The Body Covers: The 46th Interscience Conference on Antimicrobial Agents and Chemotherapy
ICAAC 2006: An Interview With Robin Isaacs, M.D.
September 30, 2006
Thank you, Bonnie. It's a pleasure to be here. MK-0518 is Merck's novel integrase inhibitor, which is in clinical development at this point. The data we presented in poster form at ICAAC on relates to changes in serum lipids for treatment-naive patients -- patients who have not previously been treated for HIV infection -- after 24 weeks of therapy. We had previously shown at the Toronto AIDS meeting [International AIDS Conference], the efficacy data out through 24 weeks for treatment-naive patients and had shown that the treatment at 24 weeks -- in terms of the percentage of patients with less than 400 copies per m/L and less than 50 copies/mL looked very similar to what you see with the gold standard which is efavirenz [EFV, Sustiva, Stocrin] in combination regimen.
This data refers to the serum lipids from those patients out to 24 weeks. Basically, what the data shows is that MK-0158 -- at the four different doses that were studied -- 100 mg, 200 mg, 400 mg and 600 mg, twice a day and in each case in combination with lamivudine [3TC, Epivir ] and tenofovir [TDF, Viread], did not materially effect serum lipids at week 24. So the serum cholesterol, the serum LDL cholesterol, the serum triglycerides were essentially unchanged after 24 weeks of therapy.
In contrast, efavirenz plus tenofovir plus lamivudine -- which was the control group -- showed that with efavirenz there was an increase in serum cholesterol and triglycerides over that same period of time. So, this is interim data from 24 weeks. We clearly need to follow it out longer. But I think it's particularly interesting to see that, at least at this stage, there's no evidence that integrase inhibitors adversely impact serum lipids in patients with HIV infections.
Do you think that it's for the class as a whole or just this one?
I don't think you can really ever say for the class as a whole, just based on a single integrase inhibitor that has gone into a late stage clinical development. This is the first integrase inhibitor which has gone into late stage clinical development. I think we can only specifically speak to the results of MK-0518 at the moment.
Could you tell me a little more about the study?
This was a study in treatment-naive patients. There were five treatment groups, as I had mentioned previously. Four of the patient groups received different doses of MK-0518 and the fifth treatment group received efavirenz. Everybody also received tenofovir plus lamivudine. There were approximately 200 patients involved in the study as a whole, with approximately 40 patients in each of the five treatment groups. The patients had to have not received prior therapy and at baseline had to have evidence of viral replication. So their viral loads had to be great than 5,000 copies/mL and their baseline CD4 cells counts were greater than 100 cells per microliter.
Where was the study recruited? Is it an international trial??
It was a study that was done both in the United States and outside the United States and included patients from Asia and South America, in addition to the United States.
What was the breakdown in terms of male/female?
Patients were predominantly male and were in their mid- to late-twenties.
This is an ongoing study. So this is just interim data, right?
Correct. This is an ongoing study. The data we showed at Toronto in terms of efficacy and yesterday in terms of the lipids relates to all patients in the study at 24 weeks. We continue to follow these patients to gain long-term data on both the tolerability of MK-0159, the efficacy of MK-0158 and the lipids, of course.
Could you talk a little bit about the efficacy of MK-0158?
The efficacy [data], which was presented at Toronto, showed that at 24 weeks over 85 percent of patients in each of the MK-0518 groups and in the efavirenz group had viral loads that were less than 50 copies/mL, which some people refer to as "undetectable." In addition, there was a very interesting observation in that the patients who were receiving the MK-0518, the investigational integrase inhibitor, actually achieved less than 50 copies/mL earlier than the efavirenz group. At four weeks and eight weeks of treatment there was actually statistical superiority, but by the time you got to week 24 the efavirenz group had caught up.
We are also going to be showing data at the ICAAC meeting, following-up on data that we showed at the Retrovirus meeting [the 13th Conference on Retroviruses and Opportunistic Infections] in Denver on our treatment-experienced phase 2 study. We will be showing data at the late-breaking oral session relating to 24-week therapy on all patients in that study. And that's a study where everybody entering the study had to have failed prior therapy, had to have genotypic and/or phenotypic evidence of resistance to at least one drug in each of the three oral classes, so they could be referred to as triple-class-resistance patients. Highly treatment experienced -- on average eight to ten years of prior therapy. The majority of patients also had a history of AIDS. So a highly treatment-experienced group [who are] very difficult to treat.
This was a study where patients were randomized to receive one of three different doses of MK-0518, either 200, 400 or 600 mg. twice a day or a placebo and, in addition to that, based on the resistance profiles of their HIV, they were given an optimized background therapy as well. So, it's really a study of MK-0518 plus optimized background therapy versus optimized background therapy.
