New Treatment for C. difficile-Associated Diarrhea

DESCRIPTION (provided by applicant): Clostridium difficile-associated diarrhea (CDAD) is a significant problem in hospitals and long-term care facilities. The primary risk factor for CDAD is treatment with broad spectrum antibiotics which disrupt the gut flora and allow the overgrowth of C. difficile. Current treatments for the disease have several disadvantages, the most crucial of which is the high relapse rate. A novel antibiotic, OPT-80, is being developed for the treatment of this disease. OPT-80 has selective and potent activity against Clostridium difficile. The selectivity of this compound should allow the patient to repopulate the colon with normal flora during the course of treatment and prevent relapse. In addition to its promising spectrum of activity, OPT-80 has other features that make it an ideal candidate for this indication. It is bactericidal against C. difficile, has low rate of resistance development, and an unusually long postantibiotic effect. It has good efficacy in animal models of CDAD and reaches high levels in the gut (the site of action) but very low levels in the plasma following oral administration. OPT-80 has been shown to be a safe compound in both pre-clinical animal toxicity testing and in single-dose administration in humans, and has been granted fast-track status by the FDA for the CDAD indication. The goal of the proposed work is to continue the development of this compound by performing the clinical and nonclinical studies necessary to enter phase 3 pivotal trials for phase II SBIR-AT-NIAID. These studies include (i) further microbiological characterization of OPT-80; (ii) detailed pharmacokinetic analysis of OPT- 80 in a selected non-human species; (iii) a phase 1B, multiple dose escalating safety study in healthy human volunteers, and (iv) a phase 2 safety and efficacy clinical trial of OPT-80 in CDAD patients.