Editor's Note:

Dr. Mark Wainberg, Director, McGill University AIDS Centre, McGill University, Montreal, Quebec, Canada, discusses the latest phase 3 data on drugs from 2 new ARV classes: the CCR5 antagonist maraviroc; and the integrase inhibitor raltegravir, formerly known as MK-518 in this interview from the 14th CROI with Medscape's Mary Anderson, PhD, Clinical Editor, HIV/AIDS.

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Transcript

Medscape: I'm Dr. Mary Anderson of Medscape HIV/AIDS and I'm speaking with Dr. Mark Wainberg in Los Angeles at the Conference on Retroviruses and Opportunistic Infections. Dr. Wainberg is the Director of the McGill University AIDS Centre in Montreal.

Last evening we heard important new data on investigational antiretroviral drugs (ARVs) presented at a late-breaker session. The late-breaker sessions included results with the investigational agents that would, if approved, be the first in their drug class. Thank you for speaking with us about this important topic, Dr. Wainberg.

Two studies with the CCR5 antagonist maraviroc were presented. What were the key study design features? And do the data support this drug joining the therapeutic armamentarium?

Dr. Wainberg: Thank you, Mary. Yes, indeed: The data were extremely exciting in regard to maraviroc, which is a compound that antagonizes the CCR5 coreceptor that is essential for viral entry into cells that express this receptor at their surface.

As you know, there are 2 coreceptors that we speak about in HIV medicine. One is CCR5. The other is CXCR4. And maraviroc antagonizes CCR5. Therefore, it is a drug that ostensibly should work best against viruses that display tropism for CCR5-bearing cells.

Having said that, the data do support the notion that patients who have viruses that are tropic for CCR5 cells will be affected by maraviroc in a very compelling way. These studies were phase 2/3 studies conducted in different parts of the world. The study designs in both cases are virtually identical and the trials are called MOTIVATE I and MOTIVATE II.

The trial designs are similar to those we've heard about in the past with regard to new investigational agents that have now entered a fairly advanced phase of testing. Notably these are studies designed to show that a new agent can have activity against viruses that are resistant to many other drugs and drug classes. The patients that have been enrolled into these clinical trials are, in fact, multiply experienced in regard to previous antiretroviral drugs. In addition, they have developed resistance to multiple other drugs and have mutations within the viruses at hand that can be demonstrated to, in fact, confer resistance to those agents.

We're talking about groups of patients who have a lot to gain if this new drug works. And they have a lot to lose, in fact, if this new drug does not work because, should it not work, there is every possibility that they'll be left without good therapeutic options.

These studies are designed as add-on studies in which a placebo is compared against the new agent -- in our case maraviroc -- in the context of the background regimen containing the best options that would otherwise be available. We call this optimized background.

The study results show that the patients who received maraviroc plus optimized background outperformed patients who received placebo plus an optimized background regimen in either situation. So it was maraviroc plus optimized background vs placebo plus optimized background. And the results that were obtained with the maraviroc once-daily regimen or twice-daily regimen were very impressive indeed, with mean viral reductions in viral load approaching 1.5 logs, and 2 logs almost in some cases. That's really sensational.

Medscape: The other investigational drug is the HIV integrase inhibitor. There has been quite a lot of excitement about this agent. Do the latest results support those hopes?

Dr. Wainberg: The other agent that was studied in 2 clinical trials, called BENCHMRK-1 and BENCHMRK-2, is an agent that we had previously referred to as MK-0518. We now call it raltegravir. This is Merck's integrase inhibitor. It needs to be dosed twice daily.

In these 2 studies the agent was also given in the context of optimized background. And the results once again show that it is an extremely potent agent causing very significant drops in viral load, and very efficacious. The drops in viral load, in fact, were also in the 1.7-1.8 log drop range, meaning that the patients who received raltegravir clearly outperformed patients who received the placebo.

This tells you that we are now likely to have yet another drug class, a family of integrase inhibitors, that is likely to become part of our armamentarium very, very shortly. In fact, it's fair to say that both maraviroc and raltegravir do represent novel drugs, each of them in a different novel drug class that we have not heard about previously in regard to compounds that have been approved by the Food and Drug Administration and other regulatory agencies.

The field has every right to be optimistic that before the end of 2007 we are going to have 2 more drugs approved from new novel drug classes that target HIV. And the consequence is that patients who have drug-resistant viruses can certainly expect to live longer, better, and more fruitful lives than had these drugs not been brought forward.

These studies demonstrate once again how patients who receive a novel investigational agent clearly outperform patients who receive placebo in the context of background-optimized therapy. And we believe as a field that the era of this type of study being permitted will be drawing to a close. We've now seen many studies in which the experimental arm well outperformed the placebo arm, going back to the studies that led to the approval of enfuvirtide, and then studies leading to the approval of tipranavir, the RESIST trials. T and more recently, the POWER studies that led to the approval of darunavir I think we can safely conclude that anybody who is going to be on a placebo arm in a future trial of this type will not do as well as people on the new drug. Therefore, it is not fair to say that we're at equipoise in terms of trial design, and probably these kinds of studies should no longer be permitted. We're going to have to figure out new ways to test some of the next-generation compounds that are certainly going to come forward. I foresee that the use of optimized background comparator treatment regimens is something that the field will no longer tolerate.

Another point to make about both of these new compounds -- maraviroc and raltegravir -- is that the safety profiles of both seem to be exquisite. For the most part, patients did not experience much discomfort. In both cases, in fact, the side effects reported in the placebo arm did not differ significantly from side effects reported in the experimental arm in which people received the novel compound. That tells us that these drugs, at least so far, seem to be pretty safe.

