POZLife: Life from the Infected and Effected point of veiw.

Worth the Wait: Isentress Arrives

Posted by pozlife on October 24, 2007

by David Evans

After 14 years of advances and setbacks, the first HIV-fighting integrase inhibitor has made its therapeutic debut. Merck & Company’s Isentress (raltegravir), approved by the FDA on October 12, is expected to arrive on pharmacy shelves this week. While activists are expressing a “mix of satisfaction and disappointment” with the drug’s $27-a-day price tag— near the top of the ranks of other relatively new and expensive HIV drugs—they are grateful that Isentress is now available to help those in need of new treatment options. And though it was approved only for use in people who are heavily treatment experienced, activists and researchers are fired up over its potential for therapy of first-timers as well.

Integrase inhibitors have been one of the most challenging classes of antiretrovirals to develop. Integration is a vital step in HIV’s life cycle. When normal uninfected cells are prompted to do so, they activate parts of their DNA—the genetic blueprint of our bodies—and the cell is able to reproduce. HIV takes advantage of this process by inserting, with the aid of its integrase enzyme, a snippet of viral DNA into the cell’s DNA. When the infected cell is triggered to reproduce, instead of making more immune cells, it begins churning out new HIV.

Merck has been trying since 1993 to develop a drug to block integration. Martin Delaney, founding director of Project Inform, an AIDS advocacy group in San Francisco, has been following integrase inhibitor development since its inception. When asked why it took so long to develop this class of drugs, he says, “You’re talking about biochemistry, and there’s no way to predict which challenges are going to be easy and which are going to be hard. And I guess reflexively looking back, this one turned out to be difficult.”

Merck and other companies put forward some promising candidates over the years, but most of them fell flat due to problems with toxicity or turning their chemical compounds into a drug that people could actually take. By the time Isentress entered the pipeline with the code name MK-0518, people were ready to be disappointed again. But the earliest human studies of Isentress—as well as Gilead Science’s elvitegravir, which is currently in Phase II studies—turned the skeptics into cautious optimists. And, as both integrase inhibitors advanced into larger clinical trials, the hope surrounding them became even more palpable.

Ultimately, the FDA looked at data from two Phase III trials of Isentress in people who were heavily treatment experienced. Most of the 699 participants in the two studies had virus that was resistant to most, if not all, of the other available antiretroviral drugs. Researchers constructed a background combination of the drugs they felt would most likely work for each individual and then added either Isentress or a placebo. After 24 weeks, 60 percent of those on Isentress plus an optimized background regimen (OBR) in one study had undetectable viral loads, compared to just 35 percent of those on the placebo plus OBR. In the other study, 65 percent of those on Isentress plus an OBR had undetectable viral loads, while only 33 percent of those on a placebo plus OBR did.

Daniel Berger, MD, medical director of NorthStar Healthcare in Chicago and one of the trial researchers, has developed a profound appreciation for the potency of Isentress. He says, “The T-cell increases that we see within two weeks of treatment is incredible. People starting at 60 T-cells came in for their follow-up two weeks later, and they had 300 T-cells. I’ve never seen that before.”

When the group tasked with advising the FDA on approval looked at the data, they voted unanimously in favor of giving the drug the green light. Matt Sharp, who has been HIV-positive since 1988 and currently serves as the director of education for Test Positive Aware Network in Chicago, testified before the committee. He feels that adding Isentress to a new combination of HIV drugs has completely turned around his failing health, and says, “The most dramatic thing was that I was able to get my virus to undetectable levels, and they’ve stayed that way for over a year now. My history with this disease is that I’ve really never had undetectable viral levels.”

Sharp anticipated that Isentress would gain approval and felt that “the data really spoke for itself,” but was surprised by the unanimous verdict of the panel in favor of approving the drug, saying, “There’s usually one or two dissenters.”

To get Isentress into the hands of those who really need it, the FDA granted Isentress a priority review and approved the drug specifically for treatment-experienced patients with drug-resistant HIV. But approval for those who have never taken HIV treatment could follow in the next couple of years, and the data reported thus far are striking.

A 200-patient study involving first-time treatment takers found Isentress comparable to Sustiva in terms of the percentage of people reaching an undetectable viral load. Noteworthy too was how quickly people taking Isentress saw virus levels drop. Dr. Berger is familiar with the study and says, “the mean time point that it took for people on Isentress to get to undetectable was only eight weeks, and that’s versus Sustiva, [where the] mean time was 24 weeks. So people [on Isentress] actually got to undetectable so much more quickly.”

While unsurprised, though pleased, that Isentress was approved, some activists are on the fence regarding the price set by Merck, $27 per day. The Fair Pricing Coalition (FPC), a group of HIV advocacy organizations and activists who advocate for reasonable pricing of HIV drugs, began meeting with Merck in March. They pleaded with them to follow the example they set back in 1996 when they priced their new protease inhibitor, Crixivan (indinavir), substantially lower than the other two protease inhibitors then on the market.

While Isentress is a few bucks below the costs of Pfizer’s Selzentry (maraviroc) and Boehringer Ingelheim’s Aptivus (tipranavir)—and significantly cheaper than Roche’s $61-a-day Fuzeon (enfuvirtide)—the FPC says that Merck neither set a new standard for low pricing nor agreed to freeze the price of the drug for the next several years—another of the group’s advocacy goals. Delaney, one of the group’s members, says “While we believe that the price should be lower still, Merck at least avoided the conventional pricing strategy of ‘whatever the market will bear,’” adding that if Merck had agreed to freeze the price of the drug, “that would have been a challenge to the rest of the industry, and I think they missed an opportunity to show some leadership there.”

Pricing concerns aside, activists and researchers agree that the timing of the FDA approval of such a potent and unique drug is its shining glory, especially for people with drug-resistant HIV who have gone through most of the other treatment options available. Isentress arrives hard on the heals of two other relatively new drugs, Selzentry and Prezista (darunavir). Although Delaney feels Isentress “is the best drug yet for HIV” it’s the timing of Isentress’s approval that makes it so special. He says, “The message isn’t just about ‘Try Isentress,’ but rather that [people] can now put together a whole new regimen of at least three drugs that [their] system has never been exposed to before…and that is a remarkable opportunity that’s never happened before.”

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