Chicago Tribune (CT) - SUNDAY, April 21, 1996 Edition: CHICAGOLAND FINAL Section: BUSINESS Page: 1 Word Count: 2,055
Chuck Hutchcraft, Tribune Staff Writer.

It may well have been the opportunity of a lifetime--to make significant headway in the battle against AIDS.

Kempf had been working on a class of compounds called renin inhibitors. Renin is an enzyme, or protease, that regulates blood pressure in humans. It also is similar in structure to the HIV protease, another enzyme that plays a critical role in the creation of the AIDS virus.

"So we said, 'Let's apply the knowledge we have of proteases in general and see if we can apply it specifically to the virus and find inhibitors of HIV,' " said Andre G. Pernet, vice president of research and development for North Chicago-based Abbott's pharmaceutical products division.

The result was ritonavir--its commercial name is Norvir--which the federal Food and Drug Administration approved with record speed in March.

It was to be the second of three protease inhibitors approved by the FDA. Saquinavir (Invirase), developed by Hoffman-La Roche Inc., was OKd three months earlier; indinavir (Crixivan), developed by Merck & Co., was also approved in March.

Together, they have put medicine "at the brink" of a major breakthrough in the battle against AIDS, said Gordon Nary, executive director of the Chicago-based International Association of Physicians in AIDS Care.

No one is ready to say a cure is close at hand for the deadly disease that has perplexed medical science for nearly two decades. And more long-term research is needed before anyone can say with certainty that these inhibitors will be instrumental in actually stopping AIDS in its tracks.

Theoretically, Nary said, "there is now reason to believe that many people who now have the HIV virus will be able to live a relatively normal life."

"Right now we know that we can suppress the virus. We don't know for how long," Nary said.

The story of ritonavir is one of thorough scientific detective work. It also is an example of what can happen when a company entrusts its employees with authority so they are not having to continually climb the corporate ladder for permission to do every this and that.

Timing also was a major factor. Abbott brought ritonavir to the FDA as the agency was deciding to step up its approval process, especially for life-saving drugs, such as those involving AIDS, said an agency spokeswoman.

And in the case of Abbott and ritonavir, "everything went right," said Ivy Kupek of the FDA, which approved the new AIDS drug in what was then a record--72 days.The approval for Merck's Crixivan took 42 days.

Nary says ritonavir "will probably be one of the more important drugs in an antiviral cocktail" that may make the breakthrough against AIDS.

That mixture now includes protease inhibitors and existing AIDS drugs that proved so effective in trials of ritonavir.

Abbott and Hoffman-La Roche, in a collaborative effort, are now investigating a combination of ritonavir and saquinavir, which Nary says could be up to 50 times more potent than the three-drug therapy.

But company officials are quick to warn physicians and AIDS patients not to gamble on combining saquinavir and ritonavir until studies determine appropriate dosage.

Nary predicts that by 1997, the standard care for AIDS patients will employ a four-drug therapy, with two protease inhibitors and two AIDS drugs, and sees a six-drug regimen in the next few years that includes another, still-to-be-approved new class of AIDS drugs.

"Most researchers are convinced that we now have the right tools," Nary said. "What we need to know is how to use those tools more effectively."

But although "most researchers and clinicians believe this is an extraordinary advance," they don't yet have the scientific proof to say how long this will keep AIDS patients alive, Nary said.

Until the advent of the protease inhibitors, efforts had been focused on treating opportunistic infections that thrive after the human immune system has been destroyed by the AIDS virus and on prophylactic measures to prevent people from contracting the disease.

There "had not been significant improvement on controlling the virus," Nary said.

That began to change roughly a year ago. Data from clinical trials showed that Abbott's ritonavir, especially in combination with other AIDS drugs, was the first protease inhibitor to demonstrate the ability to increase survival among advanced AIDS patients.

Ritonavir, used in combination with two other AIDS drugs, was able "to completely clear the (AIDS) virus from the blood" of patients, though the virus remains in the tissue, said Abbott's Pernet. The patients on the regimen also registered increased levels of CD4 (white blood cells), which is key to the body's immune system, said Pernet.

The three-drug combination also maintained its effectiveness against attempts by the AIDS virus to mutate and develop a resistance against the treatment.

Abbott officials say the study itself was a "bold effort," in that it was the first to test a drug in patients with advanced states of AIDS.

The effort to develop ritonavir began nine years ago with a pretty strong hunch by the sleuths at Abbott. The company had begun research into renin, the enzyme that regulates blood pressure, in 1982. A few years later, there was published speculation about similarities between that enzyme and the HIV protease.

"We knew the (renin) enzyme, we knew how to . . . design inhibitors that would block the renin enzyme, which is one kind of protease," said Pernet.

He continued: "At that point, we realized that the (AIDS) virus also has protease in it that we could inhibit."

Dan Norbeck, part of whose last name eventually would become part of the commercial name for ritonavir, was a senior project leader of antiviral discovery at Abbott and headed the project from its inception. Dale Kempf, said Norbeck, "was truly instrumental in creating the whole chemical program, both conceptually as well as experimentally."