In both of these instances it's obvious that the companies that produced these novel compounds -- Pfizer in the case of maraviroc and Merck in the case of raltegravir -- will not be content simply for these compounds to be used in salvage situations or for people who have resistant viruses in the context of being highly experienced. Both companies will try quickly to move these compounds forward into first-line therapy. There are certainly trials that are ongoing that test each of these drugs in first line-therapy.

One important point to make about maraviroc that we glossed over is that because it clearly does target the CCR5 antagonist, there is rationale in terms of assuring its best use to do a prescreen of patients to ensure that the viruses that they contain within their bloodstream are, in fact, those that are CCR5-tropic.

For that purpose there are assays that have been developed, the most well-known of which is called Trofile, an assay developed by Monogram Biosciences. Essentially, it will tell clinicians whether or not the virus that a patient harbors is, in fact, CCR5-tropic or CXCR4-tropic.

There is some evidence to suggest that there are populations of people who have viruses that display mixed tropism or sometimes patterns of dual tropism who might still be able to benefit from maraviroc. But clearly the potential for achieving a truly significant effect in a positive way will be with people who have populations of viruses that are virtually CCR5-pure. And that is what the data suggest to us at this time.

Medscape: One of the things that you mentioned is how the trials are going to be conducted for the next-generation ARVs. And that, of course, is the next question: How does the pipeline look?

Dr. Wainberg: I think the pipeline actually is slowing down in some ways. There are certainly many, many companies out there that are continuing with drug development projects and phase 3 clinical trials in the context of drugs that will compete against maraviroc and raltegravir over the next number of years. So the companies in the field are not sitting back and saying that Merck is going to get its integrase inhibitor approved before any other compound of this class. Therefore, we're not going to continue to be active in the field.

In fact, quite a few companies are continuing to develop their own integrase inhibitors and will put those through clinical trials. One issue will be whether or not the field will permit them to do optimized background studies. As I said earlier, I doubt that the field will permit this, so some of those companies may be at a disadvantage in regard to advancing their products in the same way. They'll have to come up with imaginative trial designs to make their points known.

Certainly it's fair to say that Gilead has an integrase program. In fact, Gilead does have a drug that has been tested in the clinic, but it's clearly not as far advanced as the Merck compound is. It also needs to be boosted with ritonavir, which is a disadvantage in comparison with the Merck compound that does not require boosting.

The Merck compound, on the other hand, needs to be given twice daily. But that might not be such a terrible thing. We'll just have to watch how some of this unfolds.

In regard to entry inhibitors that block CCR5, it's very obvious that Schering is moving ahead full-steam with its drug vicriviroc. That compound is going to be studied in advanced-phase clinical trials.

I personally foresee that vicriviroc will be successful and will also gain approval by regulatory agencies within the next few years in terms of its antiviral potency.

In regard to other companies that are developing CCR5 antagonists, it is also fair to say that they are not shying away from the idea of moving forward even though it's quite obvious that Pfizer will be first and probably Schering will be second in terms of having compounds that antagonize CCR5. And in regard to integrase, many companies are moving ahead with integrase programs.

So the question then is as follows. There will continue to be competition in regard to classes of drugs that are well established in terms of rationale. And it's fair to say on the basis of the data that we heard last night that both the integrase enzyme of HIV and the CCR5 coreceptor represent legitimate validated targets at this point in time. So we will see competition in regard to other drugs that block the same validated targets.

What is less clear is how much activity there will continue to be against targets that have been documented in the literature but have not yet been validated in the clinic. An example of this are the maturation inhibitors. We know we had a lead compound that was moving forward in the clinic very nicely, [bevirimat] PA-457, being developed by Panacos. It seems that they have now experienced formulation issues in regard to this compound and it is no longer being pursued. They have backup compounds, but it remains to be seen how aggressively this target of maturation will be pursued by Panacos and perhaps by other companies in the field that will also see an opportunity to develop maturation inhibitors. I think you can say the same about some of the concepts that we've heard about over the years, such as agents that would antagonize the viral nucleocapsid protein, agents that would interfere with the viral capsid protein.

Another good example of a target that several companies had been developing is CXCR4, the other coreceptor. In fact, at this very meeting we've heard a presentation on a drug that had been developed by Anormed that does indeed target CXCR4. But we understand that this compound is no longer being pursued in the context of HIV therapeutics possibly because the company feels that there is too much of a long-term likelihood of the compound being toxic to patients, even though it does look pretty good in the short-term studies that have been carried out so far. The reality is that any time you target a cellular product, in this case a coreceptor that's expressed at the cell surface, you do need to worry, of course, about what you're doing to people's bodies and perhaps to their immune systems over protracted periods of time.

This is a relevant question given the fact that HIV therapy is a lifelong enterprise, as we understand it. So it's not simply a question of developing a drug for the short term. In HIV medicine we're really talking about needing drugs that must be active over many years and have clean safety profiles over many years as well. That's a pretty high barrier.

It's therefore just not clear whether or not the CXCR4 target will be pursued in the way that I think we would ostensibly hope it would be. We'll just have to watch the field to see what happens.

By contrast the CCR5 antagonist family of drugs has been developed in large part because we know of a deletion that exists within CCR5 that has more or less proven to us that we might not need a fully functional CCR5. That established a key rationale: If you don't need CCR5, then it might not matter if you knock it out with a drug like maraviroc.

We don't have that equivalent experiment of nature to provide us with the same comfort level in regard to developing a CXCR4 antagonist that such a molecule will also, in all likelihood, be devoid of long-term toxicities in people who need to take such a drug over many, many years.