We've been very excited by the study. This is a group of patients who are very hard to treat [and who] desperately need new therapy. In the data that will be shown at the meeting on Friday, we have shown that approximately 70 percent of the patients in the three different MK-0158 study groups had less than 400 copies/mL of HIV at 24-weeks, compared to around 16 percent, I believe it is, in the control group that just got optimized background therapy.
I think of really particular interest is that if you break out of that group the patients who had no active drug in their optimized background therapy -- so they were really just receiving MK-0158 or a placebo, none of those patients in the placebo group actually had less than than 400 copies/mL at 24 weeks, whereas approximately 60 percent of the patients in MK-0518 group had less than 400 copies/mL. So, you can see this is a very exciting observation. Clearly, it was only 24-week data. We need to continue to follow the durability, but we have been very impressed by the efficacy that's been demonstrated. The MK-0158 has been generally well tolerated. We hope this will be a significant advance for the treatment of HIV.
What have been some of the adverse effects in the treatment-experienced group?
These were double-blind, randomized studies, so what we can do is compare the adverse experience profile we saw in the 518 group -- the patients receiving the actual integrase inhibitor -- to those receiving placebo plus optimized background therapy. The drug was well tolerated. Instances of adverse experiences were very similar to the group that were getting placebo plus optimized background therapy. There were no dose-related toxicities and very few laboratory abnormalities were seen in any of the patients. So, overall it was very well tolerated.
Were there different adverse effects seen in the treatment naive patients?
In the treatment naive study, the data that was shown at the Toronto meeting, once again the adverse experiences profile of the MK-0158 groups again showed that it was generally well-tolerated. The AE [adverse events] profile was as good as the AE profile of the efavirenz group -- which is regarded as essentially the gold-standard of care for treatment-naive patients. There were less neurological adverse experiences in the patients in the MK-0518 group than in the efavirenz group. It's well know that there is this so-called CNS [central nervous system] syndrome that some people on efavirenz get when they start the drug. It seems to abate or get less significant after they take the drug for a short period of time. In that regard, the MK-0158 didn't have similar issues as the efavirenz.
But could you be specific about any particular adverse events that were seen?
Yes. With regards to the treatment-experienced study, for example, the commonest adverse experiences -- and remember that these were similar across both the MK-0158 and the placebo groups -- were diarrhea, nausea, fatigue, headache and itching. They cleared in a relatively small number of people. There were virtually no discontinuations for adverse experiences in the clinical study. So, once again, speaking to the overall well tolerability of the drug.
How could you compare this for clinicians who are looking at MK-0158 next to, say, a drug like tipranavir [[TPV, Aptivus] in terms of efficacy?
I think that's a very hard question to answer because this is an investigational agent. We only have 24-week data in the phase 2 study. We have initiated the phase 3 program and it's ongoing, as we indicated earlier this year when we announced the first treatment-experienced results at the Retrovirus meeting.
We hope to have enough data to file with the FDA [U.S. Food and Drug Administration] for review in 2007. We have not allowed tipranavir, or the other new agent, darunavir [TMC114, Prezista], into the phase 2 studies that we are talking about now. We have allowed subsequently in the phase 3 program for both of those drugs to be used, but we don't yet have that data to talk about.
I understand that Merck announced their expanded access program for MK-0158 -- is this program open just in the United States or also internationally? Can you tell me a little bit about this program and its requirements?
There is an expanded access program. It is going to be a worldwide expanded access program. It has been initiated in the United States. We are diligently going through the process of trying to get it fired up in other countries of the world. It's designed to provide people who are in desperate need of these therapies with access to these therapies before the drug is approved in their countries, bearing in mind that MK-0158 is still an investigational agent and hasn't been reviewed yet for approval by a regulatory agency.
Basically, we are looking for people who have documented triple class resistance -- [i.e.,] resistance to at least one member of each of the classes of oral antiretroviral agents, so that there is a chance that when they get MK-0158 they can build a regimen where they have at least [one] active drug. The remainder of the criteria are not actually terribly strict in terms of laboratory abnormalities. There are some laboratory criteria. Essentially, we are trying to make it as well available as we can for those people who desperately need it.
And there's no cost to the patient.
Merck is providing the drug for free in the program.
What kind of paperwork does the physician have to fill out?
There is some paperwork. This is essentially a clinical study because the drug is still investigational. We have tried to keep the paperwork to a minimum. We know that one of the main detractions for people wanting to get into clinical studies is the paperwork. But there is still some paperwork in order to register for the study and also to collect certain adverse experience information about the drug.
Is there a phone number you should call? Or do you not happen to have that by heart? [Laughing.]
I'm sorry. I don't have it by heart [1-877-EARMRK1], but there is a Website people can go to, www.earmrk.com, in which you can find information about the study [and] print off an application. There's also other contact information there. [That number serves patients in Canada and the U.S. For expanded access for MK-0158 outside North America, physicians have to register at the EARMRK site.]
Thank you, Dr. Isaacs, for your time. I appreciate it.
Click here for more information on MK-0518.
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