March 17, 1996; Page A01

PART 1 OF A SERIES

8 YEARS AND $700 MILLION LATER, HOW A BETTER DRUG WAS FOUND

THIS BREAKTHROUGH MIGHT SAVE THE LIVES OF PEOPLE ONCE DOOMED BY AN HIV-POSITIVE DIAGNOSIS

By Huntly Collins and Shankar Vedantam

The young biochemist tried to contain her excitement as she peered through the microscope in her cramped laboratory.

The AIDS virus that she had disabled was no longer spreading from cell to cell. It was no longer infectious.

If that was true, Nancy E. 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 major breakthrough in the treatment of AIDS.

Kohl did the experiment two more times. Each time, the same result.

She called her boss, Irving Sigal, and asked him to meet her in the AIDS lab on the second floor of Building 16 at Merck’s sprawling research campus near Lansdale, Montgomery County.

An intense man who did not smile easily, Sigal arrived at the lab and asked to see what Kohl had.

She showed him the data. He studied it carefully.

Then, he smiled.

It was February 1988.

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

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 that the U.S. Food and Drug Administration approved it last Thursday 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. And 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.

In the end, AIDS activists, desperate from seeing friends and lovers dying while a hopeful drug was in reach, would defy the law and decide to make the complex medicine themselves.

Ultimately, button-down corporate executives would meet with seasoned street radicals around polished conference tables; but instead of fighting, the two sides would resolve their differences and serve a dying community of mostly young people.

§

Irving Sigal was one of the most spectacular scientists Merck had ever seen.

At 35, he had risen to become senior director of molecular biology. When Merck assigned him to AIDS research, he plunged in with characteristic abandon.

Sigal knew the AIDS virus made a biochemical called protease. Drawing on the work of other scientists, he had speculated that he could stop the virus from spreading by inhibiting or disabling the protease enzyme.

Now Kohl had proved his hypothesis.

A slightly built man with dark, curly hair, Sigal quickly energized his team of scientists to exploit the discovery.

The challenge was enormous, but so would be the rewards. Not only would this be a stellar scientific achievement that would likely make money for Merck, but it might allow people with AIDS to live much longer, possibly as if AIDS were just a chronic disease.

The goal was to find a drug that would prevent the human immunodeficiency virus (HIV), which causes AIDS, from making functioning protease.

An effective drug would have to be safe and keep the virus from replicating.

It also would have to be a compound that could be swallowed, because patients would have to take it many times a day.

And it would have to pass through the membranes of the digestive system, which would prove difficult 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 a matter of 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, the scientists had built a three-dimensional picture of the protease, a crucial step in designing the drug.

The work was moving at full speed when Sigal had to break away to deliver a long-scheduled scientific paper in London.

Privately, Sigal chafed at the trip. His work was reaching a point where he could use his expertise as a biologist and chemist, the ideal combination for developing the new drug.

The presentation and other business took three days, then he raced back to London’s Heathrow Airport.

Sigal called his wife, Catherine, also a Merck researcher. He had made two flight reservations, one much later than the other, in case he was delayed. He wanted to tell her that he was in luck.

He could take the earlier plane, Pan American Flight 103.

§

Joel Huff, Merck’s chief chemist, was home that Dec. 21 when he got the phone call: Pan Am Flight 103 had crashed over Lockerbie, Scotland. Irving Sigal was dead.

Investigators said a powerful bomb, planted by terrorists, had blown up the plane, strewing 258 bodies and wreckage over six miles.

Huff, a reserved man who kept his emotions in control, was stunned. Sigal was his friend, as well as a close colleague. Huff had headed the chemistry side of the project, Sigal the biology. Huff wondered what would become of the project now?

On the other side of the country, in the Westwood section of Los Angeles, Linda Grinberg heard the news about the terrible Lockerbie crash, but she felt no personal connection.

Grinberg was living a hectic life running the world’s largest film library. At 38, she wanted to slow down. She yearned for the prosaic - a picket fence, a station wagon, a dog. Most of all, she wanted a baby girl.

Two years later, she would test positive for HIV.

She had been infected by her ex-husband who never told her he had AIDS.

At about the same time in Brooklyn, Jules Levin, a street-smart guy with a clipped voice and an inquisitive nature, was piecing together his life after learning he was HIV-positive.

