PROFITING OFF THE FAT OF THE LAND

 

November 8, 1996

 

In April, the Food and Drug Administration approved a new diet pill for the first time since the disastrous era of Dexedrine three decades ago.  With obesity at epidemic levels in America, the agency vouched that this medicine, called Redux, is safe and effective for as long as a year when combined with exercise and calorie-cutting.  Sales are forecasted to top $600 million annually, making Redux a blockbuster in the mega-billion-dollar diet business.

Already there have been widely publicized reports of dangerous side effects from taking the drug.  What the eager public has not been told is how FDA scientific advisers voted to ban Redux a year ago because of fears that are still unresolved.  Obesity is a serious threat to health, but is Redux worth the risk?

 

Unlike Redux, the basic facts about obesity are not controversial.  Except for those few Arnold Schwartzeneggers among us who put on weight by developing mountainous muscles, obesity is defined as being 20 percent or more over the ideal indicated by standardized height-weight tables.  An astonishing one-third of American adults and a fifth of the nation’s children are afflicted.  For certain groups, such as middle-aged African American women, the problem hits 60 percent.  National life expectancy could be raised by at least seven years if all these people came down to their ideal weight.  By comparison, a cancer preventive would add only two to three years.  According to the federal Institute of Medicine, the health care costs of obesity and associated chronic illnesses like high blood pressure and diabetes exceed $70 billion a year.  Add to that figure the more than $33 billion spent annually on diet products or regimens of precious little scientific worth and the value of a possible Wunderbullet is clear.  In this regard, little has changed since irrational thyroid-digitalis concoctions were dispensed in the pre-FDA era before World War II.

In general, scientists now know what factors contribute to being fat, but they do not understand how.  Heredity plays a basic role.  “The central disorder in obesity is a genetic susceptibility among those who grow up in enormous abundance, freedom from infection, and inactivity,” says Jules Hirsch, physician-in-chief at Rockefeller University.  Most of human evolution occurred under conditions of scarcity, when individuals who were better at storing fat were more likely to live long enough to reproduce.  (In the few hunter-gatherer societies that have come under modern scientific scrutiny, obesity is nonexistent.)  Today, especially in Western nations of plenitude, their descendants are stuck with genes that make them chronically overweight.  Obesity is often called “the first disease of modernization.”

Research during  the past decade suggests that everyone is born with a “set point”—a natural weight level that the body automatically tries to maintain.  You can add or subtract pounds from your personal set point by consuming more or fewer calories than you expend, but over the long haul you will tend to drift back to where you started, regardless of whether you think that is too fat, too thin, or just right.  Hence dieting’s most familiar agony: “keeping it off.”

But there are also powerful social and psychological elements at work, particularly among women, that scramble this Darwinian picture.  For example, women of lower socioeconomic status are more than twice as likely to be fat as those in upper strata. Yet there is no significant difference between African American and Caucasian men at any level.  Such complexities have led experts to recommend programs that combine diet and lifestyle changes for the 99 percent of obese people who are less than twice as heavy as their ideal weight.  (Severe obesity beyond the 2-times range is uncommon, sometimes requiring drastic procedures such as jaw wiring, intestinal bypass, and stomach stapling.)

Though these treatments have improved over the years, none will reliably sustain weight loss.  The prognosis for obesity therefore remains grim.  It tends to get worse if nothing is done, but trying hard to lose weight often causes different problems, such as anxiety and depression.

“We’re not economically or intellectually set up to deal with this,” Dr. Hirsch observes about both the medical establishment and the body-conscious public.

 

It is against this gloomy backdrop that new appetite-suppressant drugs are roaring onto the market.  Chief among them so far is the combination called fen-phen, which is short for dosage of the depressant fenfluramine (sold as Pondamin) and the stimulant phentermine (Ionamin, Fastin, or other brand names).  Fenfluramine affects the flow of the brain chemical serotonin that figures in the transmission of signals from one brain cell to another.  It is a molecular cousin of fluoxetine, a.k.a. Prosac, which has a less pronounced ability to cut appetites.  Fenfluramine helps some people stay on their diet by enhancing feelings of fullness and having eaten enough, thus decreasing meal size.  Phentermine is a potent derivative of amphetamine, still capable of creating enough speedy buzz to earn the street name “bumblebee,” that quickens the burning of calories.  Taken together, they may cancel out some of each other’s undesirable side effects.

