ALDOSE REDUCTASE INHIBITOR CLINICAL STUDIES PUT ON "LIMITED" HOLD

ALDOSE REDUCTASE INHIBITOR CLINICAL STUDIES PUT ON "LIMITED" HOLD by FDA pending a full review of the antidiabetic drug class. FDA asked companies conducting aldose reductase inhibitor clinical trials last December not to initiate new clinical studies until further notice. However, the agency is permitting ongoing clinical trials to continue. The FDA is concerned with the results of an independent, two-year toxicology study conducted at the National Institutes of Health indicating that aldose reductase inhibitors may cause neurotoxic effects in rats. Aldose reductase inhibitors, which are being studied in humans as a potential treatment for diabetic neuropathy, exacerbated neuropathy in the NIH study, causing even more lesions to occur. Although the FDA's clinical hold was directed at the three companies developing aldose reductase inhibitors, the weight of the agency decision falls primarily on ICI and Merck -- the two companies developing ponalrestat. Ponalrestat (ICI's Statil and Merck's Prodiax) is currently in Phase III studies, with NDA submissions targeted for 1989. Pfizer and American Home Products, the two other companies developing aldose reductase inhibitors, have each suffered crippling research and regulatory setbacks. Pfizer called sorbinil clinicals to a temporary halt in 1985 while the company experimented with different dosages to deal with a 10% rate of allergic reactions occuring in clinicals that included skin rashes and live dysfunction. AHP's chances to be the first on the market with an aldose reductase inhibitor were dashed in September 1986 when FDA's Endocrine & Metabolic Drugs Advisory Committee rejected Tolrestat for approval pending further study. ICI and Merck each issued statements confirming their continued commitment to the development of ponalrestat. Despite the setback, ICI said, "worldwide clinical programs already in progress with ponalrestat, including those studies being conducted in the U.S., will continue as planned." Merck noted that FDA requested the limited clinical hold "pending completion of this review of the full database available to FDA on the entire class of aldose reductase inhibitor agents." Merck noted that "no clinical problem has been identified with ponalrestat." An NIH report of a Jan. 29 meeting on the potential neurotoxicity of aldose reductase inhibitors notes that "it is important to balance the potential risks of adverse neuropathic effects suggested by the results of the long term rat toxicity studies with the potential benefits that these drugs may have in reversing or preventing diabetic complications including neuropathy." In the NIH study, rat neuropathy was seen with both ponalrestat and tolrestat. According to the report, "the pathology observed with both drugs in an exacerbation of neuropathy normally encountered in the aging rat."