The diagnosis didn’t come as a surprise. Levin had been a heroin addict during his years in law school and he had often shared needles.

In Atlanta, Tom Blount, a tall, forceful man with a commanding presence, was worried about his lover.

Blount had just found out that Jim was infected and was determined to keep him alive. That was what love was about. He quit his job as an architect and became a full-time AIDS activist.

At the time, none of these people knew much about the politics or the science of AIDS. But their lives, and the lives of many people they knew, would be changed by the research just beginning at Merck.

§

After a somber Christmas, the Merck scientists held a lab meeting and discussed what to do now that Sigal was gone.

Huff spoke up first. He talked about the unfinished projects Sigal had started and the work that remained to fulfill Sigal’s vision of stopping the disease.

The lab pressed on, adding compounds to cultures of HIV that had been extracted from infected people.

Huff knew that finding a safe, effective, easy-to-use drug could take years, assuming it was even possible.

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.

About the same time, another pharmaceutical company, Hoffmann-La Roche in Nutley, N.J., announced that it had discovered a protease inhibitor drug of its own. It would be called saquinavir.

The race was on.

Merck’s animal study was designed to determine whether its compound was safe and, if so, at what doses. Only when this was determined could the drug be tested in people.

High doses of the drug were given to eight dogs. Almost immediately, they started vomiting. They looked tired. And in a telltale sign of toxicity, the whites of their eyes began turning yellow. Although none of the animals died, the dogs suffered significant liver damage.

Gathering the data, a Merck toxicologist rushed into the office of the senior investigator in charge of the animal trials.

“We’ve got a problem here,” the toxicologist said.

It was a trying time for the company.

Hoffmann’s protease inhibitor was moving along rapidly. And now, another big firm, Abbott Laboratories near Chicago, was also hot on the trail of a protease drug.

At the same time, Merck’s research on a different class of AIDS drugs was unraveling. Four experimental drugs similar to AZT failed in early human trials because the virus mutated around them.

And Merck, which prized its image as a socially responsible corporation, now had to face another potential problem - AIDS activists.

A small group of men from Act Up New York had taken an interest in the company’s experimental AIDS drugs. If any of these panned out, Merck knew the activists would be clamoring for them, bickering over prices and challenging the company’s authority.

The activists, who were mostly gay men, were an energetic, uninhibited bunch. They wore blue jeans and earrings to meetings, and belonged to groups with names like the “Lavender Hill Mob.” They were anticorporate, suspicious of the suits, and politically savvy.

Merck didn’t want to antagonize them. It might lead to a repeat of the noisy and embarrassing demonstrations that faced Burroughs Wellcome, the company that developed AZT.

Although some in the company counseled against it, Merck decided to let its public-relations team meet with the activists.

§

The March 1, 1991, meeting was on neutral ground at the National League of Nursing in Manhattan. When it began, both sides were nervous. Both carried tape recorders.

But they 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.

Jules Levin and Tom Blount were among them.

The board would be more than window dressing. The activists would help the company design clinical trials. They would negotiate with Merck to help get drugs to dying patients months before federal approval. And most important, they would help Merck pressure the government to speed drugs through the approval process. The suits and ties had met the jeans and earrings: They were still wary of each other, but they had shown they could work toward a common goal.

The failure of the dog trial was a major setback. A new chemical had to be found, but Merck scientists had exhausted the 200 protease inhibitors on its shelves.

Working weekends and nights, they started testing chemicals at random. They tried tens of thousands, but none worked. So they started creating their own chemicals.

They tacked atoms to the ends of a central carbon lynchpin, broke chemical bonds, rearranged and shuffled. They built 3,000 such compounds, they invented matter.

They analyzed published formulas of Hoffmann-La Roche’s protease drug, studying a particular pattern of atoms. It gave them an idea about how to improve their own compound. From this would ultimately come Crixivan, the drug approved last week by the Food and Drug Administration.

Merck worked on the problem 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 Paul Reider, the scientist in charge of producing it.

A French and Chinese gourmet chef, Reider said it was like cooking an intricate, multicourse meal - for 1,000 people. If you wrote the “recipe” for Crixivan, he said, 14 steps in all, each step would cover 60 pages.

§

Needing large quantities of the drug for human trials, Merck started producing it in its Rahway, N.J., research factory. The large building is filled with stainless steel and pipes and gauges and 20-foot-high vats that go buh-buh-buh-buh-WH-Whoosh! as they mix frothing, yellowish-green liquids.

