- The Washington Times - Monday, June 19, 2006

An experimental class of HIV drugs known as CCR5 receptor antagonists has raised concerns among researchers that the drugs, like the AIDS-causing virus itself, may attack the immune system.

But researchers aren’t giving up on the new drugs, which they think hold promise as an effective alternative for patients resistant to other HIV therapies.

Two of three major pharmaceutical firms developing CCR5 receptor antagonists have either halted or scaled back clinical trials in the wake of unexpected problems, such as liver damage or lymphomas in some patients, or disappointing results at low doses, but neither GlaxoSmithKline nor Schering-Plough has capitulated. Pfizer is proceeding with final clinical trials of its CCR5-type drug, Maraviroc, involving about 2,100 patients.

“We’re cautiously optimistic” about seeking Food and Drug Administration approval of Maraviroc later this year, said Dr. Howard Mayer, executive director of clinical research and development for Pfizer.

Unlike the 27 treatments on the market that target the virus directly, CCR5 receptor antagonists block the receptors, or secondary doorways, that HIV typically uses to enter the body’s cells and eventually destroy the immune system.

“The drug attaches to receptors [on white blood cells] and blocks entry of the infection,” Dr. Mayer said, adding that it is just “speculation” that the new drugs harm the immune system.

He stressed that the three companies’ CCR5 receptor antagonist drugs have different chemical structures, so a problem with one cannot be assumed to apply to all.

Pfizer, he said, has been testing Maraviroc both in HIV patients who have become resistant to other therapies and in patients who have not previously been on HIV drugs. One patient in the trials developed liver problems. But an independent safety-monitoring board, which has provided oversight of the trials, concluded that the drug was not responsible and recommended that all of Pfizer’s Maraviroc tests continue.

“I still think this class of drugs has a lot of potential,” said Dr. Michelle Berrey, vice president of viral diseases for GlaxoSmithKline, which terminated trials of its drug Aplaviroc in October after at least one patient experienced severe but reversible liver poisoning. Several others had elevated liver enzyme levels but no symptoms.

Dr. Berrey said further research in animals found that the problems with Aplaviroc were “specific to that compound” rather than to the class of drugs. “So we have ongoing research” into CCR5 receptor antagonists and will be coming out with another drug of that type, she said yesterday.

Dr. Berrey also said that Schering-Plough is continuing its research in the field, even though in January it abandoned a portion of its trials of Vicriviroc, or Schering D, after it was not found to be as effective as expected at small doses. “Schering-Plough is using the drug as an add-on therapy” in combination with other HIV treatments, she said.

Veronica Miller, director of the Forum for Collaborative HIV Research at George Washington University’s School of Public Health, said of CCR5 receptor antagonists: “This class of drugs has had its challenges and presents us with a lot of unknowns. There is no evidence CCR5 receptor antagonists cause any damage, but there is always the potential something could happen. HIV profoundly affects the immune system … and we’re using a drug that also potentially affects the immune system, so we have to proceed carefully.”


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