Saturday, February 13, 2016

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.

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Originally published on March 17, 1996.

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.

Inquirer Staff Writers
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