It took a year to make just over 100 pounds of the stuff, enough for only 50 patients.

The human trials began in February 1993.

In Philadelphia and Birmingham, Ala., more than 70 people agreed to swallow a small white capsule containing a chemical that had never before been given to man.

Some were desperate. They had tried many other AIDS medications and nothing had worked. Merck’s experimental protease inhibitor was their last chance.

Others were idealistic. They knew that AIDS research could not progress unless somebody agreed to be a test subject.

As they arrived at a small nursing station on the sixth floor of the Medical Office Building at Thomas Jefferson University, the test volunteers were first given a medical exam, then a supply of the experimental drug.

Each day, they filled out a diary to describe how they were feeling. Nurses drew blood samples at regular intervals as part of the carefully controlled studies.

The studies would determine whether the drug was safe, not whether it would work. That would come later.

First the capsules were given to healthy volunteers, people who did not have HIV. When no ill effects were seen, the drug was given to those infected with the AIDS virus.

After three months, the results were clear: Crixivan was safe and easily absorbed through the digestive tract.

By June, Merck was ready to conduct a small pilot study among 10 AIDS patients to see whether the drug would have any effect on the virus itself.

Eight patients were given Crixivan. Two others got only AZT, then the standard treatment. One of the volunteers was Patient X, a man who would come to play an important role in the development of the drug.

The results at 12 days looked so good that Merck decided to launch a longer and larger trial, one involving 60 patients.

Soon rumors spread through the research community that Merck was onto something big. But the details weren’t known until Dec. 15, 1993.

That’s when Hedy Teppler, an AIDS doctor who ran the trials at Jefferson, addressed the First National Conference on Human Retroviruses and Related Infections.

Scores of scientists and activists crowded into the Maryland Suite of the Washington Sheraton Hotel and watched as Teppler, a rising star at Jefferson, stepped to the podium.

Flashing graphs and numbers across a screen, Teppler said patients getting the Merck drug had a 42 percent drop in HIV after two days of treatment. The drop for the two AZT patients was less than one percent.

The patients on AZT gained ground. By day 12, there was a 58 percent drop in virus for AZT patients compared to 70 percent for those on the protease inhibitor.

One statistic was particularly interesting: The virus had dropped to undetectable levels in three patients on the protease inhibitor.

The audience greeted the data cautiously. The history of AIDS research was littered with drugs that looked promising at first, only to fail later.

Teppler was excited by what she was seeing among her patients. Some still had no detectable virus at three months. They were gaining weight, their immune systems seemed to be recovering, and they said they felt better.

As her train headed north to Philadelphia, Teppler mused that something important might be happening. This, she thought, might be the start of a new era.

§

Back at Merck, the core group of scientists working on the protease project could hardly contain themselves. A test far more sensitive than the one used in the 12-day study hadn’t detected any virus in a growing number of patients now on the drug.

“We were beside ourselves,” said Edward M. Scolnick, the company’s top scientist who heads Merck’s drug-research program. “We thought we had the cure for AIDS.”

For Linda Grinberg, the cure for AIDS was far away.

Her doctors kept telling her she was going to die, but she wouldn’t listen. Grinberg wanted to learn everything she could about AIDS. She decided to use her money to fund AIDS research. What use was money if you were dead?

So much of her life, she realized, had been spent deferring dreams, deferring good deeds.

Now there was so little time to act. She set up the Linda Grinberg Foundation. It would fund small AIDS research projects, the kind that big corporations like Merck would never consider.

A few weeks after the Washington meeting, record-breaking cold and ice brought the Philadelphia area to a virtual standstill.

Roads were closed. Power lines were out. The offices of tens of thousands of workers who never made it to their jobs were empty.

But late on the afternoon of Jan. 27, inside Building 16 at Merck’s Montgomery County campus, Jon Condra, a molecular biologist and senior researcher, sat before his Macintosh computer, studying samples of the virus from people in the Crixivan trials.

He was looking for something that Merck scientists did not want to see - signs that the virus had mutated and developed resistance to the drug. The signs would first appear as changes in the virus’ genetic code, its RNA.

Resistance had been the major problem with all AIDS drugs. At first, the drugs worked; but soon, sometimes within days, the virus mutated, making the drugs ineffective. It was Darwinian evolution, pure and simple.

