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Executive Summary

WYETH-AYERST's ALREDASE: COMPANY REMAINS "COMMITTED" TO DRUG despite the lack of clear benefit of Alredase (tolrestat) to patients in clinical diabetic neuropathy trials, Wyeth-Ayerst Senior Clinical Research Director Boas Gonen, MD, told a Sept. 4-5 workshop on aldose reductase inhibitors. "From our entire experience, we are quite confident that we have a potent inhibitor of aldose reductase in vivo, and we are fully committed to tolrestat until its development is completed," Gonen remarked at the workshop, co-sponsored by the National Eye Institute and the Juvenile Diabetes Foundation. The company said it is conducting ongoing Phase III studies with tolrestat in diabetic retinopathy, neuropathy and nephropathy and that it is "diligently" pursuing development of the drug. Ayerst is the last of the three major companies that began developing aldose reductase inhibitors 10 years ago to continue active work on the compound. In January, ICI and co-developer Merck announced that they would be phasing out development of Statil (ponalrestat) due to a lack of efficacy ("The Pink Sheet" Jan. 22, T&G-5). Pfizer halted testing of its drug sorbinil in 1985 due to a 10% incidence of allergic reactions. Ayerst experienced a major setback in the development of tolrestat four years ago when FDA's Endocrinologic & Metabolic Drugs Advisory Committee refused, in September 1986, to recommend approval of the drug because company studies did not provide sufficient evidence of efficacy in the treatment of diabetic neuropathy. Gonen presented more recent data at the workshop. The analysis of three combined studies in over 300 patients from the U.S. and Europe showed statistically significant improvement in nerve conduction velocity in patients treated with 200 mg/day tolrestat for 24 weeks. The analysis also found that patients with less advanced disease and higher glycosylated hemoglobin levels tended to respond better to tolrestat treatment. Nerve biopsies conducted in tolrestat-treated patients showed a decrease in axo-glial dysjunctions and Wallerian degeneration, and an increase in regenerating nerve fibers. The only significant adverse reaction to the drug was a reversible increase in liver transaminase levels, which led to a withdrawal from the studies of 5% of the patients. Neuropathy and retinopathy studies presented at the workshop by ICI on ponalrestat and studies conducted by the National Eye Institute with Pfizer's sorbinil showed no statistical improvement in patients receiving treatment over placebo. Commenting on the trial results, National Eye Institute Clinical Trials Branch Chief Frederick Ferris, MD said, "I guess it would be best to say that they are somewhat equivocal." He remarked that while the "best evidence [is] the tolrestat neuropathy evidence," the studies were "not over-whelmingly convincing." The high cost of the studies, which must last three to five years to show any effect, "may mean that collaboration of drug companies with each other and with the government is necessary if new trials for prevention of secondary complications of diabetes are to be developed," Ferris suggested. FDA Acting Commissioner James Benson, who attended the workshop, commended efforts with the compounds, and said that FDA involvement in the preclinical study period is "critical." With regard to early collaboration with industry, Benson said: "Although it is expensive for FDA initially...what becomes important is the cost effectiveness of getting the product to market as rapidly as possible," which can only be achieved through well-designed studies.



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