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Executive Summary

J&J's SUPPRELIN RECOMMENDED FOR APPROVAL IN PRECOCIOUS PUBERTY by FDA's Endocrinologic and Metabolic Drugs Advisory Committee at its March 26 meeting. The committee agreed unanimously that Johnson & Johnson's Supprelin (histrelin acetate) as a daily subcutaneous injection of 8-10 micrograms/kg suppressed precocious puberty in 80 children in trials conducted by J&J's R.W. Johnson Pharmaceutical Research Institute. Supprelin, a synthetic LHRH (luteinizing hormone/releasing hormone) analog, is the first approved treatment for precocious puberty. At the same time, the FDA committee narrowly rejected a supplemental NDA for Takeda-Abbott Pharmaceuticals's (TAP) LHRH analog Lupron (leuprolide acetate) Injection and Lupron Depot (a once-monthly suspension version of Lupron) for the same indication. The panel agreed four to three that the data provided by TAP on 62 children evaluated with Lupron Injection and 20 with Lupron Depot was insufficient to demonstrate either formulation's clinical efficacy in precocious puberty. An orphan disease, precocious puberty has a frequency of one in 5,000-10,000 children in the U.S., or about 2,000 new cases a year, according to FDA. The severe hormonal disorder causes premature activation of sexual steriods, including gonadotropins and gonadal steriods, in children one to nine years old. Affected children develop adult secondary sexual characteristics, and suffer stunted growth as well as emotional, behavioral and psychological difficulties. The disease occurs five times as often in females as males. J&J submitted the NDA for Supprelin in 1988, adding updated safety information in January 1990. The filing was based on two pivotal studies that enrolled a total of 183 patients, out of which 80 were considered evaluable for efficacy. Treatment times ranged from 1.4-34 months. The open-label, uncontrolled trials indicated that treatment with histrelin halted or caused regression of breast and genital development, pubic hair, menstruation and premature skeletal fusion in children with precocious puberty. TAP's 1988 submission to add the precocious puberty indication for Lupron included data from 19 independent investigators, who studied dosages ranging from 2 to 80 micrograms/kg daily by injection or the equivalent of an average 30 micrograms/kg per day supplied monthly through Lupron Depot. A total of 197 children took part in the Lupron protocols, of whom 82 were studied for efficacy. The only adverse reactions reported in either company's submission was temporary injection site reactions such as pain and redness. The advisory panel's relative postion on the two LHRH analogs was summed up by the committee reviewer for both applications, Susan Ratzan, MD, University of Connecticut. "I agree with the conclusion of the sponsor that they have demonstrated that histrelin is safe and efficacious for the treatment of children with central precocious puberty," Ratzan remarked, adding that "on the basis of the submitted data, the effectiveness of Lupron Injection and Lupron Depot is somewhat less clear to me than is histrelin." * The committee's split decision on the two drugs appeared to hinge largely on quality of data in each NDA, as opposed to absolute differences between the two LHRH analogs. J&J's submission was praised as "remarkably complete and readable" by Ratzan, who also said she was "impressed with the diligent and complete reporting" of safety data by the histrelin research teams. Problems with TAP's submission cited by Ratzan and in committee discussion included the small number of evaluable patients, the wide range of doses used, and the large number of differing protocols and investigators, which "made interstudy comparison impossible," according to Ratzan, who also criticized the TAP package for insufficient safety data. Ratzan voiced support for "the greater detail and more cautionary tone of the histrelin package labelling, including their proposed recommendations for diagnostic studies and follow-up studies." Having recommended Supprelin for FDA approval, the committee also voted unanimously that two unresolved FDA concerns on Supprelin's long term effects could "reasonably be resolved by Phase IV postmarketing studies." The areas that need further study are the LHRH analog therapy's affect on adult fertility of treated children, and whether the treatment actively aids patients in reaching normal adult height, or only decreases the damage the untreated disease would cause. Johnson & Johnson consultant Bonna Beardsworth told the meeting that the firm was already committed to Phase IV follow-up for all children receiving histrelin. The firm's follow-up plans include annual visits for children after treatment has ceased until the achievement of normal puberty, followed by written correspondence until age 21 to follow-up on patients' fertility. Syntex, Roberts Laboratories, and Hoescht-Rousell all also made brief presentations at the advisory committee meeting. All have LHRH analogs which have been studied in precocious puberty patients, although none have yet filed an NDA for the indication. Syntex's Synarel (nafarelin) has shown effectiveness in suppressing secondary sexual characteristics in 23 fully evaluated children, according to the Syntex presentation. Hoescht has had an IND protocol for open-label, compassionate use of its LHRH analog Suprecur (buserelin) to treat precocious puberty since 1984, according to the firm's presentation. Researchers evaluating 49 children who had completed six months or more of therapy, out of a total of 57 enrolled, found significant suppression of precocious puberty symptoms, Hoescht reported. Roberts, which licenses its LHRH analog Somagard (deslorelin) from the Salk Institute, reported lowering sex steroids concentrations to pre-pubertal levels in 36 children with central precocious puberty during multicenter studies. Prior to deslorelin's adoption by Roberts, the compound had been studied at NIH, which evaluated the drug in 200 children with precocious puberty over nine years. Roberts, which has permission to recover the compound's $4,000 a year cost under a Treatment IND, is currently in the midst of a two-and-a half year carcinogenicity study requested by FDA in 1989 ("The Pink Sheet" July 31, 1989, T&G-5).

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