Condra knew that resistance to the Merck drug was probably inevitable, but hoped it would take a long time.

Staring at his computer on this cold day, Condra saw something that dismayed him. Small blue letters had appeared on the screen, indicating the virus had made five changes in its genetic material, RNA. It was beginning to mutate and build resistance to the drug.

Was this the beginning of the end?, Condra wondered, as he picked up the phone to call his boss, Emilio Emini, Merck’s top virologist.

“We’ve got at least one patient with genetic changes in protease,” Condra said. “It’s got to be resistance.”

“It can’t be,” Emini replied.

“You want to bet? It is.”

Icebound at his home in Paoli, Emini called up the data on his computer. Sure enough, the patient’s RNA levels were rising.

Emini phoned Merck’s chief scientist, Edward Scolnick, who was at home eating dinner with his wife.

Scolnick was incredulous. How could this be? Another test indicated the virus hadn’t developed resistance.

Scolnick hung up. But he was too upset to finish his meal. He called an old friend from his days at the National Institutes of Health.

It was Anthony S. Fauci, head of the government’s AIDS research program. He was a first-rate scientist and knew as much as anyone about HIV.

Fauci listened intently to the data.

“You have resistance,” he said.

Scolnick protested, pointing to the conflicting data.

“I don’t care,” Fauci said. “You have resistance.”

Depression swept through Merck as the resistance problem grew. What had been seen in one patient was turning into a trend.

Three years of work - biology, chemistry, manufacturing and clinical trials - had gone into this drug. Millions of dollars had been spent, and now some wondered if it had been a waste.

The scientists looked for data that would give them hope.

Despite the rising RNA, patients continued to gain infection-fighting white blood cells, which are the favorite target of HIV. When resistance had set in with other drugs, these cells had dropped.

And Patient X, the scientists noted, was still doing well.

His virus dropped to undetectable levels soon after he began treatment in 1993. Now six months later, still no virus could be found.

Merck’s fiscal experts weren’t so impressed by these hopeful signs. They suggested that the firm cut its losses and abandon the drug in favor of a back-up protease inhibitor about to be tested.

AIDS activists who read media accounts of the resistance problem were afraid it might prompt Merck to abandon AIDS research altogether.

Fearing that negative publicity would hurt AIDS research, several activists on Merck’s community advisory board counseled the company not to be so open about its failures.

“We were very concerned the company might pull out,” said Martin Delaney, an AIDS activist in San Francisco. “We thought they were obsessed with a home-run drug.”

§

Emilio Emini, a world-class virologist, had never confronted a virus as wily as the HIV.

A tall man who talked almost as fast as his computer could calculate, Emini was fond of saying that Charles Darwin couldn’t have invented an organism to better illustrate his theory about survival of the fittest.

No matter what God or science throws at it, the AIDS virus finds a way to survive by mutating.

Reproducing extremely rapidly once inside human cells, the virus has millions of different forms even in one individual.

So far, the trouble with every AIDS drug had been that it didn’t kill every virus in the patient’s body. A few resistant viruses survived treatment, multiplied and repopulated the patient with a strain that is impervious to further treatment.

What was needed, Emini speculated, was treatment so intensive that not a single virus survives. He was convinced that the failed drug could do this if the dose were increased.

“You’ve just got to take a stake, drive it to the heart [of the virus] and pin it to the floor,” Emini said.

The Merck scientists huddled. They knew that increasing the dose might make the drug toxic. But their studies had shown that patients could withstand significantly higher doses.

They would take the risk: They would boost the dose by 50 percent.

Seven years of research and hundreds of millions of dollars would ride on the result.

§ § §

PART II

MARCH 18, 1996; Page A01

A NEW DRUG IN THE RACE WITH DEATH

RESEARCHERS AT MERCK & CO. WERE CLOSING IN ON A NEW MEDICINE, BUT AIDS PATIENTS WERE DYING DAILY. A GROUP OF ACTIVISTS FELT THEY HAD NO TIME TO WAIT. SO THEY STOLE THE FORMULA.

By Huntly Collins and Shankar Vedantam

The dying keep time differently.

Patience is the luxury of the living, and in the summer of 1994, five AIDS activists grew impatient.

A giant pharmaceutical company had developed a powerful new AIDS drug and was testing it to see whether it would work.

