XO INHIBITOR FOR THERAPY OF ACETAMINOPHEN INTOXICATION

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Treatment of acetaminophen intoxication, a leading cause of hepatic injury, represents a $250 million annual US market. The exclusive existing market entrant, N-acetylcysteine, is of limited benefit. In a Phase I NIH SBIR, we have demonstrated that administration of the xanthine oxidase inhibiter, 4- Amino-6-hydroxypyrazole[3,4-d]pyrimidine (AHPP), provided dramatic protection against hepatotoxicity in an experimental model of severe murine intoxication by acetaminophen. In a Phase II SBIR, we now propose to: 1) Develop an efficient scaled-up synthetic process to produce GMP-grade, kilogram-level, batch quantities of AHPP; 2) Determine the in vitro and in vivo genotoxicity of AHPP; 3) Determine the in vivo pharmacokinetics, distribution, metabolism, and excretion of AHPP in rats and dogs; 4) Determine the biochemical and histopathologic toxicology of AHPP in a large animal model per a gavage route of administration; and 5) Establish the synergistic efficacy of AHPP and the current market entrant, N- acetylcysteine. Range-finding toxicity studies will first establish the approximate level of tolerance and safety. Definitive one-week toxicity studies will be performed and a full behavioral, biochemical, and histopathologic profile obtained. The proposed studies in this Phase II SBIR scope of work will provide the foundation for 1) an IND application to the FDA to study safety and tolerance in a Phase I clinical trial, and 2) fund raising via private placement to support further commercial development of AHPP. PROPOSED COMMERCIAL APPLICATIONS: The domestic market for a novel, effective therapy for acetaminophen intoxication is estimated at $250 million per annum. Global markets are estimated at $800 million. Current market entrants are marginally effective: massive acetaminophen intoxication frequently results in fulminant liver failure necessitating orthotopic liver transplantation. AHPP may represent the first highly potent and successful adjunct to the current therapeutic regimen; funding of the Phase II SBIR scope of work will allow for market entry in 4 years.