The Wall Street Journal - 26 May 1992
Michael Waldholz, Staff Reporter of The Wall Street Journal

In laboratory studies, researchers at three large drug makers, unaware of one another's work, had developed remarkably similar medicines that stopped the AIDS virus from reproducing and infecting new cells. "There was a lot of excitement and euphoria" at the meeting, says Paul Anderson, chief chemist at Merck & Co. "Life looked very good."

Six months later, disaster struck. Just a few weeks after being given to patients, the medicines incited a deadly new strain of the virus that was completely resistant to the drugs.

As the scientists studied what had gone wrong, they also uncovered a terrible truth about the virus, one that casts a shadow over all AIDS research: When the virus reproduces inside human cells, it often churns out mutant copies. Researchers now believe every time they find a new medicine to beat the virus, at least one mutant version -- and often a whole new colony -- resistant to the therapy will emerge.

The mutants are a serious, and unexpected, setback in the war against AIDS. When the human immunodeficiency virus, or HIV, was isolated in 1984, Margaret Heckler, secretary of Health and Human Services, announced that with the virus identified, therapy was just around the corner. Within two years, several of the world's most successful pharmaceutical firms launched drug-hunting projects they hoped would yield quick results.

But like other viruses, including those underlying the common cold or flu, the extraordinarily complex HIV virus, which causes AIDS, is humbling scientists. The problem of drug-resistant mutants is so pervasive and severe that the big drug makers say they've hit a scientific impasse. Some drug company executives are so frustrated they're privately considering a desperate move: asking competitors, for the first time since the development of penicillin, to pool research.

Perhaps no drug company official is more distraught than P. Roy Vagelos, Merck's chairman and chief executive, who is widely credited with making Merck the world's pre-eminent discoverer of drugs. In 1988, he publicly predicted his company would develop a safe and effective AIDS treatment in five years. "My time to meet the public prediction is almost up, and I was wrong," Dr. Vagelos says. "It's an enormous disappointment."

Edward Scolnick, Merck's director of drug research, concedes the company's initial optimism was simply naive. Developing an AIDS drug "is harder than we thought," he says. "It is harder than we ever imagined."

Similar accounts now echo from the labs of SmithKline Beecham PLC, Abbott Laboratories, Upjohn Co., Hoffmann-La Roche Inc. and Boehringer-Ingelheim Corp. "Lucky breaks early on led the companies to think they were in a sprint," says Margaret Johnston of the National Institute of Allergy and Infectious Disease. "Now they realize it's going to be a marathon."

Today, drug makers concede that it may be a long time -- if ever -- before there's a cure for AIDS, which already has claimed nearly 300,000 lives. HIV is thought to have infected about 10 million people around the world. Some 30 million to 40 million people are expected to be infected by the end of the century. Pharmaceutical researchers say no single treatment will work against the disease, and none may eradicate it completely. "AIDS looks to be a disease like cancer or tuberculosis," says Ralph Christoffersen, senior vice president-research at SmithKline. "What we're hoping for are drugs that extend life."

Many AIDS researchers say it was wrong to raise expectations for a quick discovery, especially given the drug industry's failure to disable other viruses. Viruses are bits of genetic material wrapped in protein that insert themselves into a cell's inner workings, forcing the cell to become a factory that mass-produces more viruses, which invade still more cells. Most of the viruses considered to be under control, like those that cause measles, polio or smallpox, have been tamed by vaccines that prevent initial infection, not by medicines ejecting the virus from infected cells.

For that reason alone, the big drug companies initially shied away from AIDS research. But in 1986, after scientists started dissecting critical components of the virus, researchers at several companies decided it might be possible to devise a drug that would jam HIV's reproductive machinery. Without public announcements, which might tip off competition, about half a dozen companies quietly and independently launched AIDS drug projects.

In early 1989, Merck offered a glimpse of its strategy. Reporting in the scientific journal Nature, Merck researchers said they had deciphered the complex, three-dimensional structure of an enzyme, called protease, that's crucial to HIV replication. Merck said it believed the picture would help it design and develop a drug to disable the enzyme and shut down the viral factories. SmithKline, Upjohn, Abbott and Hoffman-LaRoche soon acknowledged that they, too, were hunting protease blockers.

Suddenly, scientific journals were awash with reports tracking the companies' progress. "There was real reason for hope," says NIAID's Dr. Johnston.