But even if researchers at Merck & Co. proved that their experimental drug could hobble the AIDS virus, it would take years to complete safety tests and get government approval.

That was too long for people who measure life expectancy in months. So that summer, the five thought of a way to get the drug sooner.

They would steal it.

They wrote checks totaling a quarter of a million dollars. They decided to find Merck’s manufacturing secrets and make the drug themselves.

If that meant flouting the law and disregarding the government’s safety regulations, these people felt they had no choice. If it meant making a drug that might be defective, even dangerous, they shrugged: The dying must take their chances.

§

Just weeks earlier, researchers at Merck in Whitehouse Station, N.J., one of the world’s largest pharmaceutical companies, had decided on a new tack to fight the AIDS virus.

It was in a race against two other companies - Hoffmann-La Roche of Nutley, N.J., and Abbott Laboratories near Chicago - to make the drug.

Merck’s promising experimental drug - indinavir or Crixivan - had shown that it could hammer the virus down in infected people. The problem was that some virus was surviving the assault, mutating and growing.

Scientists hoped that they could overcome this problem of resistance by hitting the virus with a lot more medicine.

They had kept the dosage low in the first trial to be safe, but animals tolerated far higher doses than the volunteers were given, so the Merck scientists decided it would be safe to increase the dose.

They gave volunteers the higher dose, waited and then checked the number of viruses circulating in the blood. The number dropped precipitously, just as it had with the lower dose.

The question was whether the viruses would rebound once the few that survived had a chance to mutate and multiply. There were no serious ill effects.

More time passed, and the scientists checked the viral load. It remained low. The patients were faring much better than those on a lower dose in an earlier trial that failed.

§

Underground drugs had been a hallmark of the AIDS epidemic.

Almost every drug breakthrough had been studied in basements or secret labs by trained AIDS activists, or professional chemists on the payroll of activists. Drugs were fashioned for dying patients many months before the Food and Drug Administration approved them.

The five activists who planned to manufacture the new Merck drug knew that no Watergate-type burglaries would be needed to get the company’s classified data.

Drug companies publish many aspects of their research to ward off patent threats later, often in obscure foreign journals not easily read by competitors.

Knowing this, the activists passed the word on the international AIDS grapevine. They wanted any technical information on the Merck drug, no matter where it was published or how unimportant it appeared.

The drug was called a protease inhibitor. It stymied HIV’s ability to reproduce by inhibiting a crucial viral chemical called protease.

Activists trained in science attended lectures given by Merck officials, hoping to glean details Merck was trying to keep secret.

They hired world-class chemists to study information being collected by their comrades. And through the vast network of AIDS patients, they obtained capsules of the experimental drug for their chemists to analyze.

§

Atlanta activist Tom Blount was desperate to get Merck’s drug. Jim, his lover, was dying.

One way was to enroll Jim in one of the company’s clinical trials. But Jim could not qualify for any of them. He was growing so weak that he could not move from his bed. Blount could feel him slipping away.

So he used his contacts around the country to get some of the drug. He begged, argued, bartered. He asked test subjects if they could spare a couple of capsules, or if they knew someone who had died, leaving extra drug in a medicine cabinet.

Through his persistence, Blount was able to get a little. On Jan. 11, 1995, he propped Jim up in bed and fed him the first capsule from his small stash.

The drug would run out in two weeks.

Then he took a plane to New Jersey. He was due that day at Merck’s Rahway plant for a conference with Paul Reider, who was making the drug for Merck’s trials, and Jules Levin, a Brooklyn activist.

The activists wanted Merck to set up a compassionate-use program to provide the drug free to patients who would otherwise die before it was approved. These patients wanted to try each new medicine even before the scientists knew whether it was effective and free of dangerous side effects.

One of Blount’s friends, a Los Angeles activist named Linda Grinberg, used to point out there was no side effect worse than death.

Reider, a Merck vice president, listened to their plea but said his production facilities were running full blast just to make enough drug for patients in the clinical trials.

There was none to spare.

Even a consultant that Blount and Levin had brought with them agreed with Reider.

Sitting across from Reider, Blount thought of Jim and their two-week supply of drug. It wasn’t enough. His anger grew. Jim had to keep taking the medicine or he could become resistant to further treatment.

