Chicago Tribune (CT) - THURSDAY, April 11, 1996 Edition: EVENING UPDATE Section: NEWS Page: 7 Word Count: 878 MEMO: COLUMN: EVENING. Health
Huntly Collins and Shankar Vedantam

The AIDS virus she had disabled was no longer spreading from cell to cell. It was no longer infectious. If true, Nancy Kohl and her colleagues at Merck & Co. had found a way to stop the AIDS virus dead in its tracks. And if this held up in human trials, it would mean a breakthrough in the treatment of AIDS. Kohl did the experiment twice more. The results were the same.

She called her boss, Irving Sigal, to meet her in the AIDS lab at Merck's research campus in West Point, Montgomery County, Pa. An intense man who did not smile easily, Sigal asked what Kohl had. She showed him the data. He studied them carefully. Then he smiled. It was February 1988.

About 75,000 people around the globe had died of AIDS; another 5 to 10 million were believed to be infected. The world's best minds despaired of finding a way to stop it.

What Kohl saw that day was the start of an eight-year quest that would lead to the most effective AIDS drug yet developed -- a drug that might prevent complications and extend the lives of AIDS patients, a drug so promising the Food and Drug Administration approved it in record time.

Merck would spend more than $700 million racing two other firms -- Abbott Laboratories Inc. and Hoffmann-La Roche Inc. -- to make the new medicines. Struck by scientific disappointments and the death of a key researcher, Merck would nearly abandon the project -- the largest and most expensive in its 105-year history.

Sigal, 35, was Merck's senior director of molecular biology. Assigned to AIDS research, he plunged in with characteristic zeal.The goal was to find a drug that would prevent HIV, the human immunodeficiency virus which causes AIDS, from making functioning protease.

It would have to be safe and keep the virus from replicating, a compound that could be swallowed as patients would have to take it many times a day. It would have to pass through the digestive system membranes, hard because protease inhibitors are very large molecules and do not dissolve easily.

Merck had hundreds of potential compounds left over from attempts to find inhibitors of another protease, renin, which plays a role in high blood pressure. In weeks, Merck chemists had found several chemicals from the renin collection that blocked HIV. But they were all weak.

Sigal would have to develop a more powerful compound. For eight months, Sigal pushed his lab. By December 1988, the scientists had built a three-dimensional picture of the protease, crucial to designing the drug, when Sigal had to break away to give a scientific paper in London. After three days there, he called his wife, Catherine, also a Merck researcher, to say he could take an earlier plane, Pan Am Flight 103.

Joel Huff, Merck's chief chemist, at home that Dec. 21 got the phone call: Flight 103 had exploded in the air and crashed near Lockerbie, Scotland. Sigal died with 257 other people.

Huff headed the chemistry side, Sigal the biology. Huff wondered what would become of the project. After a somber Christmas, the lab pressed on. Surprisingly, the chemists came up with something in less than 12 months. But would it be safe?

On March 26, 1990, Merck began to test its experimental protease inhibitor in dogs to see if its compound were safe and at what doses, so the drug could tested in humans.

Merck faced another potential problem: AIDS activists. Some in the company counseled against it, but Merck let its public relations team meet with the activists. The March 1, 1991, meeting had a common agenda -- getting lifesaving drugs to dying patients. By the end of the meeting, they had forged a community advisory board that, in the next few years, would swell to include several dozen activists.

The board would be more than window dressing. The activists would help the firm design clinical trials. They would negotiate with Merck to help get drugs to patients months before federal approval. Most important, they would help Merck pressure the government to speed drugs through the approval process.

Failure of the dog trials was a major setback. A new chemical had to be found, but Merck scientists had exhausted its 200 protease inhibitors. Working weekends and nights, they tested chemicals at random. They tried tens of thousands; none worked. So they created their own chemicals. They built 3,000 compounds, "invented" matter.

From this would come Crixivan, the drug approved last month by the FDA. Merck worked for three years, screening and testing, before coming up with a compound scientists thought would work and be safe to test in humans. The drug was fiendishly complicated to make, said scientist Paul Reider. A French and Chinese gourmet chef, he said it was like cooking an intricate meal for 1,000. If you wrote the "recipe," for Crixivan, he said, 14 steps in all, each step would be 60 pages.

CAPTION: PHOTO: Dr. Hedy Teppler (center) with her research team at Thomas Jefferson University Hospital in Philadelphia. They worked with volunteer AIDS patients to test the new drug Crixivan in 1993. KRT photo.

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