February 3, 2008
Two presentations at CROI 2008 focused on CCR5 antagonists in development. Sarah Pett, M.D., of the University of South Wales in Australia, reviewed phase 1 trial results on SCH532706. Barry Zingman, M.D., of Montefiore Medical Center in New York, discussed 48-week results from a study on vicriviroc [SCH 417690, SCH-D]. Here are their study summaries.
Sarah Pett: This was a phase 1 study of a new CCR5 antagonist, SCH532706.1 This is the first time this drug was trialed in HIV-1-infected individuals. The in vitro data for this study showed it was pretty potent against many different HIV isolates. In the healthy volunteer studies, it had a favorable pharmacokinetic profile when it was dosed with ritonavir [RTV, Norvir] 100-mg once a day.
Sarah Pett, M.D.
The mean reduction of viral load at day 10, which was the last day of dosing with the study drug and ritonavir, was -1.3 log10 copies/mL. What was interesting about the drug was that there was a post-antibiotic effect. So, on day 15, which was four days after they last received the study drug, there was a further reduction in their viral load from baseline, to a 1.6-log reduction from baseline, and that post-antibiotic effect actually continued. There was a 1-log reduction from baseline that was sustained at day 20, and the patients hadn't returned to their baseline viral load at day 25.
The drug was safe and well tolerated. The most common adverse event that was reported was gastrointestinal upset in about two thirds of patients. But in fact, in 60% of the patients, we considered that this was not related to the study drug, but possibly related to the ritonavir that they were receiving. The adverse events were just grade 1, very mild.
There was one serious adverse event reported -- a patient got pericarditis, which resolved after four days -- but this was nearly two weeks after the patient had actually received any of the study drug. So we said it was possibly related, but a remote relationship. There were no other safety concerns. There was no X4 detection. There were no ECG [electrocardiogram] changes of concern.
So in summary: This new CCR5 antagonist appeared to be safe and well tolerated. It was clearly biologically active. And it's certainly feasible to give this once daily. I didn't mention that the half-life with ritonavir was 40 hours. And this, coupled with the fact that the drug has a very slow disassociation from the CCR5 receptor means it's realistic that this could be given once daily for patients.
Barry Zingman, M.D.
VICTOR-E1 is a multinational study that was done in 12 countries. It randomized 116 patients who were screened for the presence of CCR5-tropic HIV-1. They were randomized to one of three arms. In each arm, they received a ritonavir-boosted protease inhibitor as part of their optimized background therapy. In addition, they were given either vicriviroc 30-mg, 20-mg, or placebo. They were followed for 48 weeks.
The patients needed to be fairly advanced. They needed to have been triple-class experienced in prior antiretrovirals. They had to have mutations against nucleoside reverse transcriptase inhibitors and protease inhibitors, and they had to have an RNA level over 1,000.
The primary efficacy endpoint was change in log10 RNA levels at week 48. We also looked at suppression at less than 50 and less than 400, and safety and tolerability.
The patients were evenly randomized between the three arms. They were an advanced population with a CD4 count of around 200. About 85% had fewer than three active drugs in their background therapy. I should mention that randomization was stratified for high viral loads, over 100,000, and for enfuvirtide [T-20, Fuzeon] use.
Most of the patients completed the study, except in the placebo arm. Half of the patients did not complete there, because of viral failure. The primary study's endpoint, as I said, was a reduction in log10 RNA levels at week 48. Both of the vicriviroc arms showed a superior and statistically significant drop in RNA levels at week 48. They averaged about 1.76 logs, in comparison to the placebo arm at .79 logs.
When we looked at some part of the treat groups -- for example, the group that had RNA levels over 100,000 at screening -- there were trends to improvement in the vicriviroc group, especially in the 30-mg group. There were also trends to improvement in the vicriviroc 30-mg group in people with low CD4 counts.