Jim was dying. Dying. Overcome with emotion, Blount got up and left the room. Levin wanted to leave, too, wanted to give up, but he willed himself to stay.

Reider was shaken. He had led an insulated life, safe and genteel in suburban New Jersey. Until that meeting, the AIDS epidemic only meant the deaths of some artists he admired. It meant nothing personally.

But he felt a connection to these men.

Levin and Reider had been undergrads at New York University, although they didn’t know each other then - Reider was the hippie protesting the Vietnam War and never talked to business-school types like Levin. Now he was the corporate guy and Levin was in jeans, staring him down.

When Blount reentered the room, Reider said maybe he could get the drug for 400 extra people, so few that he said he had been ashamed to suggest it.

Blount stared at him. Ashamed to save 400 people? Let 400 people die? That was like letting a fully loaded 747 crash. Four hundred people weren’t just a number, they were faces, people with friends, lovers. They were 400 Jims.

Reider listened. He didn’t make a definite offer, but that night he couldn’t sleep.

After only two days on the drug, Blount’s lover, Jim, got out of bed for the first time in months and began planning the rest of his life. He hoped he would keep getting the drug.

§

The data from the high-dose trials seemed positive by the beginning of 1995. Going to the higher dose appeared to solve the problem of resistance.

Merck officials now considered moving on to the final human testing - a Phase III trial - and plans for full-scale production.

Besides the new data, there was Patient X. He had been on the experimental drug for more than a year, and his virus had dropped to undetectable levels.

Still, going to Phase III was a tough decision. It meant making enough drug for several thousand people worldwide and working out the logistics of getting it to them. Hundreds of millions of dollars would be required to construct new factories to manufacture the drug.

There were still questions about the drug. The tests so far had studied small groups of people for short periods. No one knew how long it would remain effective.

What was happening to Patient X was wonderful, so wonderful that Edward M. Scolnick, Merck’s top scientist who oversaw all drug research at the company, checked his status every month. But he was only one patient.

Scolnick took the argument for a Phase III trial to Merck’s chief executive officer, Raymond Gilmartin, who was trained in engineering and business, not biology.

Go ahead, Gilmartin said. But if this didn’t work, Merck would cut its losses and drop the drug.

Trial sites for more than 4,800 patients were set up in 11 countries - the United States, Canada, Brazil, France, Germany, Spain, Switzerland, Belgium, Italy, the Netherlands and Australia. More than 200 doctors, nurses and technicians were picked to conduct the trials.

The company would have to supply every AIDS patient with about a kilogram of drug - more than two pounds - a year, 100 times the average drug.

Reider launched plans to retrofit Merck plants in Elkton, Va., and in Flint River, Ga., to produce 220,000 to 1.1 million pounds per year, depending on demand.

In Virginia, new roads had to be laid for trucks bringing in raw materials and carrying capsules out. In Georgia, Reider had to beg for construction workers because most were in Atlanta, building for the Olympics.

As he rushed from place to place, hurrying the project along and giving talks about the drug, Reider began to have the strangest feeling: He could swear he was being followed.

He kept seeing the same faces in the audience. Once, a man stood up after a speech and asked:

“Do you know the temperature is hard to control in the final step?”

Reider stared at him. How could the man have known? Did this have anything to do with rumors that someone was trying to make the drug?

“Yes,” Reider said slowly, “I noticed.”

During a speech at Harvard University, Reider saw another man in jeans and T-shirt sitting in the front row, scribbling furiously. At dinner with the dons afterward, Reider asked whether the man was a student.

They assured him he wasn’t. The front row is reserved for Nobel laureates and senior professors. No student would dare to venture there.

§

When the National Task Force on AIDS Drug Development met in February 1995 to discuss protease inhibitors, Jules Levin turned up the heat.

He knew Merck would be at the meeting. So would the press. It would be a perfect platform to nail Merck on compassionate use.

He made sure his friend from Los Angeles, Linda Grinberg, a woman with sharp features and watchful eyes, would attend. She was an articulate speaker, engaging and direct.

Together they would break the stereotypes about AIDS. Linda was white, middle-class and got AIDS from her husband. Levin was heterosexual, a businessman and got AIDS from sharing intravenous needles.

The meeting was held around a horseshoe-shaped table in a suburban Washington hotel. FDA Commissioner David Kessler sat in the middle of the horseshoe and Scolnick, in his dark suit, chaired the meeting.