Do they work?  Sometimes yes, sometimes no.  Fen-phen users who have lost lots of weight tend to proselytize about their experience.  “Pondamin is wicked good for cravings,” says Susan Gallagher, co-owner of the Be-Lite diet clinic in Largo, Maryland, a suburb of Washington DC.  She should know, having dropped from 208 pounds to 145 after seven months on fen-phen.  Be-Lite is one of many thriving weight-loss franchises of various repute that have popped up around major cities in the past several years, advertising on the radio to legions of commuters and deskbound workers with ever-widening girths.  About 95 percent of the clinic’s two thousand patients are women.

Customers who qualify for medication after an initial “mini physical” are asked to sign a consent form listing possible side effects, such as dry mouth, constipation, dizziness, mood swings, sleep disturbance, hypertension and diarrhea.  The form cites a pivotal four-year human trial of fen-phen sponsored by the National Heart, Lung and Blood Institute (NHLBI), released in 1992, as having turned up “no significant side effects.” In fact, 25 participants out of a total 62—more than 40 percent of the test group that started taking the pills—dropped out of that study prematurely because they could not tolerate the drugs.

“Most people we see are stable after a few weeks,” says Richard Rothman, a drug researcher for the federal government who is also a Be-Lite co-owner, vis à vis side effects.  “All of this is a risk-benefit analysis.” He appends memory glitches such as “word retrieval problems” to the list, but claims they do not occur with fenfluramine any more than with other, similar drugs.  The problems “go away when medication stops,” Dr. Rothman adds.  He estimates that 80 percent of Be-Lite’s patients start out weighing more than 200 pounds, though on the day of a reporter’s visit none of the people (all women) in the waiting room looked more than a bit plump.

Customers usually take the drugs for three to six months, though some may continue as long as a year.  The FDA originally approved fenfluramine in 1973 for only short-term doses (variously interpreted as lasting from a few weeks to three months), but the drug was virtually unused until after the NHLBI study opened the floodgates.  If patients do not make any positive changes in diet or lifestyle while on the pills, they will almost certainly regain after stopping, despite Be-Lite’s bold-print claim in magazine ads for “Permanent Weight Loss!”

Does losing weight by taking drugs have the same beneficial effect as regular exercise on heart disease, diabetes and other health problems associated with obesity?  No one knows for sure.  Fenfluramine is banned by the International Olympic Committee.

Nonetheless, fen-phen clinics have quickly gained a firm foothold in the diet business.  Pondamin is so much in demand that supplies “run out every four months,” according to Gallagher.  Nationwide, new prescriptions (not refills) rocketed from about 64,000 in 1992 to more than half a million in 1995, with 89 percent going to women.

In the face of such popularity, a sizeable faction of influential brain scientists around the country are worried about safety questions.  “Fenfluramine neurotoxicity data have been available for two decades, but are dismissed by the companies,” says George Ricaurte of Johns Hopkins University, who has published several confidence-jolting studies of brain damage in laboratory animals.  In every animal species examined to date, including mice, rats, squirrel monkeys, rhesus monkeys and baboons, injury of serotonin neurons in the central nervous system has occurred.  Strictly speaking, the relevance of this work to humans is unknown, because there have been no studies evaluating the drug’s effect on behavior thought to be related to brain serotonin neurons, such as anxiety, sexual function, cognitive function, mood modulation, and sleep.  Dr. Ricaurte suspects that “the effects are probably subtle in a general population that already has lots of problems.” The most dangerous aspect, he believes, may be the lack of a “clear, obvious warning signal,” such as the addiction that accompanies amphetamines.

“When phentermine is added to fenfluramine, we get increased serotonin neurotoxicity in rats,” says Lewis Seiden of the University of Chicago, another leading researcher.  This brain damage occurs “at doses very close to the effective dose for producing weight loss,” he adds, raising the specter, seconded by Ricaurte, that if you take enough to lose weight, you might be taking enough to sizzle your brain.

In the United States, fenfluramine has always been classified under the Controlled Substances Act.  Though it is not as addictive as amphetamine, at bout three times the recommended dose it may start to produce psychedelic effects like LSD. The fear among some physicians is not so much of abuse as of misuse—there are myriad anecdotes about healthy-weight women getting the drug just to look svelte.

 

The debate has lately turned high-stakes and bitter for an otherwise staid scientific community.  Redux contains dexfenfluramine, a mirror-image twin (technically known as an enantiomer) of the fenfluramine molecule that does not cause fen’s profound drowsiness.  Servier Laboratories, the French pharmaceutical giant that discovered dexfen, has marketed it in Europe since 1985.  But its use as a diet pill is patented by the Massachusetts Institute of Technology and licensed from Servier by a Massachusetts-based company called Interneuron, founded in 1988 by MIT professor Richard Wurtman, a longtime researcher of the relationship between eating and the production of various brain chemicals.

