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Executive Summary

Dexfenfluramine has been shown to provide successful weight loss maintenance "for periods up to one year," George Bray, MD, Pennington Biomedical Research Center, Baton Rouge, La., reported to the National Institutes of Health's Technology Assessment Conference on Methods for Voluntary Weight Loss and Control held March 30-April 1. Interneuron Pharmaceuticals has initiated U.S. clinical trials of the drug and projects filing an NDA in late 1992 or early 1993. The regulatory submission will include results from studies of over 4,000 patients, of whom 600 are from the U.S., the company said. Interneuron acquired marketing rights to the prescription anti-obesity drug from France's Les Laboratories Servier in May 1990. Servier currently markets the product in France as an appetite suppressant under the brandname Isomeride, and the drug is approved in 30 countries. Interneuron said it is currently discussing potential U.S. marketing agreements with pharmaceutical companies. Bray, who presented the drug therapy portion of the two-day conference, also reported that Lilly's fluoxetine, currently in clinical trials for weight loss, has shown initial efficacy but, he said, the weight is eventually regained. Discussing the results of a fluoxetine Prozac study on the serotonin reuptake inhibitor's ability to reduce food intake published in International Journal of Obesity (1989) by L. R. Levine, et al., Bray said fluoxetine showed "a dose-response effect on weight loss over eight weeks of treatment." However, "when patients are treated with the drug for more than 16 to 20 weeks...on average they begin to regain weight." Commenting on Bray's presentation, Lilly said in an April 2 statement that 90% of people on weight loss regimens eventually regain some weight and described the finding as "not unexpected." Lilly filed a supplemental NDA for fluoxetine (which will be marketed as Lovan) for the treatment of obesity and bulemia in the second half of 1988 and the application is still pending at FDA. Although the company has kept a characteristically low profile about Lovan's efficacy, Pharmaceutical Division President Eugene Step told securities analysts at a 1991 presentation that Lilly will try to avoid the cosmetic use of Lovan and concentrate on patients for whom management of weight is part of the management of the patient's overall condition ("The Pink Sheet" March 4, 1991, p. 18). Prior to the recent concern surrounding fluoxetine's alleged link to increased suicidal ideation, a large proportion of the drug's prescriptions were anecdotally reported to be for weight loss. Bray suggested that, based on drug-use experience with antihypertensives, "it is likely that a combination therapy" of serotonergic and noradrenergic drugs "will produce a greater effect than any single agent alone." One study, conducted by Michael Weintraub, MD, showed that the combination of fenfluramine and phentermine showed effectiveness that lasted "as long as it's been tested," Bray said. Drug therapy for weight loss made up only a small portion of the agenda for the two-day NIH conference, which concluded with observations about the lack of success in the majority of weight loss attempts. The conferees' consensus statement, issued in draft form on April 1, concluded that virtually all weight loss regimens, including drug therapy, caloric intake reduction, exercise and behavior modification, generally result in the regain of "almost all" weight within a period of five years following the conclusion of the program. During the discussion on the consensus statement, a member of the audience suggested to the panel that because currently existing weight loss programs are ineffective, drug therapy should be listed as an important area for research. The NIH panel did not include this suggestion in the final draft of the statement. Despite the consensus statement's limited discussion of weight loss drugs, which touches only on the out-of-favor use of amphetamines and concludes that drugs are no more effective than other weight loss programs, Bray told the panel that there are drugs in development that have shown some promise. Thermogenic agents, "which mimic the effect of moderate amounts of exercise" are among "the most interesting candidates" for development, Bray suggested. Thermogenic agents, which increase the potential for oxidation of fatty acids by muscle and slow bone loss, have been shown to "enhance energy expenditure in normal subjects," he told the conference. One synthetic thermogenic agent, SmithKline Beecham's compound BRL 26830, has been compared to placebo in humans and produced "a weight loss of something like 15 kg in the course of this 18 week trial," Bray said. Ephedrine, the only available nonsynthetic thermogenic agent, has been shown "to produce a larger amount of weight loss than placebo" when used in conjunction with caffeine. The unpatented drug has been tested in Denmark but no drug company has yet sponsored the drug for development as a weight loss therapy, Bray noted. Drug therapies that inhibit digestion of lipids and carbohydrates are also in development, Bray noted. Roche's tetrohydrolipstatin (Oristat), a compound that blocks lipid digestion, is in Phase II. Bray mentioned two other Roche drugs -- chlorocitrate, which inhibits gastric emptying, and RO-22-0064, which stimulates lipid oxidation; however, the company has stopped development of these products. Miles Glucobay (acarbose) is being developed to block carbohydrate digestion, and Proctor & Gamble continues work on the nonabsorbable fat product Olestra, for which FDA is requiring long-term studies. The NIH conference also heard data on the epidemiology of weight loss and updates on current methods used by Americans to try to control their weight, as well as the use of OTC diet aids. With regard to drug therapy, the consensus statement mentions only that the OTC diet aid phenylpropanolamine is an "appetite suppressant that has some efficacy in producing weight loss." The statement also states that "the long-term benefit of this drug is not well documented, and as with other over-the-counter preparations, there is potential for its misuse." Recently, FDA has expressed continued concern about phenylpropanolamine and is attempting to determine whether the use of the ingredient "may be associated with adverse reactions such as hypertension" ("The Pink Sheet," March 30, p. 3). Any determination concerning phenylpropanolamine will be included in the OTC antihistamine final monograph. Rep. Wyden (D-Ore.) has held hearings on reports of adverse reactions and abuse potential for phenylpropanolamine. Bray commented that there are several barriers to the use of drugs for weight loss, including "legislative grandstanding." Discussing the use of diet aids, Mary Serdula, MD, Centers for Disease Control, presented the results of two surveys reviewed by CDC that looked into the prevalence of different weight loss practices in adolescents and adults. The 1990 Youth Risk Behavior Survey, which interviewed 11,631 students about weight perceptions and weight loss practices, found that of the females surveyed, 4% reported using diet pills in the seven days preceding the survey, as did 2% of the males. However, a higher percentage reported ever having used diet pills, 21% of the females and 5% of the males. In contrast to the student responses, data gathered for CDC'c Behavioral Risk Factor Surveillance System found that of adult women surveyed, 1.5% reported using diet pills to lose weight compared to .5% of men. The survey takers interviewed 59,251 adults via telephone about their weight control practices. Alan Levy, PhD, FDA Center for Food Safety and Applied Nutrition, presented results from the 1992 Weight Loss Practices Survey, which revealed that use of OTC diet aids is a relatively unpopular way to lose weight. The survey involved telephone interviews with 1,431 individuals, 18 years of older, who were trying to lose weight. The diet practices in the FDA survey were organized into seven major categories. Levy reported that "diet and exercise are by far the most prevalent types of practices among those trying to lose weight." Women were more likely to use OTC drug products to lose weight (women = 14%, men = 7%), Levy said. The OTC products used were principally phenylpropanolamine, diuretics or hormonal products.

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