Star-Ledger Report

Reader's day of reckoning is coming. In April, several highly respected scientists will testify at an advisory panel of the Food and Drug Administration in Washington about studies they have done of animals given the hot new diet drug. They will say the animals suffered brain damage and that the diet drug should not have been approved last year.

The main event, however, will see two scientists who 30 years ago trained at Harvard together one of them the man who developed Redux, the other its chief opponent squaring off against each other.

Riding on the outcome are millions of dollars in sales of the first of the so-called fat pills, the hopes of many obese people and a burgeoning diet industry worth billions.

To the people who manufacture, sell and prescribe Redux, the fat pill is the discovery of the decade, a medical lifeline that will save the overweight from a maze of useless diets. Nearly 2.4 million prescriptions for the medication, which comes in black-and-white capsules, have been written since it came on the market nine months ago, according to market-research company IMS America.

Redux, however, also is one of the most intensely watched drugs in recent history. Not only are its side effects disputed, so is the way in which the FDA approved it, the first diet drug to be approved in nearly a quarter of a century.

"There are a lot of problems with this drug. There are serious questions about it," said Sidney Wolfe, director of Public Citizen Health Group, which unsuccessfully petitioned the Food and Drug Administration to withhold its approval. "And they're not going away. It'll only get worse."

Already, some doctors, including those whose practices depend on weight-loss treatments, said they are tentative about writing Redux prescriptions. While Redux got off to a strong start, the number of prescriptions written is showing signs of slowing, according to IMS America.

Even James Bilstad, the trim FDA scientist who sanctioned the drug's approval, says he wouldn't take Redux. If he had to lose weight, he said in an interview, he'd simply go jogging, something he's done in the past to lose weight. "I wouldn't take it," he said.

But with Americans spending approximately $40 billion annually to lose weight, and millions more invested to develop other diet drugs, a lot hinges on the fate of Redux.

For American Home Products Corp., the Madison drug maker best known for Advil and Primatene Mist, Redux is among the handful of new products it hopes will achieve blockbuster status -- sales of $1 billion or more annually -- and recast its image as a supplier of serious medications. American Home Products' Wyeth-Ayerst unit in Pennsylvania has a deal to market the drug.

"We're putting a lot into it," said Fred Hassan, American Home Products' executive vice president, noting that more than 1,000 sales people were devoted to the launch. A multimillion-dollar, consumer advertising campaign will eventually be rolled out, although promotion activities are blocked in some states because the Drug Enforcement Agency lists Redux as a controlled substance.

American Home Products also is seeking to convince managed-care companies to reimburse clients for Redux. So far, only a small fraction have agreed, according to market researchers Emron Inc. In part, that's because Redux is expensive -- roughly $2.50 a day or more than $900 a year.

American Home Products is positioning Redux as an important tool in fighting diabetes and high blood pressure. "If it's seen as a new diet pill of the month, it probably won't have a very long life. Our goal is to make this a mainstream product," Hassan said.

To reinforce the point, American Home Products spent nearly $2 million between May, when Redux debuted, and September to advertise in medical journals, according to PERQ Research. The company's sales people made about 285,000 visits to doctors through December, according to Scott-Levin Associates, which tracks the drug industry's sales forces.

The rights to Redux are held by a high-flying biotechnology company in Lexington, Mass., known as Interneuron Pharmaceuticals, which was formed by Richard Wurtman, a controversial professor at the Massachusetts Institute of Technology who stands to make a fortune from the diet drug.

Since negative stories began appearing in August, the value of Interneuron stock, which trades on the NASDAQ exchange, has been on a rollercoaster ride. As of Friday, the stock was $29.625 a share, well off its high of $44.50 in June. During that time, Wurtman's holdings, which number more than 915,000 Interneuron shares, dropped more than $13.5 million.

What prompted the plunge was a pair of bombshells. The first one came in August, when published data revealed a higher incidence among people of primary pulmonary hypertension, a fatal lung disease, than was previously known. The findings appeared only four months after approval, embarrassing the FDA and both companies.

A slew of worrisome stories quickly followed, including a cover story in Time magazine, replacing almost universally positive articles about Redux in such widely read publications as Consumer Reports and Reader's Digest.

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The second and potentially more devastating bombshell exploded in September, when several highly respected scientists revealed they had been invited to brief an FDA advisory panel about neurotoxicity. Their research showed extensive brain damage in animals after they were given slightly higher dosages of Redux than are prescribed for humans. Shortly after those findings became public, Redux pulled its advertising in medical journals.

And now the scientists are again preparing to square off. They were supposed to testify on Nov. 8, but have been rescheduled several times. Foes of the drug will each be given five minutes to speak, originally, the FDA promised 20 minutes. The changes have angered several of the scientists, who argue they won't have enough time to make a cogent presentation.

A few also grumble the FDA is more interested in minimizing bad publicity and that it is not really interested in what has been learned. "At this point, I have no idea what the FDA wants from me," said Lewis Seiden, a prominent neuroscientist at the University of Chicago, who pushed the FDA to conduct additional safety tests before Redux was approved. "And you know what? I'm not sure they know themselves."