Stepping in as Wurtman’s co-founder was J. Morton Davis, a purveyor of low-grade stocks who took over the old-line D.H. Blair & Co. brokerage in 1973 and turned it into an infamous dynamo for initial public offerings.  Over the years his work has attracted not only risk-loving investors but Securities and Exchange Commission sleuths following up on accusations of stock price manipulation.  Former Blair employees have told the SEC that Davis pressured his brokers not to sell their clients’ holdings in new offerings that were plummeting in value.  The SEC has also explored Davis’s labyrinthine interest in mutual funds that buy Blair-underwritten stocks.  His personal fortune has been reported to be in excess of $250 million, chunks of which have fallen into Republican campaign coffers since the days when his name was found on a list of secret contributors to Richard Nixon during the 1974 Senate Watergate investigations.  “What’s the secret of his success?” Forbes magazine asked in 1985.  “Better you shouldn’t ask.”

Blair & Co. took the largest position in Interneuron based on ownership of more than 11 million shares and warrants.  Nearly 10 million of these are controlled directly by Davis and the rest by his wife, Rozi, or a closed-end investment fund called Engex, of which he is chairman.  Engex has been the subject of repeated SEC regulatory discipline for improper purchases of stocks Blair was underwriting.  About 3 million more Interneuron shares are controlled by Davis’s adult children, sons-in-law (who also happen to be officers of Blair), and other family members or Blair employees.  To boot, Interneuron’s chairman, Lindsay A. Rosenwald, M.D., a former Blair managing director who owns the next biggest block of shares numbered at more than 2.6 million, is married to Davis’s daughter, Rivka.  As long as the market holds faith, these insiders are poised to make hundreds of millions of dollars.

With an accumulated deficit of more than $78 million, due to heavy R&D costs and administrative expenses, Interneuron might have closed down in 1995 without an infusion of about $35 million from private placements of 3.5 million new shares and warrants.  For its role as agent for more than $7 million of this total, an entity known as Paramount Capital Inc. raked in $657,433.  Paramount’s chairman, CEO and sole stockholder is Dr. Rosenwald, who majored in finance before med school.

Professor Wurtman has also done rather well on the faith behind Interneuron and, ultimately, Redux.  Because he holds an equity position in the company (about a million shares), he is not entitled to the customary 50 percent share of total patent royalties earned by MIT from a faculty spin-off.  But he does receive hefty consulting fees for the five days per month of work he devotes to Interneuron affairs–$99,000 in 1994, for example.  In addition, something called the Center for Brain Science and Metabolism Charitable Trust, of which he is the scientific director, got contributions of $93,000, $134,000, and $147,000 from Interneuron in 1993, 1994, and 1995, even as the company’s deficit was snowballing.

Interneuron’s board of directors includes peter Barton Hutt, who served during the Nixon administration as FDA chief counsel, and Alexander Haig Jr., Nixon’s Secretary of State.  Hutt’s value to a shaky company seeking FDA approval for its lead product is obvious, but Haig’s Washington connections are evidently worth much more to corporate strategists.  He gets $10,000 for every board meeting he attends, versus $2000 for Hutt.  He has also been rewarded with more than 200,000 Interneuron shares—about ten times as many as other directors.  Scientists unused to power politics were startled to find the former General glad-handing members of the FDA advisory panel last fall.

Redux’s impressive sales projections are reinforced by the presence of American Home Products as marketer.  Founded in 1926 upon a consolidation of several nostrum manufacturers, AHP is one of the more colorful food and health care conglomerates in American history, well known to Federal Trade Commission investigators for spending millions on deceptive advertising to turn marginal products into household words, notably Preparation H and Anacin.  As the parent of Wyeth-Aherst Laboratories, a $12 billion pharmaceutical producer based in Philadelphia that will churn out Redux, AHP is situated to take a lion’s share of profits if the pill soars as expected.

 

In February 1995, the FDA turned down Interneuron’s “New Drug Application” for Redux, which had been submitted in May 1993.  Despite having been amended seven times, the application was still deemed “inadequate,” especially in regard to the drug’s potential for causing a lethal heart-lung condition known as primary pulmonary hypertension (PPH) and damage to serotonin neurons.  In December 1993, six neuroscientists, including Ricaurte and Seiden, had written to FDA commissioner David Kessler warning about animal experiments performed at Hopkins, Chicago, and Stanford in which dexfen caused brain cell damage at doses “closely approaching those that would be prescribed to humans.”  Their letter was answered in January 1994 by Solomon Sobel, director of the FDA’s Division of Metabolism and Endocrine Drug Products, which was responsible for reviewing Redux.  Sobel wrote that “the cautions raised by you and others are sufficient to warrant more extensive examination.” He also agreed with their suggestion that a special panel of experts should study available data.

