A 72-patient study of Interneuron's Redux (dexfenfluramine) assessing cognitive function provides a "reassuring lack of evidence of neurotoxicity," FDA Medical Officer Leo Lutwak, MD/PhD, told the Endocrinologic & Metabolic Drugs Advisory Committee Nov. 16.

An 18-month trial assessing cognitive function, the Noble Long-Term Study, showed that dexfenfluramine did not adversely affect mood, depressive symptoms, or cognitive function on treatment and there were no changes on any parameter," including sleep, "during the post-treatment" period, Interneuron VP-Clinical Research Richard Gammans, PhD, told the committee.

The trial randomized 36 patients to dexfenfluramine and 36 to placebo. Treated patients received the recommended dose of drug, 15 mg b.i.d., for six months. At that point, all patients took placebo and were followed for another 12 months.

The committee narrowly recommended the drug Nov. 16. Committee members present voted 4-5 against approval; however, two members who had departed early left "yes" votes, bringing the final tally to 6-5 in favor of dexfenfluramine.

The committee was continuing its Sept. 28 review of the NDA (20-344) for dexfenfluramine, the first long-term obesity therapy to come before the advisory panel. If approved, Wyeth-Ayerst will market the drug. The September meeting ended without a valid up-or-down vote on approvability of the drug ("The Pink Sheet" Oct. 2, p. 4).

During the first meeting on dexfenfluramine, FDA-invited speakers presented animal data suggesting serotonin depletion and morphological changes in the brain with dexfenfluramine administration. At that point, the committee determined that data were insufficient to resolve the issue.

During the Nov. 16 meeting, Interneuron consultant John Blundell, PhD, University of Leeds, declared that some of the most dramatic neurological damage presented during the first meeting was from rats who were administered MDMA, PCA or MDA and should not be extrapolated to dexfenfluramine. He argued that those compounds test positive for accepted markers of neurotoxicity like silver staining and decreased retrograde transport, while dexfenfluramine tests negative.

Although the FDA medical reviewer appeared satisfied with the information on neurotoxicity, two committee members expressed discomfort with the data, as did another FDA official. Robert Sherwin, MD, Yale University, said that the cognitive tests used were not robust and the sample size was "totally inadequate." FDA Office of Research Resources staffer Joseph Contrera, PhD, pointed out that other animal data exist suggesting an association between morphological changes in the brain and dexfenfluramine.

At the earlier meeting, the committee found dexfenfluramine efficacious. The primary study, the 48-week, 941-patient Index trial, showed a 3% greater weight loss for dexfenfluramine compared to placebo using a last-observed carry-forward analysis method. The result does not meet one proposed endpoint in FDA's obesity drug development guidelines -- a 5% greater weight loss than placebo. The obesity guidelines were developed after Interneuron's NDA was submitted but influenced committee discussion ("The Pink Sheet" Oct. 2, p. 3). By categorical analysis, 39% of treated patients lost more than 10% of initial body weight, compared to 21% in the placebo arm.

FDA epidemiologist Bruce Stadel, MD, addressed the other major risk of dexfenfluramine, primary pulmonary hypertension. The committee found the risk of that side effect acceptable at the earlier meeting. Saying PPH is "severe but very rare," Stadel estimated 20-30 deaths per million persons per year from dexfenfluramine-associated PPH.

Stadel suggested that follow-back investigations could be conducted during post-marketing surveillance to determine if PPH "happens when people keep taking drug when it doesn't work or...happens in people for whom the drug produces substantial weight loss."

Committee Chairman Henry Bone, MD, Henry Ford Hospital (Detroit), urged inclusion of a black box warning in labeling addressing the risk of PPH. Committee member Robert Marcus, MD, V-A Medical Center (Palo Alto, Calif.), suggested that an attempt be made to find early indications that could indicate risk for development of PPH to be included in the label.

In response to committee suggestions in September, Interneuron President Glenn Cooper, MD, said labeling would recommend use in patients with a body mass index of greater than 30, or a BMI of greater than 27 in patients with co-morbidities.

FDA reviewer Lutwak concluded that co-morbidity studies showed "no clear cut evidence of any beneficial effects." Committee member Jose Cara, MD, Henry Ford Hospital, said the label should state that the long-term effect of dexfenfluramine on co-morbid conditions was not known.

Cooper also reiterated the company's intention to include in labeling the recommendation of a one-month initial treatment period to determine responders. Interneuron's proposed labeling reads: "Patients who lose at least four pounds in the first four weeks of treatment with dexfenfluramine have a statistically significant chance of losing at least 10% of their initial body weight by the end of one year of treatment. If the patient has not lost at least four pounds in the first four weeks of treatment the physician should consider discontinuation of dexfenfluramine."

Bone suggested that the drug be indicated only for patients showing weight loss after one month. Committee member Joanna Zawadzki, MD, Georgetown Diabetes Center, urged weight change further be assessed every six months. Committee member Robert Kreisberg, MD, Baptist Health System (Birmingham, Ala.), stated that the label should emphasize that dexfenfluramine is to be used as an adjunct to lifestyle modifications. Committee members also recommended the drug be contraindicated in pregnant or lactating women and juveniles and with co-administration of other seratonergic drugs.

Longer-term data was universally called for by the committee in response to FDA questions regarding Phase IV or additional pre-approval studies.

Committee member Cathy Critchlow, PhD, University of Washington, recommended post-marketing studies monitor PPH "and be powered to detect an increase" over the background rate. Surveillance should also "monitor both maintenance of weight loss as well as maintenance of improvement in markers associated with co-morbidities." Marcus urged that Phase IV studies last at least five years.

Bone urged prospective Phase IV studies as well: "I think that as a contingency for approval, the kinds of studies which would be required to meet the current guidelines should be absolutely required. This would mean a two-year study, one year randomized, one year extended observation, at minimum, in large numbers looking at effects not only on weight loss but specifically addressing questions of reduction of lipidemia and mortality, if possible, in co-morbid states."

Due to concerns of misuse of the drug for cosmetic or eating-disorder related weight loss, the committee called for extensive patient and physician education by the sponsor and its marketing partner Wyeth- Ayerst. Wyeth VP-Medical Affairs Marc Deitch, MD, assured the committee that the company would undertake such efforts. He also noted that Interneuron and Wyeth-Ayerst have met two times with FDA since the September committee meeting to discuss post-marketing considerations.

If dexfenfluramine were not approved based on current data, Critchlow joined Bone in calling for studies complying with the FDA obesity drug development guidelines. Committee member Colleen Colley, V-A Medical Center (Portland, Ore.), suggested that studies not only look more closely at co-morbidities but address changes in body composition. Bone suggested that non-approval would give FDA an opportunity to gather experts to resolve issues surrounding neurotoxicity and the proper studies required to assess brain changes.

INTERNEURON DEXFENFLURAMINE COGNITIVE STUDY FINDS NO EVIDENCE OF NEUROTOXICITY; ADVISORY COMMITTEE RECOMMENDS OBESITY THERAPY BY SLIM MARGIN

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