WASHINGTON _ A promising new treatment forobesity on Thursday won mixed reviews from an FDAadvisory committee whose members were impressed bythe drug's apparent effectiveness but troubled bylingering safety questions.

The Endocrinologic and Metabolic Drugs AdvisoryCommittee agreed, after almost 10 hours of debate, by amargin of seven-to-one that the drug, dexfenfluraminehydrochloride, appeared to be useful for the treatment ofobesity.

But five of eight members decided that long-term safetyconcerns outweighed their desire to recommend that theFDA approve the drug.

Robert Sherwin, a professor of medicine at YaleUniversity in New Haven, Conn., summed up thesentiments of several committee members when he said:"I'm not convinced there are toxic effects, but I don'tthink they've proven the drug is safe over the long term."

Nemat Borhani, professor emeritus at the University ofCalifornia, Davis, School of Medicine and one of thethree members who voted to approve the drug, said,"Now the ball is in the FDA's court. It is up to them todecide."

The FDA decision could come in a matter of months oryears. In March, the FDA _ concerned about thepotential for nerve damage and a rare, but deadly lungdisease _ rejected the drug, manufactured by InterneuronPharmaceuticals Inc., of Lexington, Mass. The companyresponded with two studies intended to alleviate theagency's concerns.

Those studies and others presented to the advisorycommittee failed to resolve members' concerns. Instead,they kindled controversy as scientists working forInterneuron, for the FDA and various academicinstitutions debated complex points of epidemiology,neurology and pulmonary medicine.

What no one could say with any certainty was whetherdexfenfluramine would translate into a new, usefultreatment for obesity or a small but devastating epidemicof deadly primary pulmonary hypertension, whichpermanently destroys the lungs' circulatory system.

Dexfenfluramine, discovered by the Paris-based LesLaboratoires Servier, is an organic molecule that worksby stimulating the production of the neurotransmitterserotonin and its re-uptake. For reasons that are notcompletely understood, serotonin shuts off the humanappetite alarm, making people feel full. Foods rich in fatsand carbohydrates stimulate serotonin release.

Richard Wurtman, director of the Clinical ResearchCenter at the Massachusetts Institute of Technology(MIT) and a founder and director of Interneuron, told theFDA advisory committee that a 15 mg dose twice a dayenables people to cut their food intake by 600 calories aday and increase their energy usage by 100 calories a day.

"People cut their meal time intake by 300 calories andtheir snack intake by 300 calories," he said. "People eatas many meals, but they don't eat as much, and they don'tcrave carbohydrates."

`Highly Favorable Safety Profile,' Interneuron Says

Bobby Sandage, Interneuron's vice-president ofinternational research, said that 18 double-blind, placebocontrolled trials involving 2,300 patients _ 800 in theU.S. and 1,500 in Europe _ found the drug was moreeffective than placebo in helping obese people loseweight. The studies found only minor side effects,including weakness and chills, diarrhea, dry mouth,nausea, vertigo and somnolence. Based on those studies,he said, the drug has a "highly favorable safety profile."

But a 10-year, post-marketing survey conducted byServier in Europe found 101 cases of primary pulmonaryhypertension (PPH) among 10 million patients who weregiven the drug. PPH is an extremely rare disease, StuartRich, chief of cardiology at the University of IllinoisSchool of Medicine in Chicago, told the meeting. But it isa devastating illness, with a median survival of just underthree years.

The committee deadlocked on whether the benefits ofdexfenfluramine _ which advocates believe may savesome 200 people each year who might have died ofobesity related complications _ outweigh the risks thatsome patients might die of PPH.

Gerald Faich, of the University of Pennsylvania and aconsultant to Interneuron, said the risk of developing PPHafter taking the drug is low, with an estimated 9.6 deathsper million patients.

But the question lingered after Faich's discussion ended.

In addition, scientists at Interneuron and at two researchinstitutes debated _ without approaching anythingresembling an agreement _ whether the drugpermanently damages nerve tissue in the brain.

Robert Moore, a neurochemist from the University ofPittsburgh and a paid Interneuron consultant, maintainedthat although the drug blocks the action of serotonin, itdoes not appear to degrade the neurons that secreteserotonin. Studies in rodents showed that the drug"cleared" the rodents' systems within six months, Mooresaid.

A separate rodent study showed no change of serotoninblood levels after two years of treatment withdexfenfluramine _ suggesting that the drug leaves theneuronal architecture of the brain intact after treatment,he said.

Others Reported Less Positive Data

But two independent scientists presented unsettlingevidence on the effect of dexfenfluramine on nerveterminals in the brains of mice and other experimentalanimals. Mark Molliver, professor of neuroscience andneurology at Johns Hopkin's University in Baltimore,said the drug is as damaging to the brain as otheramphetamines.

The slide presentation he used to hammer home his pointportrayed a once-flourishing field of tendril-like nerveterminals virtually eradicated after just four doses of thedrug. The neuronal bodies themselves survive intact andwithin a matter of months begin to produce newterminals. But the new sprouts are tangled and swollen,and resemble those that are found in Alzheimer's diseasepatients.

Lewis Seiden, professor of pharmacology, said the drugseems to hasten some of the effects of aging. Herecommended that the advisory committee vote againstapproving the drug.

Interneuron, founded by MIT's Wurtman, who conductedsome of the early studies of the French compound'seffectiveness in obesity, owns the license to produce andmarket the drug in the U.S. Interneuron has grantedexclusive marketing rights to Wyeth-Ayerst, according tocompany spokesman William Boni. Wyeth-Ayerst couldhave the drug on the market by mid-1996 if the FDAdecides to approve it.

FDA approval would be worth millions to all threecompanies, officials say. Federal statistics suggest thatone-third of all Americans are obese for a potentialpatient base approaching 60 million people.

Interneuron would earn royalties of up to 12 percent ofsales, Servier would earn slightly less than 12 percent,and Wyeth would earn the rest. n

-- Steve Sternberg Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.