The acute hepatotoxicity of acetaminophen is a major health concern since this analgesic is one of the most commonly used drugs in intentional overdose. Current treatment regimens for acetaminophen-induced hepatotoxicity have limited efficacy. A recently discovered mechanism of inflammatory injury, the """"""""Poly (ADP-ribose) Synthetase (PARS) Pathway"""""""", has now been strongly implicated in the pathogenesis of acetaminophen-induced hepatotoxicity. PARS activation induces AP-1 dependent pro-inflammatory gene expression and NAD consumption, resulting in ATP depletion, cellular energetic failure, granulocytic infiltration, and end-organ injury. In this proposal, we present experimental evidence that pharmacologic inhibition of PARS activity and genetic ablation of the PARS gene have potent anti-inflammatory effects and dramatically protect against acetaminophen-induced injury. Inotek is developing a highly potent, specific, non-toxic, and proprietary PARS inhibitor, 5-iodo-6-amino-1,2-benzopyrone (INH2BP). INH2BP requires demonstration of efficacy in a clinically relevant and stringent experimental model of acetaminophen intoxication in order to justify its commercialization as a novel anti-inflammatory agent for the prevention of liver failure. In this proposal, we will test the protective effect of INH2BP, administered at various timepoints and dose levels, in comparison with N- acetyl cysteine, the current gold standard of clinical therapy. Biological endpoints, indicative of therapeutic efficacy, will include neutrophil infiltration, histiologic damage, poly ADP-ribose formation, lipid peroxidation, and serum transaminasemia. The demonstration that INH2BP is effective in this model in a post-exposure paradigm would represent a breakthrough in the design of novel regimens for the treatment of acetaminophen intoxication and would justify its further commercial development.
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 have limited efficacy: massive acetaminophen intoxication frequently results in fulminant liver failure necessitating orthotopic liver transplantation. INH2BP may represent the first highly potent and successful adjunct to the current therapeutic regimen; funding of SBIR Phases I and II will allow for market entry in 4 years.