The companies presented their data. Then the public got its turn. Grinberg went to the microphone.

“My name is Linda Grinberg and I come here before you, out of the shadows, to plead for my life and the lives of thousands of others,” she told them. “You have the power to decide my fate, to add seconds, minutes, days and possibly years to my life.”

The room was deadly quiet.

Scolnick, a tall, slender man more comfortable with facts than emotion, listened.

At the end, he turned to his Merck colleagues, “We’ve got to see if we can do something.”

§

When the Merck people returned to their offices, voice-mail messages started flying around the corporation’s vast domain.

Could they possibly come up with enough drug for compassionate use? For how many people? For how long? Would there be enough left for the major expansion into the worldwide trials? Reider crunched his numbers.

Linda Distlerath, in Merck’s public-relations office, was deluged with more than 3,000 preprinted postcards demanding a compassionate-use program. They came from as far as Japan and as near as Newark.

Most also carried scribbled notes.

“This is a very personal issue for me,” wrote one.

“Please! I know too many who will die within the year’s wait,” said another.

In San Francisco, an AIDS treatment group published an open letter to Merck, demanding that the company provide the drug to at least 3,000 people with advanced AIDS.

Merck was inundated with thousands of facsimile copies of the letter - so many that it installed a new fax line and put the machine in its own room.

Although the company was now committed to a compassionate-use program, it hadn’t decided how large it would be.

Finally, Merck made an offer. One thousand patients.

Not enough, the activists working with Merck said.

The Merck people huddled. Fourteen hundred. And that’s the final offer, said Scolnick.

Deal.

§

Details of the compassionate-use program were ironed out with a small group of activists, drawn from the company’s community advisory board, shortly afterward at Merck’s bucolic research farm in Branchburg, N.J.

After much debate, they decided the best way to select patients was through a lottery.

More than 140,000 letters would be sent to doctors across the United States - anyone whom the company could identify as having the potential to treat AIDS patients.

An 800-number would be set up for AIDS patients to register and get registration forms, which had to be signed by their doctors certifying their condition. Each applicant would be assigned a number.

One hundred phone operators were put through sensitivity training about AIDS.

Phone registration went on seven days a week from 8 a.m. to 11 p.m. for a month. When it ended on Aug. 11, more than 11,100 people had applied for a program with only 1,100 slots.

Merck added 300 others to an ongoing trial.

To select the winners, Merck hired an outside auditing firm, which used a computer to generate a random listing of numbers. The first 1,100 names on the list received a first-class letter mailed in a plain white envelope without the Merck name.

One of the people who got the letter was Jim, Tom Blount’s lover. It was Aug. 18. He died two days later. Blount said Jim had started the drug too late to help him.

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The underground laboratory was successful in making the drug, but it took longer than expected.

One of the five investors said it was the hardest drug that activists had ever attempted to make.

The plan had been to make a year’s supply of the drug for 10,000 patients by Jan. 1, 1995. The activists estimated that they would have a year to sell the drug before the legal version hit the market.

It wasn’t until July 1995 that they figured out how to make it. And Merck was moving fast.

They had to decide whether to go ahead. They knew once Merck got on the market, patients would rather buy the legal drug, leaving the activists with millions of dollars worth of unsold medicine.

They debated. They had commitments for more than $300,000 from dying patients, one of the original five said. It was a hard decision.

They would not go ahead.

“It failed for economic reasons,” the activist said. “By the time we were ready, we knew Merck would do it before us.”

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Hoffmann-La Roche’s drug saquinavir, trade name Invirase, had beaten Merck to the market. And when Abbott Labs beat Merck in applying for FDA approval in late December, Merck feared that it might lose the protease drug race altogether.

Still, Merck scientists consoled themselves, even if they got to the market last, they felt they had the best drug. And the corporation would decide to price the drug significantly below the competition. Saquinavir cost $6,900 a year. (Abbott would turn out to cost $7,500 and Merck’s drug would cost around $5,000.)

But even then, Merck’s scientific breakthrough would prove beyond the reach of many poor people in the United States and virtually all the AIDS patients in the Third World. Ninety-five percent of the more than 17 million infected people worldwide live in these poor countries.

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The Third National Conference on Human Retroviruses and Related Infections, the nation’s premier forum for AIDS research, opened on Jan. 29.

