By Debbie Strickland

The maker and marketer of the popular but controversial diet drug Redux (dexfenfluramine hydrochloride capsules) are seeking to resolve lingering questions about its neurological safety with a two-year Phase IV multisite post-marketing clinical study.

The companies—developer Interneuron Pharmaceuticals Inc., of Lexington, Mass., and marketing partner Wyeth-Ayerst Laboratories, of Philadelphia—agreed to the Phase IV trial as a condition of FDA marketing approval, granted in April 1996.

Interneuron's shares closed Wednesday at $20.313, down $0.313.

"The implications of this are, I think, fairly minimal," said David Crossen, an analyst with Montgomery Securities, in San Francisco. "Redux has been declining fairly steadily from its peak because of concerns about primary pulmonary hypertension [PPH] and valvular heart disease . . . The fate of the product is that it will establish a small niche."

Crossen, who recommends Interneuron because of its developmental pipeline, said he already has adjusted his Redux sales projections downward to $100 million for this year, with long-term annual sales projected to stabilize at about $70 million.

The more important product to Interneuron's future is likely the ischemic stroke treatment CerAxon (citicoline), for which the company plans to submit a new drug application this year.

According to the companies, the Redux Phase IV study—a double-blind, randomized, placebo-controlled trial—may be the first to investigate the neurological effects of long-term (one year or greater) use of a serotonergic drug, a category that includes antidepressants such as Prozac.

The study will test cognitive, behavioral and neuropsychological functioning in three groups of patients—those taking Redux, those taking fluoxetine (Prozac) and those taking placebo. Researchers will measure, among other things, mood states, aggression, sexual functions, memory and problem solving.

"Prozac is probably the widest-used drug that increases serotonin levels," said William Boni, Interneuron's vice president for communications. "We want to make sure we test other drugs in the same category [as Redux]."

Patients will be recruited at five medical centers: Columbia Presbyterian Medical Center and St. Luke's Roosevelt, both in New York; the University of Pennsylvania Medical Center, in Philadelphia; the University of Rochester Medical Center; and the University of Pittsburgh Medical Center.

Led by researchers at the Columbia University College of Physicians and Surgeons, in New York, the study is designed to address questions raised by earlier animal studies that indicated brain serotonin levels are reduced following administration of extremely high doses of dexfenfluramine.

Redux reduces appetite by stimulating release and availability of the neurotransmitter serotonin in the brain. Researchers have observed neurochemical changes in animals receiving dexfenfluramine doses that resulted in brain concentrations approximately 10 times those seen in humans.

However, according to the companies, the neurochemical changes were generally found to be reversible when administration of the drug ceased, and were likely the result of the high doses used in the studies.

"The clinical relevance in humans of these high-dose animal studies is unknown," the companies said. "An estimated 10 million patients have received dexfenfluramine in the 10 years it has been available on the market without significant epidemiologic signals indicative of neurotoxicity."

The Phase IV trial will not investigate further what has been the hotter story in the obesity drug industry this summer: the off-label "phen-fen" diet pill combination. Phen-fen and to a lesser extent Redux have both been linked to an increased risk of regurgitant valvular heart disease. Phen-fen is co-administration of both phentermine and fenfluramine (which is a mixture of dexfenfluramine and levo-fenfluramine).

In July, a Mayo Clinic report linked phen-fen to valvular disorders, after which a class action lawsuit was filed in San Francisco against manufacturers of phentermine, fenfluramine and Redux. Wyeth-Ayerst, a division of Madison, N.J.-based American Home Products Corp., markets fenfluramine.

As for PPH, the risk associated with prescription weight-loss drug usage of at least three months is estimated at about 23 to 46 cases per 1 million patients per year. In the general population, the yearly incidence of PPH is one to two cases per million persons per year. *