When we further analyzed for the endpoints of achieving less than 400 copies or less than 50 copies, both of the vicriviroc groups performed significantly better, statistically better, than the placebo group. This was seen across all levels of activity of the background therapy. So, if somebody had a background therapy with no active drugs, or three or more active drugs, the vicriviroc, especially dosed at 30 mg, added additional efficacy. That was both for less than 400 and less than 50.
There were increases in CD4 counts in the vicriviroc arms: about 100 to 130 versus 60 in the placebo arm. Significantly, there were no differences in adverse event rates between the vicriviroc-treated patients and those on placebo. There were no changes in liver function abnormalities. There were some patients in each of the arms who started the study at screening with CCR5-tropic virus, who did have emergence of dual/mixed or X4 virus during the study. This was seen in all the arms. There were a few patients more in the 30-mg arm. In general, especially in the 30-mg arm, DMX-4 virus emerged very early. In fact, many of them were at baseline before the first dose, or at week 8, which was the first testing on therapy. And only half of these patients in the 30-mg dose were stopped with a high viral load. I'll just mention that efficacy correlated with levels, and the levels in the 30-mg group were better than those of the 20-mg group.
The conclusions were that: the vicriviroc plus background therapy is significantly superior to optimized background therapy alone; there was added benefit to the vicriviroc, regardless of the number of active drugs; and the 30-mg dose had a special efficacy in the hard-to-treat populations. There were no relevant safety differences. Based on these results, the 30-mg dose was chosen for phase 3 studies of this agent.
John Mellors: Thank you very much. One question for Sarah and Barry: You have a drug in phase 1 development and a drug in phase 3 development with the same mechanism of action; which is the priority?
Barry Zingman: I don't know the answer to that.
John Mellors: OK. Open for questions.
Reporter #1: Are the two drugs cross resistant? Is the new one [SCH532706] active against vicriviroc resistance?
Sarah Pett: I don't know that.
Reporter #1: Barry, it says in the abstract that viral failure was not associated with switching to X4 or mixed. Does that mean that people who came out with mixed virus during the study had a good viral response?
Barry Zingman: Yes, especially in the more potent 30-mg arm. There was more development, or emergence, of DMX-4 virus early in the study. In fact, about half of the people who developed DMX-4 variants had it detected before they even got their first dose. Then, subsequent to that, they were treated with vicriviroc and a background therapy regimen. Many of them improved; they did better. So there was less of an association with high viral loads in the 30-mg group. There was much more of an association between the development of DMX-4 and discontinuation with viral loads over 400 in the lower dose vicriviroc group and the placebo group. In the 20-mg and the placebo group, it was about one to one. But in the vicriviroc 30-mg group, only half of the patients ended up being discontinued with viral loads over 400. So I think we're seeing the combination of a potent drug, vicriviroc, and optimized therapy.
John Mellors: I have a direct follow-up to that question for you, Barry. You said that many of the patients were already dual or mixed tropic at the time of the first dose. And yet, at baseline, weren't all these patients screened for being purely R5 tropic? How much of a lag was there? Was that shift in tropism developed between the time of screening and the time of first dose, and about how long a time was that?
Barry Zingman: Patients were enrolled in the study based on the tropism assay done at screening. They had one tropism assay done at screening. It could be a maximum of about six weeks before they got their first study drug dose. So, a maximum of six weeks. At their very first study day they got more blood drawn and started the dosing that day. They got a tropism assay done that day. So they had tropism assays done once at screening, once at day 1, once at day 8, once at day 24, once at day 48. So all throughout the study. And much of the shifts in all three arms, actually, happened earlier. In the placebo and 20-mg groups, they occurred more evenly throughout the study. In the 30-mg arm, it was especially early, probably because it's a more potent drug. It suppresses CCR5-tropic virus, so underlying DMX-4 virus comes out earlier.
John Mellors: What percentage shifted between screening and day 1?
Barry Zingman: It was six patients out of 39 patients.
