Isentress Moves One Step Closer to Becoming a Viable Treatment Option
by Chael Needle
LifeGuide [Treatment Horizons]
Having been granted priority review status by the FDA, Isentress (raltegravir), formerly MK-0518, received a strong recommendation by the FDA’s Antiviral Drugs Advisory Committee for accelerated approval as part of combination therapy in treatment-experienced patients who are experiencing ongoing viral replication even on their current regimens. Merck’s drug candidate might become the latest anti-HIV treatment option—as well as the first approved in the integrase inhibitor class of antiretrovirals—as early as mid-October if the FDA as a ruling body comes to the same conclusions as its advisory committee.
Integrase inhibitors in general are much anticipated as they represent a novel mechanism of action and will not be cross-resistant with the other anti-HIV drug classes, though a patient becoming resistant to integrase inhibitors is of course a possibility down the road.
Though “accelerated” seems to be on the lips of both patients and researchers, especially in an era when multidrug resistance often limits the treatment options of those on HAART, integrase-inhibitor research seems to have taken a long time to mature, especially compared with other classes that already have drugs on the market. By way of explaining the slow build, some have pointed out that protease-inhibitor science had a head start, having already been established when HIV researchers began looking at protease as an enzyme target. Others have pointed out that integrase-inhibitor research has suffered from a lack of knowledge about the structure of the enzyme itself, as well as the process of integration necessary for HIV replication.
Dr. Robin Isaacs, executive director of clinical research at Merck, adds, “We’ve been working on the integrase enzyme as a potential target since the early 1990s. And Isentress is one of the compounds that we’ve brought forth into the clinics. It’s really a bit of hit or miss. These targets are all difficult, and we’re just glad that we’ve finally managed to get Isentress to the point that we have.” Merck has indeed been one of the leaders on this front; Merck was the first to demonstrate inhibition of HIV integrase in vitro and in vivo, for example. Dr. Isaacs, and his colleagues, are excited about the potential of Isentress. “The treatment community and the patient community seem to be pretty excited about it as well,” he adds.
As part of the HIV replication cycle, HIV RNA is converted, via the enzyme reverse transcriptase, into viral DNA. This viral DNA then needs to be integrated into the genomic material, or cellular DNA, of a human host cell in order for the virus to replicate and multiply. Integrase is an enzyme that makes this happen in three steps—assembly with the viral DNA, cleavage of the viral DNA ends, and strand transfer, or integration, of the viral DNA into cellular DNA. Isentress works by blocking the last step.
Building on Phase II studies that showed Isentress can effect significant drops in viral loads, notably in those participants on failing regimens, two ongoing Phase III randomized studies, BENCHMRK-1 and BENCHMRK-2, are evaluating Isentress (an oral formulation of 400mg, twice daily) compared to placebo, both combined with an optimized background regimen (OBR), in patients with multidrug resistance and a history of treatment failure (including regimens taken prior to enrollment). Sixteen-week results in BENCHMRK-1 showed that sixty-two percent of patients taking Isentress had viral loads below fifty, compared to thirty-three percent of those taking placebo. Similar sixteen-week results came out of the BENCHMRK-2 study: Sixty-two percent of those on Isentress had viral loads below fifty compared to thirty-six percent of those on placebo. Treatment results were particularly strong among those with at least one active drug in the OBR—participants who started therapy with Fuzeon and/or Prezista for the first time, for example. Additional Phase III studies of Isentress are being conducted.
Side effects were similar between the Isentress-plus OBR groups and the placebo-plus OBR groups in the two phase III studies reported to date. Across the two arms, approximately eighty-three percent of the patients experienced at least one mild side effect, most commonly diarrhea, injection site reactions (among those receiving Fuzeon), and headaches. Serious adverse experiences were reported in approximately twelve percent of patients.
The two BENCHMRK studies will in the future provide more information on long-term efficacy, and also long-term tolerabilty. “In addition to those studies we have an ongoing Phase III treatment-naive study. A pediatric program is being initiated to study the drug in children,” notes Dr. Isaacs, adding that two worldwide studies are looking to see if patients who are stable on Kaletra-based regimens can be switched to Isentress with efficacy maintained but with tolerability improved.
EARMRK, an expanded access program for Isentress launched by Merck, is still enrolling on a worldwide basis. For more information and participant criteria, log on to www.benchmrk.com and click on “EARMRK” or call 1 (877) EARMRK1.
Chael Needle covered highlights from the IAS Conference in the August issue.
September 2007
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