For Kempf, the project "was a target of high interest to me because of its social relevance and also . . . it was a brand new target that was interesting from a medicinal chemistry standpoint."

It also was "high profile," he said.

As the detective work into the HIV inhibitors progressed, it turned up more clues about the HIV protease, its role in the reproduction of the AIDS virus and the amount of destruction the virus wreaks upon the human body.

"Probably the single most exciting insight that comes out of the protease field in the last year and half, and I would even say in the AIDS field, is that we now understand what is going on," said John Leonard, a divisional vice president and head of the antiviral venture at Abbott.

"People believed until about a year and a half ago that AIDS was a largely indolent disease. You couldn't do much about it. It would slowly wear you down," Leonard said.

"Physicians believed that one of the central paradoxes was that there was a small amount of virus in only a small number of cells. It made no sense that the small amount of virus could ultimately ravage the immune system . . . the way it did."

That is not the case.

Leonard likens the virus to a fire that burns cells as fast as the body can make them. "We estimate that a billion to 10 billion cells are consumed every day, and that a similar number of viruses are actually being made every day," Leonard said.

When the virus enters a cell it creates enzymes and long chains of proteins, the tools it needs to reproduce. The long chains of proteins enter the enzymes, or proteases, which then cut the proteins, making new viruses that go on to infect more cells.

The trick for Norbeck, Kempf and the rest of the Abbott sleuths, was to create a molecule that would act as a Trojan horse, entering the HIV protease and keeping it from cutting the strands of HIV protein. To do that, the inhibitor molecule had to fit the unique shape of the HIV protease exactly.

The molecule also had to have strong drug-like qualities: It had to be effectively absorbed into the blood stream and it had to stay there long enough to be effective.

"I had enough background to know some strategies that could be used for designing novel compounds," said Kempf. He also knew there were "chemists all over the world" trying to do the same thing, "so I tended to steer away from the obvious strategies and go for some less obvious ones."

Using computer-assisted design technology as well as basic laboratory bench work, Kempf and his colleagues "literally made hundreds and hundreds of compounds," Kempf said.

"There was exploratory stuff going on all over the place," Leonard said. "No one knows today what's going to be a drug 10 years from now, but if we don't explore a wide range of possibilities, the possible set of drugs we have 10 years from now will be much smaller than if we cast our net as widely as possible."

Still, there were moments of doubt.

"Think about it," Leonard said, "you're in Dale's chemistry lab and you've made the 1,000th protease inhibitor and nothing's gone into people and you don't know if you are going to have one that is going into people in the next 500 compounds you make."

But the support within the company remained, and by 1991 the major step of studying a protease inhibitor in humans was drawing near.

The next year, a compound coded A (for Abbott)-84538 was selected for development along with two other compounds, and given the generic name ABT538-ritonavir.

In July 1993, Abbott stopped clinical trials of a compound that was administered intravenously but made a poor showing in tests. The same month, Abbott began Phase I of ritonavir, determining dosage levels in animal studies.

Studies of a second compound, this one administered orally, were stopped in December of that year, after it also failed to show any effectiveness against the AIDS virus.

In January 1994--14 months after the first compound had entered human trials--tests with ritonavir were begun in Amsterdam. Pernet credits the fast turnaround to "a very entrepreneurial team that reacts to things rapidly" with "no bureaucracy to slow them down." That team, which had started with 20 to 30 members, would grow at times to 250.

Eventually investigations would be conducted with more than 1,000 AIDS patients in 67 medical centers in Australia, Europe and the United States, Leonard said. Abbott researchers visited each site every two to four weeks, generating 250,000 pages of documents over two months. Abbott would send a total of 400,000 pages to the FDA for its perusal.

Abbott's internal goal, said Pernet, was to win FDA approval of ritonavir by Dec. 25, 1995.

The results from ritonavir were promising from the start.

The next concern then became how to maintain a sustained response against the virus as it developed a resistance to the inhibitor. Success was achieved by increasing the dosage, but the most dramatic results came when ritonavir was combined with two other AIDS drugs--ddC and ZDV.

With the three-drug combination, patients have been "actually HIV negative in their blood" for six months and counting, Pernet said.

For its part, the FDA virtually became a part of the Abbott team, he said. The agency has "not been anything other than a catalyst for this project getting done efficiently."

CAPTION: PHOTO: Dale Kempf (wearing glasses) and John Leonard at work on the protease inhibitor. For Kempf, the project "was a target of high interest to me because of its social relevance." Tribune photo by Bob Langer.

GRAPHIC (color): A drug that slows the HIV virus In the last four months, the Food and Drug Administration has approved three new AIDS drugs, each of which combats the HIV virus in the same way. Called protease inhibitors, these drugs slow the spread of HIV and work most effectively with other available AIDS drugs.

- How HIV infects the body - Slowing HIV spread by stopping the protease - How the FDA approves new drugs

See microfilm for complete graphic.

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