John Mellors: This is very consistent with what's been observed before. Because we're at the detection limit for dual/mixed.
Reporter #2: I have a question for Mr. Zingman. Could you explain the difference between both CCR5 antagonists -- between maraviroc [MVC, Selzentry, Celsentri] and vicriviroc? Are there any benefits, or non-benefits?
Barry Zingman: That's the question that everybody hears. The first way to answer that question is that certainly there have not been any head-to-head studies between the two drugs. One of the nice things with vicriviroc is that, when it's given with a ritonavir-boosted protease inhibitor, it has excellent pharmacokinetics. It has reliably high minimum concentrations. It has a long plasma half-life, over a day. It can be given regardless of food intake. It's, so far, very, very well tolerated.
Reporter #3: Barry, given the fact that X4 emerges so rapidly, could you comment upon the need for more sensitive assays to detect minority populations at screening?
Barry Zingman: It's clear that we need the most sensitive assays we can get. What we also need to see, though, in future clinical trials, is whether or not all the CCR5 inhibitors -- at all doses, all potencies -- can be still active with a small minority population. But right now, certainly we strive to rule out DMX-4 presence before giving somebody a CCR5 receptor antagonist.
Reporter #4: Barry, regarding the immunologic benefit of the 20- and 30-mg groups, are you looking at immune reconstitution syndrome? Are you seeing any episodes of that? And also, the correlation to CD4 percentages?
Barry Zingman: We looked at all the adverse events (serious and non-serious) and there were no noted immune reconstitution syndromes. Of course, patients were not enrolled in the study if they had a recent active opportunistic infection. I think it was within four to eight weeks. So they would be a little bit less likely to develop immune reconstitution syndrome.
Reporter #5: This question is also for Dr. Zingman. I'm curious if you could help me put in perspective how I should think about the tropism switch with the CCR5 inhibitors. Are we worried down the line that the virus will just get in through the other door, so to speak?
Barry Zingman: At least what we think is happening in many of these patients is that they actually already have DMX-4 virus: that it's there, it's a minority population, or the virus is already present. There's relatively little evidence that these agents drive the development of the X4 virus. We need to take further studies to evaluate.
Reporter #6: I just have a simple nomenclature question. We like to call everything inhibitors. You just referred to CCR5 inhibitors, yet your abstracts use the term antagonists. I understand the mechanism difference. Is there any crime in calling them CCR5 inhibitors? Is there anything wrong with that?
John Mellors: Well, CCR5 is a receptor, really. We refer to things that bind and block function of receptors as antagonists. Whereas, inhibition is an enzymatic process, generally, a catalytic process.
Reporter #6: We're all going to use these terms. It seems to me that there is inhibition of binding to the receptor.
John Mellors: Well, put it this way: You're typically antagonistic, but not an inhibitor. [Laughter.]
Reporter #7: In, I think it was, only one early study with a CCR5 inhibitor, there was noted to be an increase in malignancies. I haven't heard that replicated in any other CCR5 inhibitor studies. Is that considered by principal investigators sort of a dead issue, something that happened by chance? Can you comment on that?
Barry Zingman: Some malignancies -- I believe three different kinds -- were seen in seven or nine patients in an early ACTG [AIDS Clinical Trials Group] study of vicriviroc.3 There was an expert panel that met and reviewed the cases, and judged that there was not significant evidence that it was related to the drug itself, but more that it was occurring in an overall very sick population of patients who were entered into the study. There were no malignancies that occurred during the 48 weeks of the study. Now, after the end of the study, eligible patients who still had CCR5 tropism were able to continue on open label medication, maraviroc 30-mg. One person, three months into his course, did develop Hodgkin's disease, and is under treatment. That's all I have to say about that. Otherwise, there's been very, very few malignancies since then. That one patient who developed it also had a CD4 count under 100 pretty much the whole time, so never really had an immune response.
John Mellors: Thank you all, presenters and participants.
This transcript has been lightly edited for grammar and clarity.