Mechanisms and Clinical Use of Lenacapavir for Multidrug-Resistant HIV

Daniel R. Kuritzkes, MD, describes how the unique mechanism of lenacapavir allows clinicians to maintain viral inhibition over time.

Joseph Eron, MD: So, Dan, maybe now you could talk to us about lenacapavir and its mechanism of action. And how is it that we can give it every 6 months?

Daniel R. Kuritzkes, MD: Lenacapavir is the first in a class of drugs called capsid inhibitors. People remember the virus particle has a protein core that encapsulates the genomic RNA, and what we call p24 antigen is the capsid. Lenacapavir binds to the capsid, which is composed of these 6-molecule subunits, or hexamers, and it disrupts the capsid. It has a really interesting mechanism of action because it acts at several places in the virus life cycle. We’ve learned through some very elegant molecular virology studies that capsid doesn’t actually dissolve when the virus enters the cell.

Joseph Eron, MD: Which we thought before.

Daniel R. Kuritzkes, MD: Exactly. It chaperones the reverse transcriptase [RT] and the RNA, the pre-integration complex, or the whole reverse transcription complex, into the nucleus through the nuclear core. So if you disrupt capsid, then the important part of the virus, the RNA and the RT, doesn’t make it into the nucleus. You don’t get reverse transcription, so you’ve blocked infection at the outset. In addition, it blocks assembly of the capsid and prevents a proper release of the virus particle at the back end of the virus life cycle. So it’s a double hit in that respect.

Joseph Eron, MD: It’s incredibly potent, in part, maybe because of that.

Daniel R. Kuritzkes, MD: So the drug is active at picomolar concentrations.Which is 10-12 . Because you can use so little drug, then you can formulate it in a way that with sustained release you can be releasing tiny amounts of drug every day and achieving sufficient concentrations to maintain viral inhibition.

Joseph Eron, MD: It really has the potential to help transform. It’d be better to have other partners that were equally long-acting, and Dan, I’m going to ask you about that in a second. We now have data on lenacapavir in people who are highly treatment-experienced.

Daniel R. Kuritzkes, MD: Exactly. The CAPELLA study looked at people like those that we’ve been discussing, people who’ve had multidrug resistance, and used a kind of clinical trial that really emerged from many discussions between the FDA, and treatment advocates, investigators like ourselves, and the Forum for Collaborative Research that Veronica Miller leads, to come up with a trial design that would prove the point that these new drugs are active without insisting that people also be on a placebo arm for weeks to months where they were going to ruin whatever remaining drugs they had.

Joseph Eron, MD: Whatever background they had.

Daniel R. Kuritzkes, MD: In this trial design, you look at how much of a virus load reduction do you get after just a very brief period of adding this drug to the failing regimen, and then if you get a half log or more reduction you’ve achieved the end point. Then it continued to follow people to get data on long-term durability as well as long-term safety. So that’s exactly what CAPELLA did. It showed that if you added lenacapavir to somebody’s failing regimen that you achieved substantial reductions in virus load and that is really the basis of the approval of the drug.

Monica Gandhi, MD, MPH: The more active drugs in the background the better, though, which is obvious.

Daniel R. Kuritzkes, MD: Well, after the primary end point people optimized their background regimen and then continued on.

Joseph Eron, MD: Though the differences are actually pretty small with the more active drugs in the background.

Monica Gandhi, MD, MPH: It is tiny. That’s very fair. There’s a poster here but they said half the drug.

Joseph Eron, MD: There’s a poster at IDWeek in Washington, DC, actually. But at a year’s time, 70-some percent, way more than half of the people, have maintained suppression.

Monica Gandhi, MD, MPH: That’s what you showed in the VIKING study. It was 73% suppression when there was hardly anything holding it up, and that is very hopeful about lenacapavir. It’s something though.

Joseph Eron, MD: But as you pointed out,it’s possible if the person stops their therapy. I think there was maybe 1 example of someone who just had no active drugs where we did see emergence of resistance. Lo and behold it mapped to where the drug binds to the capsid.

Daniel R. Kuritzkes, MD: Absolutely. There had been work done in the laboratory trying to generate drug-resistant virus and they identified a number of mutations. Several of the mutations that were seen in the lab are the same mutations that appear in some of the people who had virologic failure on lenacapavir.

Joseph Eron, MD: Monica is going to have to develop a contact for lenacapavir.

Monica Gandhi, MD, MPH: I’m going to send you right after this.

Joseph Eron, MD: Right after this.

Monica Gandhi, MD, MPH: When I’m lonely I sometimes call doravirine. They’re very responsive.

Joseph Eron, MD: They’re very responsive.

Transcript Edited for Clarity

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