- The Washington Times - Tuesday, February 11, 2003

BOSTON, Feb. 11 (UPI) — Researchers at an AIDS conference Tuesday described promising new drugs that have found new vulnerable areas to attack and defeat human immunodeficiency virus.

"I would say we have a bumper crop of new drugs," said Dr. John Mellors, professor of medicine at the University of Pittsburgh. "The message that you should take from this meeting is that the pipeline of new drugs has an impressive number of candidates in it. This is something that we haven't seen in the past years."

In a series of presentations at the 10th Conference on Retroviruses and Opportunistic Infections in Boston, researchers presented an array of novel treatments including an antibody that finds cells under attack from HIV, which causes AIDS, and prevents the virus from completing its invasion of the cell.

When HIV tries to invade a cell it first latches onto an immune cell receptor. The antibody — delivered by a half-hour intravenous infusion every two to three weeks — prevents the virus from completing its molecular cascade that allows it to enter the cell.

In early human trials, high doses of the "anti-CD4 monoclonal antibody" designated as TNX-355, caused the circulating virus in patients' blood to drop more than 90 percent.

"There were no significant side effects and no loss of immune function," said Dr. Daniel Kuritzkes, associate professor of medicine at the Harvard Medical School. The antibody is being developed by Tanox Inc., based in Houston.

Mellors, referring back several years when antiretroviral therapy had to be taken every few hours, noted "We are talking about taking a single dose of a drug that can be effective for two to three weeks."

Another drug in the pipeline disrupts the process by which viral cells mature from virions to infectious agents. Carl Wild, chief science officer at Panacos Pharmaceuticals Inc., Gaithersburg, Md., said his researchers had to do detective work to find out why their drug PA-457 stopped HIV from replicating in laboratory experiments.

Through a process of elimination and use of sophisticated tests and electron microscopy, Wild and colleagues found PA-457 inhibits the final step of the process by which HIV becomes a menace in the body. The maturation disruption results in molecules that are malformed and unable to cause infection, he said.

He said his company will seek Food and Drug Administration approval to begin human studies later this year.

Researchers also have created a potent next-generation protease inhibitor that can fight off virus even if that virus has developed mutations that make protease inhibitor drugs ineffective. TMC114, a drug developed by Tibotec of Belgium, was able to reduce the level of circulating virus in these HIV patients by more than 90 percent — in some cases more than 99 percent.

In fact, in four out of 10 patients, a standard assay was unable to find any virus in the blood of patients who took higher doses of MC114 for just 14 days, said Dr. Keikawus Arasteh, director of internal medicine at the Auguste-Viktoria-Klinikum in Berlin.

Other researchers reported progress on drugs that attack HIV's ability to enter cells, to create copies of itself that increase its ability to infect other cells, to prevent integration of the viral DNA into cells, again frustrating the ability of the virus to replicate and cause damage.

"There are many drug candidates that target the old enzymes such as protease and reverse transcriptase, as well as new targets that affect binding, fusion and maturation of the virus," Mellors said.

He said in the past few years there might have been one or two drugs that looked impressive while at the present meeting he thought there were at least a half-dozen such drugs in clinical trials. He noted he found "there were no real clunkers."

"Usually you can tell after a 10-minute presentation that a drug isn't going to make it. I was impressed that these drugs are very promising," Mellors said.

Mellors also was impressed by reports on the experimental T-1249, a drug that inhibits the virus from fusing with cells to begin the infectious procedure. T-1249 is the second fusion inhibitor in development. The first, T-20 or enfuvirtide, is expected to receive approval shortly, but T-1249 is a backup if patients develop a viral mutation that makes T-20 ineffective.

"For a while I was pessimistic that we could keep up with the rate of evolution of HIV drug resistance in treated patients," Mellors said. "I'm very encouraged this year that we are keeping up with the virus; that we are able to treat resistant viruses with new drugs in the same class — such as TMC114 or T-1249 — as well as identify new inhibitors that are potent and effective."

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