DEVELOPING DRUGS ATTACK AIDS

By Daniel Haney

AP 25 Feb. 2002

Seattle -- Medicines are in development to attack the AIDS virus in entirely new ways, including several designed to keep HIV from ever gaining entry to the cells it kills. The goal: Find alternatives to the drugs already on the market, which lose their punch over time as the virus develops mutant forms that are oblivious to them.

"All the currently available drugs are losing their impact. There is obviously room for improvement," said Dr. Douglas Richman of the University of California at San Diego.

Scientists gave their status reports on this arms race Monday at the Ninth Annual Retrovirus Conference.

"Resistance remains a formidable problem," said Dr. Richard Colonno of Bristol-Myers Squibb. "We can try to stay ahead by coming up with the next generation of drugs. But in the end we will likely lose that race. The advantage of new classes of drugs is that they will work against all the currently resistant virus. You are resetting the clock."

While work continues on new versions of the standard drugs already sold, much of the interest is in one new approach -- blocking HIV from entering the blood cells in destroys. "This will be remembered as the year of the entry inhibitor," said Dr. Robert Schooley of the University of Colorado.

Entry of the virus into the cell is a three-step process, and drugs are in the works to gum up each of these. First, the virus attaches itself to a molecule on the surface of cells called CD-4. Then it hooks onto another called CCR5. Finally it fuses with the cell and squirts its genes inside.

One drug that attempts to block this first step is Bristol-Myers Squibb's experimental medicine, code-named BMS805. The drug works by covering up the spot on the virus that sticks to CD-4. In the test tube, it appears to work against strains of HIV that can resist all the other AIDS drugs. However, it has not yet been tried on people. Another drug, SCH-C, developed by Schering Plough, blocks the next step in viral entry, the attachment to CCR5. In a pilot study of 12 people, the drug used alone for one week dropped viral levels dramatically.

Furthest along in testing is Roche's and Trimeris's T-20, which blocks the third step of viral entry, fusion of HIV to the cell. Large-scale studies are under way, and the company says it hopes the results will enable it seek Food and Drug Administration approval later this year.

All of the drugs now on the market block one of two enzymes the virus uses to incorporate its genes into cells and use them to reproduce itself. These chemicals are called reverse transcriptase and protease.

A new drug reported at the meeting, developed by Shionogi & Co. of Japan, attacks another of these enzymes, called integrase. Dr. Tamio Fijiwara said the drug looks effective in test tube studies, and initial experiments on people are under way.

Scientists are also working on a variety of new versions of older classes of drugs. Among these are medicines known as non-nucleotide reverse transcriptase inhibitors. Researchers presented data on one of these, developed by Tibotec-Virco, that appears to be especially potent in initial testing. The drug was designed to work against viruses that are already resistant to Sustiva and Viramune, two widely used similar drugs.

In initial testing, Dr. Joep Lange of the University of Amsterdam said the drug alone appeared to work as well as an especially powerful five-drug combination during the first week of use.

"After a lull of two or three years, these data are very exciting," Dr. Brian Gazzard of Chelsea and Westminster Hospital in London said Monday's reports. "It's a phase of accelerated development that is likely go on keeping pace with the problem" of drug-resistant viruses.