The protease enzyme turned out to be physically similar to a kidney enzyme called renin, which, when produced in excessive amounts, can cause blood pressure to rise. Since the late 1970s, the big drug companies had invested heavily in finding renin blockers, but in vain. Beginning in 1986, the companies started looking for a protease blocker by modifying drugs first designed for renin.

Meanwhile, Mark Goldman, a young researcher at Merck, quietly set off in a different direction. In 1987, Dr. Goldman, then a 31-year-old pharmacologist, decided to search for a better version of AZT, a drug developed by Burroughs Wellcome Co. that had just won Food and Drug Administration approval as the first anti-AIDS medicine.

AZT disrupts another enzyme, called reverse transcriptase, or RT, that the virus uses to reproduce itself. But the drug, and several chemical cousins recently sanctioned by the FDA, produces severe side effects. "My mission was to find nontoxic compounds to block reverse transciptase," Dr. Goldman says.

His plan was simple, based on a tried-and-true drug discovery technique. He and a few assistants devised a test that could measure whether the enzyme was turned off when combined with another chemical. With the help of a robot that conducted experiments 24 hours a day, the tiny lab evaluated more than 23,000 chemicals from Merck's shelves, including extracts from fungi, herbs and plants harvested from around the world.

Finally, two years later, in the spring of 1989, Dr. Goldman's lab found a promising lead in a chemical that deactivated the RT enzyme in a different way from AZT. But the chemical, which had been synthesized as part of an earlier Merck effort to find an arthritis treatment, needed to be refined.

Dr. Goldman -- earnest, highly disciplined and very ambitious -- soon became obsessed with the chemical, colleagues say. "The guy was relentless," says Dr. Anderson, Merck's chief chemist, who under intense lobbying from Dr. Goldman dispatched an unusually large crew of 30 chemists to the task. "He was racing around the labs, pressing people, keeping things moving," Dr. Anderson says.

By the summer of 1990, Dr. Anderson's chemists, each cranking out about two new chemicals a month, finally produced four drugs, two of which, code-named L-639 and L-661, the company decided to test in humans. It had taken only 15 months from discovery of the active compound to a usable drug, a record for the company, Merck officials say, noting that such projects usually take at least three to five years. "We were working in the dark and assumed we alone" had found a new kind of AIDS drug, Dr. Goldman says.

But when Merck officials huddled with FDA staffers and federal AIDS scientists to design human studies for the drugs, they found they had competition. Researchers at Boehringer-Ingelheim, the Ridgefield, Conn., unit of the German drug company Boehringer Ingelheim International G.m.b.H., had a remarkably similar research project. Janssen Pharmaceuticals, a Belgian unit of Johnson & Johnson, was also testing an RT blocker of similar design.

Last May, researchers who gathered in Buffalo shared data showing the drugs had cleared two crucial hurdles in preliminary laboratory tests: They reached the white blood cells of the immune system that are overcome by HIV, and they produced no major side effects. The remaining test -- whether the drug kept the AIDS virus from spreading to uninfected cells in humans -- had just begun.

The first details that trickled into Merck and Boehringer were positive. Early blood analyses found crucial blood counts measuring cells killed by the virus steadily rising, suggesting the drug was quelling viral reproduction. Then, quite suddenly, after only six weeks of treatment, these blood counts started dropping sharply.

In Paris, where he was attending a scientific seminar, Dr. Goldman was called with the news. He immediately suspected the problem's cause. A year earlier, test-tube studies had suggested the virus might develop resistance to RT blockers. "We hoped that in people the resistance would take a very long time to develop," he says. "The speed of it completely surprised us."

How, the Merck scientists wondered, could the virus outwit the drug so swiftly? The question wasn't academic, says Emilio Emini, head of Merck's basic AIDS research. AIDS research is now Merck's largest, and most expensive, drug discovery program. "Normally, drug makers invest heavily like this when the probability of success is high," he says. "But for AIDS you have to do a large-scale, high-resource effort even though in the end you may get nothing for it." For the scientists, HIV represents the challenge of a lifetime. For companies, it represents a chance to earn enormous prestige and profits.

