Joseph Eron, MD, Daniel R. Kuritzkes, MD, and Monica Gandhi, MD, MPH, discuss the implications of recent data regarding the use of fostemsavir and ibalizumab.
Joseph Eron, MD: Are there any additional data you want to share about fostemsavir or ibalizumab?
Daniel R. Kuritzkes, MD: From the perspective of ibalizumab, you can develop resistance. It’s a little counterintuitive because the antibody binds to the CD4 on the patient’s cells, not to the virus. But when we did the phase 1 studies, they showed that people who failed did so with resistance. It looks a lot like maraviroc resistance in the sense that you don’t get full inhibition. You get a flattening of the inhibition curve.
Joseph Eron, MD: Somehow, the virus seems to figure out how to use the receptor with the drug still in place.
Daniel R. Kuritzkes, MD: Exactly, that’s the concern. If you’re not going to achieve full suppression, then you’ll lose ibalizumab. With fostemsavir, the issue is that not all viruses are susceptible to fostemsavir. In particular, viruses that are prevalent in Southeast Asia, like in Thailand, may be much less susceptible, and there isn’t a good genotypic test to determine that.
Joseph Eron, MD: Right, because it’s binding to the viral envelope, which isn’t a nice long line like a protease or a reverse transcriptase. At least structurally, that’s how you can think about it. There’s some suggestion that with fostemsavir there may be some immunologic effect or a robust CD4 response.
Daniel R. Kuritzkes, MD: Yeah. In the BRIGHTE study, which was the study that—like the CAPELLA study—looked at people who were highly treatment experienced with multidrug resistance and then treated them with fostemsavir in an optimized background regimen. Among those who achieved virological suppression and stayed suppressed, they continued to see CD4 increases over time, which is unusual. Usually, you see a big increase, and then it plateaus. The way the drug acts, it locks the envelope into this early confirmation, and it interacts with antibodies—especially neutralizing antibodies—in a very different way.
It’s been hypothesized that perhaps that mechanism of action is having some favorable immunologic effect. At the moment, that’s still a hypothesis. It’s not entirely clear that the CD4 increase isn’t simply an attrition effect, in which the people who aren’t responding or who had lower CD4s are dropping out, so you’re left with the best participants. There’s still some more work to be done on that, but it’s an intriguing area for the study.
Joseph Eron, MD: When they do a true intent-to-treat analysis, they still see this. But if people are gone, you have to carry something forward. It’s just a little more difficult.
Daniel R. Kuritzkes, MD: You need an attrition-adjusted analysis, as you taught me years ago.
Joseph Eron, MD: What about ibalizumab? In the study you published, that there wasn’t as much of a CD4 change. Has that played out, or do we not have enough data to know?
Daniel R. Kuritzkes, MD: We don’t know. Ibalizumab has odd effects on CD4 count. In the phase 1b study, in which people had repeated doses, we saw wide swings in CD4 count. Immediately after the infusion, there was a big increase in CD4, and then their CD4s dropped. Some of those dropped far enough to be considered grade 3 adverse events, and then they would rebound. When they got their next dose, their CD4s would go way up. The levels seesawed.
That wasn’t clearly described in the phase 2 study done more than a decade ago. I remember being here in Washington, DC, for IDWeek—the first time we were at the new convention center—when those phase 2 data were reported. It’s that long ago. That study showed that most people eventually failed because they didn’t have adequate background regimens. They all got resistant, and they didn’t have any significant CD4 benefit over the time of that study.
Joseph Eron, MD: I see. That makes more sense.
Monica Gandhi, MD, MPH: By the time of the registrational trial, they also had fostemsavir in the background with ibalizumab later?
Joseph Eron, MD: For the phase 3 trials.
Monica Gandhi, MD, MPH: For the phase 3. But for phase 2, that wasn’t around to provide bolstering.
Transcript Edited for Clarity