February 27, 2007
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David Cooper: My name's David Cooper, and I'm a principal investigator for the BENCHMRK-1 study, which was carried out on behalf of Merck & Co., Inc.. My colleague, Dr. Roy Steigbigel, from Stony Brook in New York, is the principal investigator for BENCHMRK-2. These are two phase 3 studies, looking at the first HIV integrase inhibitor called raltegravir. It was previously known as MK-0518, but now has a new, generic name of raltegravir. This [integrase inhibitor] is a new target of the HIV virus, the third enzyme to be able to be targeted by a small chemical entity that blocks the integration of proviral DNA into the cell.
These studies are very similar in structure to the studies presented by my colleagues at Pfizer, Inc[on maraviroc]. They are identical phase 3 studies in a randomized, double-blind, placebo-controlled trial. They compare raltegravir at 400 mg twice a day with placebo on an optimized background [regimen]. The patients had to be triple-class experienced with [treatment] failure.
The primary endpoint of this study is at 16 weeks, and is ongoing to 48 weeks. This is a pre-planned analysis at 16 weeks, on the basis that some regulatory agencies, particularly in Europe, like to see 16-week data for this very hard-to-treat population with limited options.
The study enrolled a very typical population that we see with triple-class failure: usually men in their mid-40s, [with] a CD4 count of 150, quite immunosuppressed, [with] a viral load of 4.5 logs, and lots of [past] antiretroviral therapy, both in duration and number of different drugs. Many of these patients were highly resistant [to HIV therapy].
The results of the two trials at the primary endpoint at 16 weeks, with very few dropouts for toxicity, was [that] 77 percent of patients achieved [viral loads of] less than 400 copies in both trials in the raltegravir group, [versus] 41 and 43 percent in the placebo groups.
The figures for the less than 50 copies: 61 and 62 percent [in the MK-0518 group], and 33 and 36 percent [in the placebo group].
There were good CD4 count responses of around 80 cells [over baseline] and a viral load response of 2 logs.
There is limited resistance data in those patients who have failed. Forty-one raltegravir failures have been genotyped, and 32 of them have changes consistent with what's known about the in vitro generation of resistance with raltegravir. There appear to be two pathways to the development of resistance. The data is limited, because not all the failures have been genotyped, and there are no temporal trends yet in the association and its resistance.
So I'll turn it over to Roy, who will just say a few words about some of the sub-analyses and the safety.
Raltegravir is, as was previously stated, a new class which blocks the integration of HIV DNA after it's been reverse transcribed into the host genome. It is active against in vitro, active against HIV-1 and HIV-2, as well as all of the HIV [subtypes]: A, B, C and D. [In] the subgroup analysis, which has been looked at -- and I'll be giving you now the combined efficacy from BENCHMRK-1 and 2 -- the overall efficacy, as previously stated, in the individuals who received raltegravir plus optimized background, was 79 percent. That is, 79 percent of the people at week 16 achieved [viral loads of] less than 400 copies. In contrast, those who do not have raltegravir, [but were taking] the placebo plus optimized background, 43 percent [achieved viral loads of less than 400 copies]. The data for less than 50 copies is analogous in the differences between the two groups, but with a lower magnitude of response.
Now, in terms of subgroup analysis, there's an examination of those individuals who received enfuvirtide [Fuzeon, T-20] or darunavir [Prezista, TMC114] for the first time during the period of the study. These are important because these medications generally will be active against virus which the people already had. For example, enfuvirtide, sometimes called T-20, is an entry inhibitor; darunavir is a protease inhibitor, which is active against many, but not all, viruses which are resistant to PIs.
For example, in those individuals that received both of those [medications] for the first time, 98 percent [in the MK-0518 group] versus 87 percent [in the placebo group] achieved the endpoint. [For] those that received only enfuvirtide, 90 percent versus 63 percent. [For] those that received neither of those drugs, 74 percent reached the endpoint in the raltegravir group, versus only 29 percent [in the placebo group].
A second type of analysis which is important, is to understand the background therapy of the individuals who entered the study. This was done by looking at both the phenotype and genotype, according to the Monogram characterization. Individuals at zero -- that is, no medication active by geno- or phenotype -- the results were 61 percent [reaching the endpoint] in the raltegravir group versus 5 percent in the placebo group. Of the genotype, the results are analogous.
The other aspect, which is important to look at, is the individual who entered [the trial] with greater than or less than 100,000 copies of HIV RNA. Again, this is the combined data for both BENCHMRK-1 and BENCHMRK-2 at 400 cells, less than 400 copies of RNA at 16 weeks. For those [who began the trial] with [a viral load of] less than 100,000 [copies]: 88 percent in the raltegravir group versus 55 percent in the placebo group [achieved viral loads of less than 400 copies]. Those entering at greater than 100,000 HIV RNAs at baseline: 64 percent [achieved viral loads of less than 400 copies] versus 19 percent.
The CD4 baseline analysis in those who entered with less than 50 cells: In the raltegravir group, 63 percent reached the endpoint versus 24 percent [in the placebo group]; of those [who entered with CD4 cells] between 51 and 199, the results were 86 percent versus 46 percent. In those with [a CD4+ cell count of] greater than 200: 88 percent versus 59 percent.
So in summary: It was quite clear that, across all baseline characteristics, there was marked superiority of the individual who had raltegravir added to the optimized background. A summary of adverse clinical, as well as laboratory, abnormalities showed no differences across the two, BENCHMRK-1 and BENCHMRK-2, and no difference between those who received raltegravir versus placebo. These are the standard types of analyses done for both clinical manifestations of adverse effects, as well as laboratory, including inflammation of the liver, sometimes referred to as liver function tests.
To read an analysis of the MK-0518 data by Edwin DeJesus, M.D., click here.
To listen to an interview on MK-0518 with Roy Steigbigel, Ph.D., click here.
To learn about the MK-0518 expanded access program, click here.
To view study abstract, click here.
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