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April 25, 2007
Maraviroc, the New Drug on the Block
by Lucile Scott
Yesterday’s recommendation to approve Pfizer’s HIV drug Celsentri (maraviroc) followed a day-long hearing before the Food and Drug Administration’s Antiviral Drug Advisory Committee (ADAC) that was anything but a rubber stamp. The meeting—a sea of suits at the Crowne Plaza Hotel’s Kennedy Ballroom in Silver Spring, Maryland—was a meaty, often tense, discussion of HIV science and policy at a key moment in treatment history.
Urgent calls for a new class of HIV meds are up against a brand new set of safety concerns raised by a drug that, for the first time ever, would target cells in the human body, as opposed to the HIV virus. If the FDA approves it, Celsentri will herald the arrival of the first new class of oral HIV drugs in a decade.
The question on the table yesterday was whether or not the FDA should give the drug “fast track” approval, speeding its availability (while clinical trials continue) because of the great demand for fresh options among those with resistance to other classes. An estimated 10% to 15% of the 270,000 HIV positive Americans on antiretrovirals have developed resistance to at least three classes of drugs. “The pressing need gives a sense of urgency,” argued Michael Dunne, MD, who led a group of Pfizer researchers to the podium just after 8:00 A.M. to introduce their findings.
The Pfizer team presented early data from the 48-week Phase III MOTIVATE studies, which included just over 1,000 people with treatment-resistant R5 HIV and viral loads above 5,000. Twenty-four weeks after starting the drug, most saw their viral loads plummet below 400, many even to undetectable levels.
FDA researchers followed Pfizer to the mic with their own reviews of Pfizer’s findings. They backed the company’s report for the most part but pointed out that 90% of the study participants had been men and 83% of them white. Lisa Naeger, PhD, observed that Celsentri seemed to work less well in African Americans but noted that it was hard to know for sure because there had been so few enrolled in the study.
Next, the presenters were queried by the approval committee members themselves, who were interested in whether messing with a CD4 cell’s receptors, as Celsentri does, might cause increased susceptibility to other diseases and infections.
There was also discussion about one of the trickier twists in the current debate about approving Celsentri: the fact that the drug may not actually work for many of those for whom it’s intended. In order for HIV to enter a CD4 cell and begin destroying the immune system, it must bind to a receptor. Most strains, at least among those in the earlier years of infection, hit up a cell’s CCR5 receptor for this task. However, some use the CXCR4 receptor and some strains of the virus—known as “dual tropic”—use both. Maraviroc blocks the CCR5 receptor, just the thing to keep HIV from even getting in the door. But many treatment-experienced individuals, for whom maraviroc is currently up for approval (trials on treatment naïve patients are ongoing) have a dual tropic virus—so the drug doesn’t work for them.
Concerns about a lack of information on race and gender intensified after the lunch break. “It would have been nice if we had a demographic representation of the U.S. epidemic,” said Robert M. Grant, MD. MPH. of the J David Gladstone Institute of Virology and Immunology, University of California, San Francisco.
Lynda Dee of AIDS Action Baltimore, the advisory panel’s official patient representative, suggested that if the drug is approved, the FDA should be required to do more research on how the drugs affect women and people of color. “I get so sick of sitting here drug after drug and there are not enough women or non-white people,” Dee said emphatically into her microphone. “If [more diverse testing is] not required, it will continue…the same way.”
Mid-afternoon, Cicely Reese of the Centers for Drug Evaluation and Research, requested each voting member offer up a yes or no vote—along with any caveats for the FDA to consider along with the committee’s overall recommendation.
Each member made several such demands, most of them requests for studies involving diverse demographics, looking at the drug’s effects on children and focusing on people with hepatitis. Some also called for more information on how Celsentri affects the liver and how tests ascertaining whether or not people had developed X4 or dual tropic viruses will be implemented.
Despite all the unanswered questions, everyone seemed to be able to agree on one thing. “If you weigh efficiency and need of patients, the need burns through,” as Dee put it. Indeed, the yeas were unanimous. The next move is the FDA’s.