3rd Major Drug for AIDS May Win Early OK
Setting the stage for possible federal approval of a third antiviral AIDS drug, early findings in an ongoing study have shown that the experimental AIDS drug DDC, used in combination with AZT, produces more than twice the crucial immune system cells than AZT alone.
The findings were presented Monday to a Food and Drug Administration advisory panel that is expected to vote today on whether to recommend approval of DDC, which is manufactured by Hoffmann-La Roche Inc. of Nutley, N.J. While recommendations by such advisory committees are not binding, the FDA almost always follows their advice.
If approved, DDC would become the third licensed antiviral drug in the AIDS arsenal.
Antiviral drugs, which are considered the big guns in the fight against AIDS, attack the underlying virus, unlike drugs that fight the opportunistic infections and other conditions that result from an impaired immune system. Most researchers believe that the key to controlling AIDS ultimately lies in developing a successful combination of antiviral therapies.
AZT, which is manufactured by Burroughs Wellcome Co., was approved in 1987; DDI, made by Bristol-Myers Squibb Co., was approved last fall.
The latest findings are important because the same kind of evidence--an increase in CD4 cells, the primary target of the human immunodeficiency virus--served as the basis for the agency’s approval of DDI. Subsequent findings, released at a meeting of AIDS researchers last week, showed that DDI was more effective than AZT in slowing the progression of the disease in individuals who had been treated with AZT, although there was no difference in overall survival.
The latest study also appears to confirm the findings of a study published in January that showed similar increases in CD4 cells but was met with reservations because it involved far fewer study participants.
“The FDA wanted the CD4 cells analyzed (in the latest study) to see if the rise correlated with the earlier study,” said Dr. Robert T. Schooley, head of the infectious diseases division at the University of Colorado Health Sciences Center, who presented the data. “It does. Over the first six months, the rise on both drugs (DDC and AZT) was roughly twice as much as with AZT alone.”
Early evidence that a drug elevates CD4 cells is not necessarily an indication of how effective a drug will be. However, apparently it has been reliable to some extent for both AZT and DDI, both of which have proved beneficial to patients.
In 1987, when AZT was approved, the FDA did not act until studies had established that the drug prolonged survival and improved the quality of life for patients with AIDS. Later research showed that the drug also delayed the onset of AIDS in HIV-infected individuals.
The agency approved DDI much more quickly, however, basing its decision largely on studies that showed a sustained elevation of CD4 cells compared to patients on AZT.
The FDA, which has been seeking to speed AIDS drugs to the market as rapidly as possible, has become increasingly willing to rely on so-called “surrogate markers,” in this case the increase in CD4 cells, to license drugs, and is likely to apply the same standards in evaluating DDC.
It was unclear Monday, however, whether panel members would be inclined to use the same measures in deciding today whether to recommend approval of DDC. Several expressed concerns about the continued use of CD4 cells as a surrogate marker for early approval of AIDS drugs, saying that more definitive measures are needed. But others insisted that there are no other alternatives now.
CD4 levels are “the best we have for now,” said Dr. Mark Smith, vice president of the Kaiser Family Foundation in Menlo Park, Calif.
And FDA official David Feigal told the panel: “It’s not an issue of when we’re going to use them (surrogate markers), but how we’re going to continue to use them.”
If DDC, or dideoxycytidine, is licensed, it is likely to be approved for use only in combination with AZT. Clinical studies of DDC used alone have shown it to be less effective than AZT. In fact, one study was halted late last year because it showed that the relative risk of dying was far greater for patients on DDC than on AZT.
The earlier study of DDC/AZT combination therapy used 56 patients divided into six comparison groups, meaning that only about nine individuals actually received the combination dose that showed the greatest rise in CD4 cells.
The latest study involves about 150 patients in the United States, Australia and the Netherlands, with advanced HIV infection. Most had not experienced symptoms of disease and most had not been treated with antiviral drugs previously.
The study is being conducted to determine whether combination therapy can prevent the kind of viral resistance that can develop against a single drug. There are three comparison groups, including one taking AZT and DDC, a second taking AZT and DDI and a third being treated with AZT alone.
For the purposes of measuring CD4 cell levels, however, only the DDC/AZT and the AZT groups were examined, Schooley said.