Back in the lab, Dr. Emini's technicians pored over blood specimens from test subjects, looking to see whether a mutant, drug-resistant strain was overwhelming the patients' cells. Eventually, the researchers found that the chemical structure of the RT enzyme had made a subtle shift, exchanging just one of the enzyme's hundreds of molecules for another. The change, however slight, was enough to evade the Merck drugs: Like a lock whose tumblers had been changed, the virus no longer fit the drug.

Weeks later, scientists at Boehringer made the same discovery. The virus, the scientists now know, churns out millions of copies of itself, and no two are alike. Among those mutants was one with a molecule change that made it invincible to the RT blockers.

The discovery has cast a pall over Merck's program because it means the virus may be able to dodge quickly almost any drug the researchers develop. It may explain why Dr. Emini often refers to the virus as "a dirty bastard," adding that he gives "no odds, none at all" on when, or if, Merck might devise something new.

To make matters worse, Dr. Emini says that in testing blood from other AIDS patients, his researchers found the virus is mutating somewhat more quickly in the presence of AZT than previously believed, producing AZT-resistant strains after 12 to 18 months of treatment. "The very bad news is that AZT has a limited period of effectiveness," says Dr. Emini.

Dr. Emini says his colleagues, while frustrated, are also excited by challenge. "Now that we have an understanding of the virus's variability, our job is to find drugs that counter this means of escape," Dr. Emini says. "That doesn't mean that the virus won't figure something else out. We'll just keep tracking it and when the virus moves we'll hit it here, and when it moves again we'll hit it there. One of these times we'll hit" it where it can't escape.

Merck and several competitors say overcoming resistance may require use of several different drugs at once, each disarming one of the half-dozen other enzymes that run HIV's life cycle. Merck is testing one of its RT blockers in combination with AZT. Still, the most hotly pressed attack is on the protease enzyme.

"It's the Holy Grail of drug targets," says Alan Rosenthal, senior vice president-scientific affairs at Boehringer. Scientists believe the protease, absolutely critical to the spreading infection, may be less likely to mutate than other enzymes.

But protease-blocking drugs have another problem: They must be very large to be recognized by the enzyme. And because of their size, the drugs are destroyed by the body's digestive system when taken orally.

In recent months, Upjohn and Abbott have developed "prototype" protease blockers that can be injected directly into the bloodstream. Upjohn says it plans to test the injectable version to determine if a protease inhibitor produces resistance. But most drug company officials say a drug that must be injected would be very difficult to administer, especially in the inner cities and in the Third World.

Hoffmann-La Roche says it already is testing an oral protease inhibitor in Europe, but researchers familiar with the effort say too little of the compound gets through the gut to be effective.

And some drug researchers and AIDS activists say the companies' drug-seeking techniques are too stodgy to beat HIV; that resources committed to AIDS research are relatively small; and that the companies' failure to formally share research is retarding the effort.

"I applaud Merck because it was very aggressive in going after the RT drugs," says Michael Becker, a New York lawyer associated with the AIDS group ACT-UP. "But now things don't seem to be getting anywhere. It's very depressing." Mr. Becker has written to several drug companies, and to federal AIDS officials, asking the companies to share their research findings, but only one company has privately expressed interest.

That has some academic and government researchers perplexed. Alexander Wlodawer, a protease researcher at the National Cancer Institute, says he thinks the drug companies' unwillingness to share has slowed things down. "There have been times when the companies could have published findings more quickly," he says.

Several companies say they will resist such calls, hoping to keep the glory -- and profit -- from discovering an AIDS drug themselves. "Competition is good for science and business," says Martin Rosenberg, head of SmithKline's project, noting that his researchers are driven by the race to solve an "extraordinary problem."

And several veterans of the AIDS drug war are convinced that no amount of sharing, or even additional research funds, will overcome the virus right now. Dr. Goldman, who led Merck's RT blocker project, recently left the giant company and AIDS drug research to work at a small, private biotech firm in San Diego called Ligand Pharmaceuticals Inc. "Right now," Dr. Goldman says, "the virus is just smarter than we are."

(See related letter: "Letters to the Editor: Vaccines Offer Hope In Battle Against HIV" -- WSJ June 24, 1992)

920526
WJ920504

Copyright © 1992 - The Wall Street Journal. Reproduction of this article (other than one copy for personal reference) must be cleared through the WSJ Permissions Desk.

Always watch for outdated information. This article first appeared in 1992. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 1992. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .