March 8, 2010
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Myles Helfand: Your comment about the difficulty in developing drugs for treatment-experienced patients leads pretty nicely into some news that is not as good as the quad tablet: the results that were presented about the vicriviroc [SCH 417690; SCH-D] phase 3 study.
Joel Gallant: Yeah. This was a disappointment. This is the presentation by Joe Gathe on the VICTOR-E3 and VICTOR-E4 studies, looking at vicriviroc, which is a CCR5 antagonist, versus placebo plus an optimized background regimen in patients who've had extensive treatment experience and have R5 tropism.
Just to remind people: This is the same study design we have used ever since the TORO studies led to the approval of Fuzeon [enfuvirtide, T-20]. It's been a standard study design, where you take people who are experienced; you pick the best combination for them, using available drugs; and then they are randomized to either take that combination with the investigational drug or without it. It's served us well. It led to the approval of Fuzeon, of Prezista, of Selzentry [maraviroc, MVC, Celsentri], of Isentress. All of these recent drugs were approved in this way.
The problem is, I don't think this design works anymore. And this study was a classic example, because what happened is, even though the drug worked virologically, they couldn't really determine a difference between the people who were on just the background regimen arm versus those who were on the vicriviroc arm, because the people on the background, the control arm, did so well. That just reflects the fact that we have lots of drugs we can use now, and that most people will do fine with existing drugs. Therefore, the ability to detect a difference, using an experimental drug, is very low.
If you looked at the subset of patients who had zero, one or two drugs that were active in their background regimen, you did see that vicriviroc helped, that they had a better response. But overall, the people in the background regimen arm did just as well as the vicriviroc arm.
I think this is telling us what we probably already knew: This TORO-style study design is not going to work anymore. We're going to have to figure out a new way to get investigational drugs approved, if they're being used for treatment-experienced patients. Because it's certainly not ethical to restrict the number of active drugs people get. And yet, without doing that, there's almost no way to see the benefit of your investigational drug.
Myles Helfand: For people who had two or fewer active drugs in their background regimen, we're talking about a pretty large difference: It was something like 70% in the vicriviroc arm, versus 55% or so in the placebo arm, obtained viral loads below 50 copies/mL. Why was that not enough to define superiority?
Joel Gallant: Because it was too small of a number. In the overall numbers, you're looking at almost 500 patients randomized to get vicriviroc, and over 200 randomized to get the placebo. The group that had two or fewer active drugs was a subset, and the numbers simply weren't great enough to allow the overall study results to reflect that difference.
Essentially, you'd have to either do the study over or somehow continue it out using only patients who met that criterion. It would be very expensive, and it would take a very long time to get the study done.
Myles Helfand: In this case, the maker of the drug has already announced that it's not going to continue to develop it in treatment-experienced patients.
Joel Gallant: Yeah. And you know, look at the way maraviroc is going: Very few people use it, even though it's a really great drug. I think right now the problem is that the CCR5 antagonists are probably not very exciting to investors, CEOs and boards of directors because they see that the first drug in that class is hardly selling at all. So why come up with a competitor that just has a modest advantage over the one that's already out there and kind of languishing?
I think that's not a function of the drug; it's a function of the fact that we're dependent on a very expensive Trofile assay to be able to use the drug. There were some data presented suggesting that we might be able to move towards less-expensive genotypic tropism assays in the future. That would be great, because we would potentially combine them with our standard genotypes that we're doing, and would, for a modest increase in cost, get tropism results. That could really move us to use these drugs more often than we're doing now. But right now, it doesn't look like a very exciting field to get into.
Myles Helfand: Stepping back a little bit to the broader view of drug development: Is this a regulatory issue? Or is this a study design issue?
Joel Gallant: I think, in this case, it's hard to know. But I would say it's a study design issue. And I think the writing was on the wall. I think a lot of people knew that we really weren't going to be able to use this design anymore. There were so many drugs and so few people who really were desperate for brand-new drugs.
I look at my own patient population: I think I have one patient out of 350 who has truly untreatable virus with current drugs. It's pretty hard to do a study when the numbers are so few.
I think the question, then, is, "OK, what do you do instead?" The way that Gilead has approached this with studying elvitegravir for treatment-experienced patients is to abandon that type of study design and instead compare elvitegravir with raltegravir. You simply compare it against another drug in its class; that way, you're not denying patients access to anything. And you'll at least be able to say, well, this works as well as raltegravir. I would assume that they wouldn't be doing this if they hadn't talked to the FDA [U.S. Food and Drug Administration] and made sure that it was going to be acceptable to allow them to get this drug approved.
I think that's probably the way we're going to move. Maybe the way that a CCR5 antagonist should be tested in the future is just a head-to-head comparison with maraviroc.
Myles Helfand: So ultimately, then, the same general kind of study that we just talked about with the quad versus Atripla -- but obviously for treatment-experienced patients.
Joel Gallant: With the quad versus Atripla, it's easy: You're taking people who have never been treated, and you're just comparing; you're comparing two things that suppress their virus. So that's pretty straightforward.
The problem with this new design that I'm mentioning is, let's say you give people a combination of a background regimen plus raltegravir, versus a background regimen plus elvitegravir. And everybody does great. How do you know that the integrase inhibitor had anything to do with their doing great? How do you know that they wouldn't have done great without the integrase inhibitor? Because you don't have an arm that's showing that.
So the FDA could come back and say, well, maybe they were doing great because they were on a boosted PI and some nukes [nucleoside/tide reverse transcriptase inhibitors]. You haven't shown me that your drug contributed to the success, whereas, with the quad versus Atripla, it's obvious that it did.
It's tricky. I don't know what the answer is. But it's clearly not going to be a TORO-style design.
No comments have been made.
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