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ORPHAN DRUG UCEPHAN FOR TREATMENT OF UREA CYCLE ENZYMOPATHIES

Executive Summary

ORPHAN DRUG UCEPHAN FOR TREATMENT OF UREA CYCLE ENZYMOPATHIES was recommended for approval by FDA's Endocrinologic & Metabolic Drugs Advisory Committee Sept. 12. Ucephan (benzoate and phenylacetate) is produced solely by Saul Brusilow, MD, a researcher at Johns Hopkins. He is seeking an NDA approval in order to find a manufacturer to commercially produce the drug. Kendall McGaw VP Scientific Affairs Floyd Benjamin commented that his firm has worked with Ucephan "for quite a while" and intends "to continue to improve this product in association with Dr. Brusilow." Benjamin stated: "As we come out with additional combinations or additional products that would improve the therapy [for urea cycle enzymopathies] it would be our intention to make those products available for the consumer." Committee Chairman Frederick Singer, MD, Orthopaedic Hospital, Los Angeles, Calif., stated that it is "highly appropriate" for the committee "to give very strong support" for approval of Ucephan. Commenting on the components of the drug, he said data had not been presented on the effect of phenylacetate alone and that benzoate does not seem as effective as the combination. Ucephan has been used to treat three conditions of urea cycle enzymopathies: (1) carbamoyl phosphate synthetase deficiency; (2) ornithine transcarbamylase deficiency; and (3) argininosuccinate synthetase deficiency. Individuals with these conditions are unable to excrete waste nitrogen. Ucephan forms a bond with amino acids, which contain nitrogen, and helps the body eliminate nitrogen. FDA supervisory medical officer Gloria Troendle, MD, stated that "the most meaningful outcome on which to base the approval of [Ucephan] is its effect on neurological status." She noted that in the studies done for the NDA "most of the patients were in hyperammonemic coma before treatment was begun. It is likely that most of them would have died of hyperammonemic coma if they were not treated" with the Ucephan combination. Brusilow presented data on the use of Ucephan in three disease states. Among 11 infants aged 10-72 months with ornithine transcarbamylase deficiency, there were six survivors following treatment with benzoate/phenylacetate. Five patients died from hyperammonemic coma. Among 12 infants aged 27-64 months with carbamoyl phosphate synthetase deficiency, eight infants survived and four died, two from a coma. Finally, there were 17 survivors and one death due to a coma among 18 infants aged 15-22 months suffering from citrullinemia. In response to a question from a committee member, Brusilow noted that the average IQ of disease survivors is 42 and that they therefore require custodial care. Troendle noted that FDA has little information about the contribution of phenylacetate to the combined therapy. She said that although Ucephan is constituted as a combination, in the studies presented "some patients received only sodium benzoate even at a time when others were receiving" both drugs. Brusilow said 90% of the patients received both drugs.
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