This panel was never created.  Moreover, members of the FDA advisory committee on dexfenfluramine—eight outside physicians and researchers, none neuroscientists—who met to vote on approval in September 1995, were uninformed about the brain damage issue.  Among the background papers collected for them by FDA staff on all scientific aspects of dexfen, nothing represented the alarming research that had been brought to Kessler’s and Sobel’s attention.  Nonetheless, after a day of hostile debate between company scientists—including Richard Wurtman, who insisted that dexfen was not neurotoxic at all—and Seiden and Johns Hopkins neuroscientist Mark Molliver—who pressed for human trials based on their concern from animal studies—the committee voted five-to-three that Redux was unsafe for public use.

Fear also arose from new information about PPH.  A Servier-funded study in Europe (primarily France) had found that taking fenfluramine or dexfen increased the odds of contracting PPH, and that risk rose with time on the drugs.

In early October, Seiden and Molliver each wrote to the committee to clarify their worries and send directly the pertinent scientific literature.  Meanwhile, a second meeting was arranged by James Bilstad—a director of drug evaluation for the FDA and Sobel’s superior—expressly for another look at neurotoxicity.  It was held on November 16, which just happened to coincide with the annual Society for Neuroscience convention in San Diego, despite protests from Seiden and Molliver that they and other outside experts would be unable to attend because of prior commitments to the convention.  At the November meeting, after a full-dress attack by Interneuron scientists against the neurotoxicity data, the committee approved Redux by a one-ballot margin, with the chairman voting in opposition.

Curiously, the vote this time around was on a question phrased differently than in September.  At the end of the first meeting, Bilstad had intervened to ask whether Redux could be approved if the drug’s therapeutic value outweighed its safety problems.  He said that he believed there had been “some misunderstanding of the intent of the agency,” that the vote on safety was actually supposed to be a risk-benefit decision.  Because a quorum no longer existed, however, the matter was dropped with an agreement to poll all the members by telephone.

“After that we had further discussions internally,” Bilstad later revealed, wherein the phone poll was nixed in favor of a second meeting.  Under his personal direction, the committee was then told to consider safety and efficacy together, rather than as separate issues.  There was thus no chance for the members to express themselves again about brain damage and PPH, versus whether they thought the drug worked as advertised (a matter of comparatively little disagreement).

“This meeting was somewhat unusual,” admitted Janet Woodcock, Bilstad’s boss in the FDA’s Center for Drug Evaluation and Research, in a letter four months later to Paul Ernsberger, a neuroscientist at Case Western Reserve who had queries Kessler about “irregularities” in the Redux review process.  “We regretted the resulting schedule conflicts for these scientists, but were unable to reschedule the advisory committee meeting with causing excessive delay in reviewing [Redux].”  In fact, according to FDA insiders, the second meeting was highly unusual, with a rescheduling within two months virtually unheard of.  November 16 was the only date acceptable to Interneuron.

“None of us really appreciated how much of an issue neurotoxicity was going to be,” claims Gloria Troendle, Solomon Sobel’s deputy.  She takes responsibility for not including neurotoxicity studies in the background material given to committee members, but says this was inadvertent.

As for holding the second meeting when the most qualified neuroscientists opposed to dexfenfluramine could not be present: “We chose to do it that way,” James Bilstad says.  “Ideally, they would have been there.  They weren’t there, but we didn’t view that as a fatal lesion, by any means, in the process.”

Hopkins’s Mark Molliver recalls being invited to the meeting and told by FDA staff that it would take place on November 17.  He went so far as to reserve a flight back East from the convention that could have enabled him to attend on that date.  A week before the meeting, he says, FDA staff informed him that he was “disinvited” because the 17th was impossible.  Lewis Seiden says that he was never officially invited.

What about the different question for the November vote?  “We continue to learn about the wording of questions,” Bilstad says obliquely.