Interneuron insists the meeting is not unusual in that the FDA had required follow-up studies as a condition of its approval. An FDA spokeswoman agreed. While the panel could recommend that the drug be taken off the market, there is no guarantee that anything will change after the hearing. Recommendations of the advisory panel are not binding, but the FDA usually follows its guidance.

Several scientists who have been following the debate said the hearing is likely to become a showdown between two brilliant scientists whose careers have tracked one another for three decades.

Heavyweight confrontation
In one corner is Wurtman, the MIT scientist who's championed Redux ever since he sat in his Cambridge lab and rejiggered the drug's chemical cousin, which is made by Servier, a French drug maker. MIT filed a patent on the drug, while Wurtman went on to form Interneuron, which holds the U.S. rights and contracted with American Home Products to sell the product here.

In the other corner is Wurtman's nemesis, neuroscientist Mark Molliver, a Boston native who has spent much of his career at Johns Hopkins University in Baltimore.

The two were 1963 classmates at Harvard Medical School They are not friends.

Molliver has spent his career studying the effects of brain hormone-altering drugs on the minds of lab animals. He says he has evidence showing they suffer brain damage after being given slightly higher doses of Redux than humans would receive.

While he comes across as courtly, Molliver is also persistent. He has relentlessly pursued the FDA, accusing the agency of ignoring his offer to use a pioneering brain scanning technique on humans -- developed by a Hopkins colleague -- to test the safety of Redux before it reaches wider use.

Said Wurtman about Molliver, "Some of these scientists are pursuing an agenda They have their own reasons for wanting to scuttle this drug. Their careers may depend on it."

Said Molliver of Wurtman, "He refuses to listen to the facts. And he's misrepresented what. we've presented in a gross manner."

The myriad diet pills now being developed by other companies also have problems.

Knoll Pharmaceuticals in Mt. Olive brags that its Meridia pill doesn't show any traces of neurotoxicity. Yet the drug inexplicably raises blood pressure, which is precisely what a diet drug shouldn't do. Not surprisingly, an FDA panel wouldn't recommend approval at a hearing in September. The FDA, however, more recently said it may approve the drug If Knoll offers further proof of its effectiveness.

Then there's Orlistat, a Hoffmann-La Roche drug that is supposed to leach fat from the body and requires a restricted diet. Unfortunately for the Nutley drug maker, Orlistat closely resembles Procter & Gamble's Olestra, the fat substitute that slips through the body, often taking vital nutrients along with it. Olestra also produces bowel leakage.

Hoffmann-La Roche executives concede their drug does sap some vitamins from the body, but not a "significant portion." There's one other problem -- the company calls it intestinal discomfort. Others describe the problem as flatulence.

Still, nothing generates as much passion as the scientific squabbling about Redux. Known to scientists by its chemical name, dexfenfluramine, Redux works much like its older sister drug, fenfluramine, or Pondimin, which has been on the market since 1973. Pondimin, which is also sold by American Home Products, wasn't widely used until 1992, however.

That year proved to be a turning point. Clinical pharmacologist Michael Weintraub produced a study showing decided weight-loss, some of it profound, in patients using fenfluramine with another drug called phentermine, an amphetamine derivative. The combination is popularly known as fen-phen. Since then, Pondimin has been a hot seller.

The serotonin factor
Redux and Pondimin both affect mood by altering the levels of a powerful brain chemical called serotonin. Although it's not clear how serotonin suppresses appetite, it appears to create a feeling of satisfaction and fullness. American Home Products and Interneuron compare Redux to Prozac, the popular anti- depressant that also manipulates serotonin levels. But these two drugs work very differently, which may explain why concerns about neurotoxicity center on Redux.

Serotonin influences the desire to sleep and eat, but its full effects are far more pervasive: Serotonin also controls the "tone" of life. Within the extremes of the pathologically shy and the grotesquely overbearing are a thousand shades to the personality spectrum modulated by serotonin.

And if the nerve fibers delivering serotonin to the brain burn out from Redux, as they do irreversibly in lab animals, a group of scientists worries what a serotonin deficit could mean for humans. The drug companies point out that 10 million European patients have taken Redux and Pondimin for a decade without reports of devastating effects.

In Europe, however, prescriptions are tightly controlled by specialists who only dispense Redux for three months. A fatal lung disease called primary pulmonary hypertension increases dramatically with use, especially beyond three months. In the United States, critics say, there's evidence that fen-phen and Redux are prescribed by physicians with little expertise in treating obesity. This fuels concern that fatal side effects will increase if there is widespread use.

The FDA approved Redux in April. after a favorable recommendation from an advisory committee. Eight members of the committee, composed of doctors and academics, spent nine hours at a September 1995 hearing arguing over safety concerns raised by several neuroscientists, including Molliver and Seiden. Though invited by FDA staff, the scientists shocked the committee, which hadn't been told anything about the issue beforehand. Officials later said this was due to "an oversight."

