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CROI 2010 Wrap-Up: The HIV Drug Development Pipeline

A Discussion With Joel Gallant, M.D., M.P.H.

March 8, 2010

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TBR-652: A CCR5 Antagonist -- With Anti-Inflammatory Properties?

Myles Helfand: All right. Let's talk briefly about some of the other drugs in development that were discussed at CROI. Since we just came off of vicriviroc, let's begin with another CCR5 antagonist in development: TBR-652.

Joel Gallant: TBR-652 is another CCR5 antagonist, as you mentioned. There was a study presented, again by Cal Cohen, showing excellent results in a short-term study. It was very well tolerated, as most of these drugs seem to be.

What was interesting is, they commented on the fact that it also seems to inhibit CCR2, which is a coreceptor that most of us haven't spent much time thinking about until now. The argument that they made was that CCR2 has been associated with a number of inflammation-related diseases, so perhaps this [drug] has some kind of anti-inflammatory activity as well. An interesting concept, but I don't know what it will mean yet.


Myles Helfand: Is there any actual proof that something that can potentially inhibit the CCR2 receptor on CD4 cells is going to help reduce any of those signs of inflammation that research increasingly indicates is happening even in fully treated people with HIV?

Joel Gallant: No; I don't think there's that kind of proof. We know that the biggest thing we do to decrease inflammation is give people antiretroviral therapy. And you see a big decrease in inflammation when you do that. But it's true that you don't get to normal levels; people who are HIV negative have even lower rates of inflammation than people who are fully suppressed on therapy. Is it possible that blocking CCR2 could further decrease that level of inflammation? It's certainly worth looking into, but I don't think we know that yet.

And you know, whenever you block things that are part of us, you have to wonder what could be the downstream implication. So far, blocking CCR5 seems to be pretty safe, but I don't think we can just say that blocking all of these coreceptors is going to be a safe thing to do. They must be there for a reason.

Myles Helfand: Also, like you said, despite all of the hype before maraviroc was approved, it has not turned out to be a particularly popular drug. I think price may be part of it. The Trofile assay, the need to use that, is certainly part of it. I also think the fact that it was approved for treatment-experienced patients, many of whom are CXCR4 tropic or dual tropic, and can't benefit from the use of the drug -- that might have had a role, too. Plus, given that I think the results of this particular study found that the drug [TBR-652] did decently well, in terms of suppressing viral load, but it wasn't outstanding; it didn't knock the ball out of the park, necessarily. There wasn't a 2-log reduction in viral load.

Joel Gallant: No. It was a little more than a 1.5-log reduction.

Myles Helfand: What does that mean we're looking at, as this drug moves through the development process?

Joel Gallant: I think, if you want to think of the best possible outcome for this class of drugs, it would be that, for an extra 50 bucks, when you do a baseline genotype in somebody who has just been diagnosed, you get a tropism [finding] in addition to the resistance test results. If they are R5 tropic, you say, hey, this is a really well tolerated, very safe class of drugs, and if I use it now, I'll get a benefit from it. If I wait till later, I might not -- they may have lost their R5 tropism. So why not use it first?

I think that makes a lot of sense, to use this incredibly well-tolerated class of drugs as early as possible. But we just can't do that right now with a $2,000 tropism assay.

I'm not dismissing this class. I think that, with improvements in the laboratory tests that we use, we could definitely move these drugs up sooner. And if we had a once-a-day, very safe, well-tolerated drug, it would be a logical approach to do this early. So I think that it's worth continuing to develop these drugs as we work on the laboratory issue in tandem.

Other Drug Development Highlights

Myles Helfand: What other pipeline drugs did CROI tell us about?

Joel Gallant: We heard a little more about the Glaxo[SmithKline]-Shionogi integrase inhibitor, which I don't think has a name yet.

Myles Helfand: It does have a very long denotation, though: S/GSK1349572.

Joel Gallant: Yeah. It probably has a nickname to its friends, but I'm not privy to it. This is supposed to be the first second-generation integrase inhibitor, one that will be active if you fail Isentress and elvitegravir. They didn't present a big clinical trial using this drug, but they did present some resistance data that suggest that, in fact, no single integrase mutation will knock it out, and the common integrase mutations that we see with Isentress failure will not cause cross-resistance to this drug. So that does look promising.

Myles Helfand: What else have we got?

Joel Gallant: That's about it. There were other drugs out there, and some other ones that were talked about. But on my radar screen, those were the ones that I paid attention to.

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