At the top of the agency sits commissioner Kessler, whose personal experience with obesity consists of having shed 55 pounds through dieting without the help of drugs after he joined the FDA in 1990.  Known as a hands-on manager, he has staked out an historic position against the tobacco industry, but as a Republican appointee of Reagan-Bush vintage has continued to allow the pharmaceutical business great influence within the agency.  He distances himself from the Redux review process, saying that he “only became involved as it became controversial,” that Bilstad “kept me informed” about it “on two or three instances.”  In particular, “they also kept me posted on how they planned on handling the second advisory committee [meeting.”  Overall, “dexfenfluramine was a complicated decision, a hard decision, for the agency—it’s fair to say a close call—and it was made by Bilstad.”  Brain damage?  “Everyone acknowledges the findings, but the implications are unknown.”  PPH?  “Rare, but probably real.”  In the end, the FDA found “comfort” in the twenty years of experience with fenfluramine, since “dexfenfluramine is really not a new drug.”

If Redux was such a hard, close call and not a new drug anyway, why then approve it?  “The issue for me was that the [Redux] data went beyond three-month use and we approved it for longer, for a year,” Kessler says.  Yet the prospect of long-term use was precisely what alarmed many PPH and neurotoxicity experts.

On December 7, 1995, 22 neuroscientists wrote to Solomon Sobel urging the FDA to “forego a final decision on dexfenfluramine until more information is available on its serotonin neurotoxic potential in humans.”

On April 29, 1996, the FDA released Redux for public use.

 

“Unfortunately, dexfenfluramine is more potent at producing both efficacy and neurotoxicity” than fenfluramine, George Ricaurte said recently from his office in Baltimore.  “We shouldn’t be alarmist about brain damage in people—we don’t know that yet, because we just have animal data.  But before the FDA makes a decision, they should know.”

“I think FDA approval of dexfenfluramine is a mistake,” Lewis Seiden now insists.  “I only hope that physicians and patients are in a position to decide that they really need it.”

Even Leo Lutwak, the FDA medical officer for dexfenfluramine, admitted during last fall’s hearings that “to me, [neurotoxicity] remains a wide open question.”

Interneuron’s position is that the same type of case reporting in Europe that turned up PPH has not flagged any neurological syndromes among millions who have taken fenfluramine or dexfen.  “You can call something neurotoxicity until you’re blue in the face,” quipped Richard Wurtman, denying the relevance of animal studies.  Wyeth-Ayerst’s Redux marketing literature uses the term “neurochemical,” instead.  Reflecting the debate even inside the company camp, Theodore Cicero of Washington University’s School of Medicine, who is a consultant for Interneuron and Wyeth, says, “Let’s call it what it is: neurotoxicity.”

Despite Redux’s victory, Wurtman continues to lash out at its critics, faxing—on MIT stationery—all 22 signers of the protest letter last May to denigrate Mark Molliver’s September, 1995, presentation and assure them that “dexfenfluramine, in doses similar to those recommended for obese patients, has zero neurotoxic potential.”

As for PPH, the FDA ordered Wyeth to rewrite Redux’s label to reflect final conclusions from the Servier-funded study published in the New England Journal of Medicine.  Users of dexfen proved to be at least 23 times more likely to develop PPH than non-users.  An editorial in the journal that seemed to mollify this finding sparked an outcry among scientists when both of its authors turned out to have been paid consultants to companies involved with Redux.  One of them, Gerald Faich, had met privately with FDA officials on Interneuron’s behalf between the September and November 1995 advisory committee meetings.

The question of who gets the drug now goes to the heart of the matter.  All the experts agree that it is not for cosmetic slimming.  Yet Prozac was originally approved for cases of severe depression and has become the aspirin of pharmacotherapy.  Although the FDA okayed Redux for patients whose body mass index (a number derived from height and weight—a 5-foot-6 person who weighs 185 has a BMI of 30) is at least 30, or 27 for those with obesity-related conditions such as hypertension and diabetes, doctors and patients will make their own decisions.  Ironically, Redux’s benefits as shown in scientific trials would not be great enough to pass new FDA guidelines for obesity drugs promulgated since Interneuron submitted it for agency review in 1993.

“There’s no way to control who gets it,” Lewis Seiden warns.  “There’s a difference between saving someone’s life and just making them look thinner.”

The medical establishment’s attitude is perhaps best summarized by Louis Aronne, director of the weight-loss clinic at New York Hospital-Cornell Medical Center.  “Should dexfenfluramine be put in the water supply?” he asks.  “No—if you don’t get legislated or sued out of existence, you reach a suitable level of use.”

Since the time of Hippocrates, who advised his fat patients to “sleep on a hard bed and walk naked as long as possible,” obesity has been both a stigma and a killer.  Now the great American epidemic will be accompanied by a great American experiment.