Interneuron Pharmaceuticals (NASDAQ:IPIC) saw its shares dropMonday $1.25, or 17 percent, to $6, after the company issued astatement criticizing a study that found flaws in its prescription anti-obesity drug. Dexfenfluramine is Interneuron's appetite-suppressant,awaiting approval by the FDA (See BioWorld Today, May 10, p.1).The stock price remained unchanged in trading on Tuesday.The study, published today in the Journal of Pharmacology andExperimental Therapeutics, carries the title: "Dexfenfluramine andserotonin neurotoxicity: Further preclinical evidence that clinicalcaution is indicated."The study of dexfenfluramine out today follows up initial animal trialsthree years ago. Its senior author, neurologist George Ricaurte of JohnsHopkins University School of Medicine told BioWorld that heundertook the new research to examine three objections to his 1991findings raised by proponents of dexfenfluramine:y Dexfenfluramine's effects on brain serotonin neurons are onlytransient;y Humans take the drug by mouth; test animals got it by injection;y Squirrel monkeys are not a suitable animal model to test the drug'salleged neurotoxicity; mice are ideal.Ricaurte's six co-authors include NIH researchers at the NationalInstitutes on Drug Abuse and on Mental Health as well as JohnsHopkins. Their controlled trial assayed the effects on brain serotoninneurons of dexfenfluramine injected subcutaneously twice daily forfour days in four squirrel monkeys, 22 rats and 14 mice _ plus anequal number of controls.The primates, 14 months later "had large depletions of regional brainserotonin," and at 17 months, "a striking reduction in the density ofserotonin-immunoreactive axons in the forebrain . . . and other brainregions."Rats received the drug either by injection or orally. Both groups hadidentical serotonin depletions. So did mice, but they displayed half asmuch sensitivity to the drug's serotonin-depleting effects. Incidentally,"regardless of dose, dexfenfluramine did not induce significant weightloss in mice."Animal doses, Ricaurte noted, "were not far from those given tohumans."Behavioral Side-Effects, Seen Or UnseenAsked whether the neurotoxic findings were reflected in the animals'behavior, Ricaurte observed, "This study did not examine behavior, butall of them appeared to act normally." He added that the question"touches a key issue. If functional consequences do exist, they're likelyto be subtle and hard to detect in subhumans and humans."He explained, "One has to recognize that the functions in whichserotonin has been implicated _ sleep disturbance, mood regulation,impulse control, aggression _ all have their own incidence in thepopulation at large, be it a population exposed to fenfluramine[dexfenfluramine's already-approved analog] or not. As a neurologistwho is treating someone with, say, fenfluramine, if I happen to see thatthat individual is depressed, I would be presumptuous to jump to theconclusion that fenfluramine did it."The Johns Hopkins neurologist made the further point: "It may be thatindeed there are no functional consequences in humans, or that theymay take years to become apparent."To nail down these possibilities, he said, "you really have to go out anddo a case-control study retrospectively, perhaps in Europe, recognizingthat there's a certain incidence of serotonin-linked disturbances alreadyout there in the population. So one has to ask: Is it higher in peopleexposed to dexfenfluramine, particularly at higher doses?"At the same time he emphasized that such a study "will have itslimitations, because our methods for assessing serotonin function in theliving human brain are imperfect."Although dextro-rotary dexfenfluramine is intended as a prescriptiondrug, like its already-approved racemic analog, fenfluramine, Ricaurteforesaw that, "It can be used for a lot more indications that thoseapproved by the FDA."Given our society's mores as to weight and body image, this drugcould be misused by the teenager who wants to be five pounds thinner.I don't think it's likely to be prescribed only for a morbidly obesepatient."MIT Neuroscientist Rebuts Hopkins PaperNeuroscientist Richard Wurtman directs the Massachusetts Institute ofTechnology's clinical research center. He is a co-founder ofInterneuron Pharmaceuticals, and chairs its scientific advisory board.After reading Ricaurte's dexfenfluramine paper in the pharmacologyjournal, he told BioWorld: "It's dja vu. I saw this 18 months ago."Wurtman has just finished a 1,000-patient FDA-authorized trial ofdexfenfluramine, and found no adverse behavioral side-effects."Among the 10 million people in Europe who have takendexfenfluramine, and the 20-odd million who took fenfluramine, whichis 50 percent dex, for over 25 years," he observed, "You would thinkthere'd be some symptoms. To say they're really there but too subtle tobe seen sounds to me like paranoid schizophrenia."He denies that dexfluramine causes neurotoxicity. "The fact that a druggiven in very large doses causes a persistent decrease in serotonin isnot toxicity, but a sign of drug action." As for the dead neurons thepaper reports, Wurtman demurs, "These people say, `I see changesunder the microscope; therefore, cells are dead.' Qualifiedneurotoxicologists say, `No, this is not a sign of cell death."Turning to the dosage levels, he recalls that in his recent clinical trials,human subjects, who weighed an average of 100 kilograms (225 lb.),took a total daily dose of 30 mg, or 0.3 mg/kg. Monkeys in the JohnsHopkins study, Wurtman said, got 5 mg/kg twice a day, or 10 mg/kg_ 33 times as much as people."Those animal doses," he objects, "are inappropriate; they don't tellyou anything." Nor does he prefer the oral to the injection route ofadministration. "What really matters is what gets into the bloodstream."
-- David N. Leff Science Editor
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