Long-Acting Injectable Lenacapavir Works in Both Prevention, Treatment of HIV: Gordon Crofoot, MD, PA

Gordon Crofoot, MD, PA, president and principal investigator at The Crofoot Research Center, spoke about how lenacapavir can be used as both a means of prevention and treatment of HIV as the approval decision on lenacapavir approaches later in June.

This transcript has been lightly edited for clarity; captions are auto-generated.

Transcript

How does lenacapavir work to treat and prevent HIV?

It works both ways. Lenacapavir is in a brand new class of drugs called a capsid inhibitor. And the first time we used it, actually, I gave the very first injection to a human in the world, I think it was seven years ago. I may be a little off, but quite a few years ago, and that was in the very first phase 1b pharmacokinetic study for lenacapavir, where they were really looking at how long does this drug work? I remember talking to the chemist that made this molecule, Winston (C. Tse) from Gilead (Sciences). He and I spent some time together before we started the initial treatment study for pharmacokinetic and we talked, and he didn't know how long it was going to last. He thought it might work for a month. Wow, wouldn't that be great? It works for a month. And so we did the very first pharmacokinetic study to determine how long it really worked, and we gave different doses of the drug because they didn't know what dose would work, and there was a placebo and multiple doses. People who got the drug, a month later [they had] very nice blood level. Two months later, very nice blood level. Three months later, 6 months later, still, 3 of the 4 doses had very nice drug level. And we even found that a year after injection on the highest dose, we still found drug in the blood a year after the first and only injection. So this became a very long-acting drug for Gilead.

But it's a capsid inhibitor, and it works both for (pre-exposure prophylaxis) PrEP and for treatment in basically the same way. When this virus, when HIV comes up and it attaches to a T helper lymphocyte canal to enter the cell, it comes up and it attaches with its GP 120 receptor, opens a hole in the envelope, and it then injects its genetic material, which is single-stranded RNA, into the cell. And that single-stranded RNA is in a little kind of football shape covering called a capsid. And that capsid is injected into the cell. The membrane of the cell closes off, the envelope of the virus disappears, and everything else is from the virus is gone. So you've got this capsid that contains the RNA genetic material to make this virus and make the cell it infects replicate the virus. But that capsid has to be broken down or nothing happens. So if you can't break the capsid down, it eventually gets destroyed and nothing happens. If you use the capsid, which is an enzyme that's injected with the capsid. The enzyme starts breaking down the capsid, and now you've got single stranded RNA segments that reproduce into single-stranded DNA, then double-stranded DNA, and the double-stranded DNA now looks exactly like human double-stranded DNA. Those little segments of double-stranded DNA then go into the nucleus of the cell, open up the human DNA, inserts itself kind of into it. It's a little more complicated than that, but now you don't have virus, but you have genetic material inside of the cell, in the human DNA of that cell that can now replicate virus. That's how it infects the cell. If you can block the capsid for treatment, great. Cells don't get infected. And now, if you don't have HIV, but you're exposed to it, the virus starts to get in your system, you now prevent it from entering any cells, and it doesn't develop into an infection. So it works the same way for treatment or for PrEP.