Inflammatory bowel disease (IBD) is a major source of chronic morbidity in the US population. Current treatment regimens are of limited efficacy, as there are no entirely non-toxic pharmaceuticals which totally halt or reverse the progression of IBD. Inotek Corporation proposes to test the feasibility of a novel therapeutic agent, INH2BP, in a definitive sub-human primate model of idiopathic colitis which demonstrates the classic features of clinical IBD INH2BP is a highly potent specific inhibitor of poly (ADP- ribose) synthetase (PARS), a nuclear enzyme whose activation by inflammatory oxidant stress results in energetic depletion and tissue dysfunction. In rodent models of regional and systemic inflammatory injury, PARS inhibitors increased survival, blocked tissue injury, preserved tissue energetics, and reduced neutrophil infiltration, prostaglandin formation, weight loss, and mucosal hyperpermeability, PARS inhibition in a rodent model of trinitrobenzenesulfonic acid (TNBS)- induced colitis completely prevented mucosal damage, PARS knock-out mice are likewise totally protected from TNBS-induced colitis. Inotek now proposes to establish proof-of-principle in an idiopathic model of colitis in Rhesus macaques, as assessed by histologic and biochemical correlates of tissue injury. Animal studies will be conducted at the Tulane Regional Primate Research Center, the largest primate research colony in the US. Upon confirmation that INH2BP is efficacious in this stringent and clinically relevant model of colitis, Inotek intends to apply for Phase II NIH SBIR funding to support formal toxicologic studies and a Phase I FDA-approved clinical trial.
The domestic market for a novel, effective therapy for inflammatory bowel disease is estimated at $150-200 million per annum. Global markets are estimated at 600 million. Current market entrants are marginally effective: Chronic colitis is recurrent, with weight loss, bleeding, and frequent progression to malignancy. INH2BP may represent the first highly potent and successful candidate therapy; funding of SBIR Phases I and II will allow for market entry in 3.5 years.
| Mabley, J G; Jagtap, P; Perretti, M et al. (2001) Anti-inflammatory effects of a novel, potent inhibitor of poly (ADP-ribose) polymerase. Inflamm Res 50:561-9 |
