Transcript:
MICHAEL SMITH:
I'm Michael Smith of
MedPage Today. I'm here with Dr. Joseph Eron of the University of North Carolina at Chapel Hill. Dr. Eron, welcome
.
JOSEPH ERON, MD: Thank you. Thank you for inviting me.
SMITH: We now have a couple of dozen drugs approved for HIV. Obviously, however, more drugs are needed. What's your view about the pipeline? Is it robust or is it kind of flaccid?
ERON: I wouldn't call it robust. I think there are some very interesting drugs in the pipeline, but there aren't many really novel agents in the pipeline, and I think we'll get to that. But, yeah, I think there're some very interesting drugs we can talk about, but the flow in the pipeline is not quite as steady, perhaps, as it has been in the last decade or so.
SMITH: Perhaps a garden hose rather than a fire hose?
ERON: I would say you're right, a garden hose, but it's still got some flow.
SMITH: There are several drugs in development and at various stages. There are really only a couple in phase IIIs, and one of them is only technically in phase III, and we'll talk about that in a minute. Elvitegravir. This is probably the drug that's going to hit the market most quickly. It's got phase IIIs under way.
ERON: Right.
SMITH: What do we know about elvitegravir?
ERON: I think probably everybody knows elvitegravir is an integrase inhibitor, and it has some real advantages. It is a drug that clearly can be given once a day, and it's very well tolerated.
The key with elvitegravir is that it has to be boosted, so it has to be either given with a ritonavir-boosted protease inhibitor, which you might do in a kind of salvage situation or second-line situation, or it's given with a drug called cobicistat, which is a ritonavir-like drug that has some unique characteristics.
Elvitegravir has been compared to raltegravir in treatment-experienced but integrase-naive patients, and these data were presented just this past summer, and they were very, very similar -- elvitegravir and raltegravir. Noninferior was the technical term, but very, very similar in these experienced patients who were naive to integrase.
So it's well tolerated, it's once a day, and at least in integrase-naive patients, it's as good as raltegravir.
SMITH: Okay, so that's a very promising drug. You mentioned it had to be boosted, and that leads us into what's been dubbed the quad pill, and that is, again, not approved, because it includes elvitegravir. It includes this novel booster, cobicistat, and it includes two drugs that are approved, tenofovir and emtricitabine. And it will come as a single pill.
ERON: Right.
SMITH: Let's talk first of all, about the quad pill, what do we know about it, and then we'll talk about this issue with the booster.
ERON: Sure. The quad pill is really designed to be a first-line regimen. It is four drugs, although only three of them have activity against HIV -- elvitegravir, tenofovir and emtricitabine. It's really being compared head-to-head with one of our gold standards, which is Atripla or efavirenz, tenofovir and FTC.
We just saw in a press release, we haven't seen the data yet, that in the phase III study, they had very comparable efficacy at a 48-week time point, and so the quad would be another single pill regimen to go along with Atripla.
And then we have Complera, which is the rilpivirine-based single-pill regimen.
The advantage to the quad, basically, is it's not an NNRTI; it's an integrase inhibitor-based therapy. It may have tolerability advantages. We'd have to see the data, but it certainly won't have the efavirenz-related side effects, we're pretty sure of that, because it's not efavirenz. So I think it's going to give us another very good option for a single pill complete regimen for our treatment naive patients.
SMITH: Now the booster itself, you said it does not have anti-HIV activity.
ERON: Right.
SMITH: Whereas the other booster that's commonly used, ritonavir, does.
ERON: Right.
SMITH: It was originally approved as an anti-HIV drug. What do we know about the booster?
ERON: Well, the booster has got some very important features. I think the most important one is that it doesn't have HIV activity, because one of the concerns of boosting an integrase inhibitor with a very low dose of a protease inhibitor, is if the patient messed up, you could end up with both integrase resistance and protease resistance, without ever really treating them with a fully active protease inhibitor. So there's a big push to develop a compound that doesn't have HIV activity, so cobicistat doesn't have HIV activity.
