that people could probably be trained to do it themselves."
Conference on Retroviruses and Opportunistic Infections 2021: Abstract 127 and 121LB. Presented March 9, 2021.
Heather Boerner is a science and medical reporter based in Pittsburgh, PA and can be found on Twitter at @HeatherBoerner. Her book, Positively Negative: Love, Sex, and Science's Surprising Victory Over HIV, came out in 2014.
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Cite this: Lenacapavir Linked to Significant Drop in Viral Load in Multidrug Resistant HIV - Medscape - Mar 11, 2021.