Hundreds of the country’s leading AIDS researchers, doctors and activists packed the ballroom of the Washington Sheraton Hotel. People were lining the walls, jamming the aisles, sitting on the floor.

An optimism not often found at AIDS meetings filled the air as Emilio Emini, Merck’s chief virologist, launched a “state-of-the-art” session on protease inhibitors. Word was out that exciting things would be discussed.

Emini started with a review of the science of HIV protease and went over the work of Abbott, Hoffmann-La Roche and several smaller companies trying to catch up.

Then he came to Merck.

Used by itself, the Merck drug cut the viral load to undetectable levels in about 40 percent of patients, he said.

More powerful data were then presented about the effect of the drug when used in combination with AZT and ddI, a chemical cousin.

Finally, he dropped the blockbuster. He explained what happened when the Merck drug, Crixivan, was used in combination with AZT and a related drug, 3TC.

After six months on the triple combination, almost 90 percent of AIDS patients had undetectable levels of virus. The combination was achieving more than a 100-fold drop in the virus.

It was the strongest data anyone had ever seen in the 15-year history of the AIDS epidemic.

As the new data appeared on the screen, Anthony S. Fauci, the government’s leading AIDS researcher who was sitting in the front row, elbowed Levin, the activist.

“Isn’t that fantastic!” Fauci, director of the National Institute of Allergies and Infectious Disease, said.

The idea behind the triple combination was to hammer the virus with a one-two punch. The AZT drugs would hit viruses entering human cells and Crixivan would hit viruses leaving the cells.

This would make it much harder for the virus to mutate its way around the drugs.

But even though Crixivan could drive viral loads to undetectable levels in a large proportion of patients, scientists wondered if it was good enough. If a few resistant viruses survived, they would eventually multiply and overwhelm the immune system. The question no one could answer was, how long would that take?

In a six-month study of 1,090 patients, Abbott showed that its protease inhibitor - called ritonavir or Norvir - reduced the incidence of secondary infections and cut the mortality rate in half. This was the first evidence that a protease inhibitor could extend lives.

But Abbott’s study also showed that after about five months, the viral RNA levels began to rise, suggesting that the virus was beginning to mutate.

In addition, Abbott’s compound interfered with many of the other drugs that AIDS patients needed to fight secondary infections.

Merck’s drug, too, had some side effects, but they were less serious - kidney stones in about 3 percent of patients.

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Jules Levin looked straight into the television camera and hailed the new era in AIDS treatment: “Many of us have been waiting for this day to come. This is the best wave of optimism we’ve had yet.”

It was Feb. 24 and Levin was among a panel of experts, most of them doctors, talking about the new protease drugs to AIDS patients gathered in 10 cities for an interactive video conference.

In Philadelphia, 80 people came to Graduate Hospital that Saturday, the first warm day of a long winter, to watch the proceedings on a huge screen in the basement auditorium. One man arrived pushing his portable IV pole.

The patients talked about their treatment in the years ahead, not the months.

The doctors talked about new treatment options, a mix-and-match smorgasbord where, if one drug combination didn’t work, another might. Never before had there been such choices.

Norma E. Muurahainen, an AIDS doctor at Graduate, fielded questions.

Should you start taking the drugs early in the course of infection or save them for later? What was the best drug to start with? What were the best combinations? What about cross-resistance between the drugs? What were the comparative side effects of the compounds? Were the drugs any less powerful for those who’d already been on AZT compared to those who hadn’t?

No one had the answers. Said Muurahainen: “Treatment chaos has started.”

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On March 1, the Food and Drug Administration approved Abbott’s drug.

The same day, the FDA’s scientific advisory panel recommended approval of Merck’s drug.

The recommendation came after Linda Grinberg, who had begged for a compassionate-use program a year earlier, addressed the panel.

Now, Grinberg had been on the drug for many months.

“One year ago, I came before you, in failing health, to plead for my life and the lives of countless others in late-stage disease.

“Today, I come before you with renewed energy . . . to implore you once again to approve this drug.”

A week later, Ginsberg’s doctor told her that her immune system was doing better than ever. But there were signs the virus was creeping back.

Last Thursday, the FDA approved Crixivan. It was the fastest drug approval in the agency’s history.

Scientists are still unable to detect any virus in Patient X. He has been on the drug for more than two years.

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