It also is not as much of an inducer as ritonavir. Ritonavir is mostly an inhibitor of P450, but it has some inductive properties, so it has lots of drug-drug interactions. Cobicistat is still going to have drug-drug interactions; it's still a P450 inhibitor, so it's going to have many of the interactions that ritonavir has, and in terms of tolerability, I think we're just going to have to see. Will it be better tolerated than ritonavir? The hope is yes, the initial thoughts are probably, and then we need to see the data.
SMITH: And of course in the long run, it might well be used more widely than in the quad pill.
ERON: Sure, of course. It could be used with protease inhibitors, and there are studies with atazanavir with cobicistat, there's a planned study with darunavir with cobicistat, so absolutely. It could have very wide use.
SMITH: Now, I said that there was a drug that's technically in phase IIIs, and that's apricitabine. It's a nucleoside reverse transcriptase inhibitor and it's in a way a poster boy for not bringing a drug to market, I think. It was first owned by BioChem Pharma; it was transferred to Shire. It's now owned by the Australian biotech company Avexa, and last year they had it in phase IIIs and then stopped the trial. Now they appear to have gone back to the FDA and have some sort of agreement as to how they can move forward. So when I say "in phase IIIs," you see where we are.
ERON: Sure, sure.
SMITH: What do we know about this drug?
ERON: Apricitabine appears to be well tolerated. It clearly has activity. It has activity against nucleoside-resistant viruses. Its Achilles' heel that's complicated the development -- you can't give it with another cytidine analog. You can't give it with 3TC or FTC, because they compete for activation within the cell, so they're antagonistic.
Therefore, you have to then dream up a schema where you're going to develop this drug without pairing it with 3TC or FTC. So it becomes kind of a second-line or a third-line drug, and those studies are just more complicated to do, harder to enroll, the patients you enroll tend to be a little bit more difficult, because they've probably already had some trouble with adherence. And so I think it's a challenging drug.
What I've seen in the press releases and smaller studies that you've mentioned, is that it's a well-tolerated drug, it appears to have activity, just like you said. The question is can they do a large enough trial to show that it actually meets its goal?
SMITH: Right. And then I guess the issue is how would one use it in clinical practice.
ERON: Sure.
SMITH: Let's move on. There are several drugs in phase IIs or that have completed phase IIs. They're a lot further away from approval. But there is one that we have a lot of data on and there are several phase III trials of, and that's the integrase inhibitor, dolutegravir. Again, what do we know about this drug?
ERON: It has, I think, a couple of advantages over both raltegravir and elvitegravir. First of all, it's a once-a-day drug and it doesn't require boosting. So for treatment naive patients, it's being studied as a once-a-day drug with no boosting, so you don't have to worry about either ritonavir or cobicistat.
It gets very good levels, has very good pharmacokinetics, and there are two large phase III studies in treatment-naive patients ongoing, as you mentioned.
The other advantage to dolutegravir is that it has activity against raltegravir-resistant viruses. Now the activity is not perfect, but just literally last week in the European meetings, there was a study that showed that in raltegravir-resistant viruses, if you combine dolutegravir with at least one additional active agent, you can actually get a substantial proportion of these very experienced patients suppressed at least over 24 weeks.
So it has the advantage of working against some of the most common raltegravir-resistant variants.
SMITH: I expect we'll see that pretty soon. Let's move on to another class, actually, the entry inhibitors. There are, I think four in phase IIs. There's one called P-R-O 140 or PRO 140, ibalizumab, a drug called BMS-663068, and cenicriviroc.
ERON: Yes.
SMITH: The first two are antibodies. What's happening with those?
ERON: I think antibodies are developed more slowly, because they're kind of hard to manufacture. They almost always have to be delivered parenterally, so either IV or through a shot. I think they're working on kind of a subcutaneous delivery for both of those drugs. PRO 140 is essentially a CCR5 inhibitor, so it's not quite as novel. Ibalizumab is novel, it blocks a different step in entry.
It appears to block the step from after the virus binds and before it attaches to a second receptor, so it's active against both R5-using viruses and the dual-tropic and the X4-using viruses, so it's really active across the viral spectrum, but it is a shot. I know that it's now being looked at as a subcutaneous shot, which would be good.
The BMS drug is an attachment inhibitor, so that is actually working by an entirely different mechanism. Unlike the first two that I mentioned, the attachment inhibitor is a small molecule, so it's going to be developed as a pill. But, in contrast, it binds to the virus, not to the host cell, and probably most people know that the virus envelope is quite variable.
So the challenge for an attachment inhibitor is is it going to work against the broad array of variants that exist out there? And so far so good, but I think that's going to be a challenge.
And then finally, cenicriviroc is a CCR5 inhibitor, so similar to maraviroc, but it is once a day, it's well tolerated, and it has this interesting feature that, depending on who you are, you might think it's good or you might think it's bad. It also blocks CCR2. Now CCR2 is something us HIV guys don't know anything about, but basically it's part of the inflammatory pathway. So you might say, oh, we're all worried about inflammation, perhaps it's a good thing that it has this second activity.
On the other hand, CCR2 is involved in activating macrophages to kill certain bacteria, so maybe people would be weakened in their ability to fight certain bacteria, and that just has to be studied. It's pretty exciting. It's in, like you said, phase II development, and I think there are people who are very interested in this compound.
SMITH: Excellent. Going back to a more established class, the NRTIs, there's again four of them pretty much in clinical trials, mid-advanced clinical trials. KP-1461, festinavir, racivir, and elvucitabine. The one that interested me was KP-1461. It causes something called accelerated mutation.
ERON: Yes, it's a fascinating drug. Basically what it does is cause the virus to mutate at even a higher rate. You might say, well, that can't be good, already we're worried about virus mutation and resistance emergence, but it turns out, it causes the virus to mutate so much, that the virus essentially mutates itself into nonexistence, so it cannot replicate further. The challenge with this drug is that, of course, you can't give it with drugs that suppress replication. So in order for it to mutate, it has to be replicating.
Where would you test it? Well you could test it in treatment-naive people who don't need therapy, maybe high CD4 patients, but again the FDA is a little cautious about taking people who are otherwise pretty healthy and giving them something brand new, especially something that causes mutations.
So the other place you could test it is in people who have very few treatment options, and maybe you can kind of soften the virus up by causing it to mutate wildly and essentially weaken the virus. So I think that's a fascinating drug, although I think it's going to be a real challenge, because we're really going to have to think about novel ways to develop it.
As for the other three NRTIs that you mentioned, I think it's always good to have treatment options, and it's going to be interesting to see where these drugs go. I think festinavir has some potential, because it has pretty good activity and it may not have the toxicity issues. It's kind of a cousin to d4T, which might be a bit of a bad rap sort of thing, but I think that should have some legs, so to speak, and we'll see where the other ones go.
SMITH: Finally, there's one new non-nuke, lersivirine.
ERON: Yes.
SMITH: Is there anything we can say about this drug?
ERON: I think there were data presented this summer at the IAS meeting in Rome, and I think it again showed good NNRTI-like activity, but there were just a few issues. There was some nausea that was a little bit more common than the people developing the drug might have liked, and I think they need to decide whether this drug would really compete successfully with drugs like etravirine or rilpivirine or our standard NNRTIs.
So I'm a little skeptical about that drug but, again, it's good to have alternatives. What we're waiting for now is their design for their phase III trial, which we haven't heard yet.
SMITH: Well, an interesting collection of drugs coming down the pipeline. Dr. Eron, thank you for your insights and your expertise.
ERON: Great. Well, thank you for inviting me, it was a great time, thanks.
SMITH: I'm Michael Smith,
MedPage Today.
Eron has disclosed the following relevant financial relationships:
Research Grants to University of North Carolina (Joseph J. Eron PI): Bristol-Myers Squibb, GlaxoSmithKline/ViiV Healthcare, Merck & Co., TaiMed Biologics, Tobira Therapeutics
Ad hoc Consultant: Argos Therapeutics, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Merck & Co., Tibotec Pharmaceuticals, Tobira Therapeutics
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