First, the group voted 5-to-3 to reject the drug until Interneuron could prove users would not be at risk. But, shortly after that vote was taken, three members left the meeting, which was still going on, for other engagements. Bilstad, the FDA scientist who oversaw the approval process, asked those still there to vote again.

The remaining members voted 3-to-2 in favor of approval, but they did not constitute a quorum. That meant the issue had to be settled at the next meeting, two months later, which coincided with a big conference of neuroscientists. The annual Society for Neuroscience conference is the Woodstock of brain bashes. Molliver said he informed Bilstad and other FDA officials that the neuroscientists had a scheduling conflict, but was told nothing could be done.

At the November 1995 hearing, Interneuron provided a 72-patient study showing that Redux didn't adversely affect mood or sleep or cause depression. Two committee members and one FDA official weren't pleased. Robert Sherwin, a Yale University medical school professor, criticized part of the methodology as "totally inadequate."

At first, it appeared the committee had rejected the drug by a 5-to-4 vote. Then came a shocker. Two members who had left early had submitted "yes" votes, bringing the tally to 6-to-5 in favor of Redux.

Bilstad, the chief FDA physician-scientist responsible for the approval of Redux said in an interview later that he had no regrets. He said he does not believe that neurotoxicity is a central issue and told committee members so. "This is our business. making judgment calls about whether a drug should be approved," he said, noting he has been with the agency 20 years. "Some are very easy and some are more difficult. In this case, I would still make the same decision."

"There was a fair amount of pressure on the FDA to approve this drug," said Robert Kreisberg, a Birmingham. Ala., physician and panel member. "The drug industry had been having a great deal of difficulty getting anti-obesity drugs through the FDA. There was a sense that the drug companies needed an encouraging sign. It was almost like a trial case."

Wurtman works out of MIT's department of brain and cognitive sciences, located on the sixth floor of a brown-brick, industrial style tower at the edge of the Cambridge campus. Spry, energetic and intense, the 58-year-old scientist seems as if he might spring up any moment and scale a mountain. He glows when asked about Redux.

Wurtman and his wife, nutritionist Judith Wurtman, found a connection between serotonin and eating disorders by identifying a chain reaction linking carbohydrate binging and mood elevation. They later found that dexfenfluramine affects appetite and weight. Wurtman wondered whether it might be more potent than,Pondimin, but cause fewer side effects, such as dry mouth, diarrhea and memory problems.

In 1982, after striking a deal with the French company marketing in Europe a product based on the same chemical as Redux, the Wurtmans approached several big drug makers. including Merck & Co., Abbott Laboratories, Warner-Lambert Corp. and American Home Products, seeking backing. Everyone blew them off. "The drug companies were still stuck in the mode of blaming the victim," Wurtman said. "They were looking at obesity as a weakness in will power, not as the disease of the brain that I believe it to be." After six years of trying, the Wurtmans founded Interneuron.

Simultaneously, a group of neuroscientists at Johns Hopkins began investigating the effects of some notorious street drugs, hoping to shed light on brain chemicals, such as serotonin. They were so enmeshed in their own pursuit, it never occurred to them that their path would intersect with the trajectory of the diet industry.

Serotonin and the brain
Molliver is a low-key if integral part of the Hopkins operation. Although very much the picture of a sedate scholar, he is actually a bit of a risk-taker -- he kayaks regularly. He arrived at Hopkins in 1967 to study how the brain controls mood and, 15 years later, was convinced that serotonin was pivotal in mood alterations. He and some colleagues studied Redux and Pondimin to gauge the effects on the brain.

Later, they stumbled across disturbing results in studies conducted on squirrel monkeys, rats and baboons that were given Redux. After two to three days, at doses ranging from just slightly above what is prescribed for humans to 10 times that amount, the nerve endings in the brain shrivel up and splay. The damage is irreversible.

In public testimony before the FDA and in private letters, Molliver has urged regulators to place a warning label on Redux indicating higher doses have been shown to cause brain damage in lab animals.

In humans, the urge to take higher doses may be tempting, since the higher the dose, the more pronounced the weight loss. FDA guidelines spell out dosage levels, but Molliver is worried some patients may be unaware of potential dangers.

George Ricaurte, one of Molliver's colleagues, unsuccessfully urged the FDA to withhold approval until studies show that Redux doesn't cause brain damage in humans. Interneuron officials say the long history and scale of use of the drug in Europe, without any widespread fears or complaints, speaks for itself. The FDA's Bilstad said that even if there were complaints, it would be impossible to investigate the workings within human brains, short of conducting numerous autopsies.

But Ricaurte says he has developed an imaging technique that could measure serotonin by looking inside the brain. He said he informed Bilstad and other FDA officials of the process long before they approved Redux. The technique, perfected on baboon brains, uses a process known as positron emission tomography or PET scans, which can follow the ebb and flow of a substance overtime, assessing biochemical changes in the body.

"The idea is fairly straightforward," Ricaurte said. "Everybody wants to know whether what happens in the brains of lab animals on dexfenfluramine can happen in humans. With this technique, we can know."