SBIR-STTR Award

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

Clostridium difficile, a toxigenic, gram-positive anaerobic bacterium, is the most common cause of nosocomial diarrhea. Over the past 15 years there has been a steady increase in the incidence of Clostridium difficile- associated diarrhea (CDAD), a disease that is now epidemic in parts of North America and Europe. Serious morbidity and mortality due to CDAD has increased sharply with the emergence of antibiotifc-resistant, hypervirulent strains in the US and Canada. The primary risk factor for CDAD is the use of broad-spectrum antibiotics, which disrupt the gut flora and allow overgrowth of toxigenic C. difficile. The most significant disadvantage of current treatments is the high recurrence rate (~20%) following the withdrawal of therapy. OPT-80, a novel macrocyclic antibiotic also known as PAR-101, is being developed for the treatment of this disease. This compound is selective, with potent activity against C. difficle. The selectivity profile of this compound should allow the patient to repopulate the colon with normal flora during the course of treatment and reduce the probability of recurrence. The goal of this proposed work is to further demonstrate the safety and effectiveness of this compound and its major metabolite (OP-1118) by performing toxicology and microbiological studies, some of which will be ancillary studies to the upcoming pivotal trials in CDAD patients. These studies will include (i) microbiological characterization of OP-1118, (ii) in vivo toxicological studies of OPT-80/PAR-101 in Beagle dogs, (iii) examination of possible resistance mechanisms, including reduced uptake and target modifications, in C. difficile to OPT-80/PAR-101, (iv) molecular typing (REA and Rep-PCR) of C. difficile isolates from subjects enrolled in the PAR-101 Phase 2B/3 pivotal trial to demonstrate efficacy on all clonal strains and confirm the low recurrence rate in OPT-80/PAR-101 treated patients, (v) ecological examination (with both traditional culture methods and DGGE and fish analysis) of gut flora following treatment with OPT-80/PAR-101 to establish optimal dosing for narrow spectrum activity and minimize development of drug resistance during treatment, and finally (vi) perform a surveillance study of C. difficile isolates across North America to monitor antibiogram shift of those isolates vs. OPT-80/PAR-101 as well as against current and other potentially effective future CDAD treatments. Clostridium difficile is an important cause of antibiotic-associated diarrhea (CDAD) in hospitals and long-term care facilities and has been responsible for major outbreaks of CDAD in North America and Europe. The increase in CDAD has been associated with a significant rise in healthcare costs and excess hospital stays. The microbiological and toxicological studies proposed in this application will provide further support for development of a novel and more selective antibiotic (OPT-80/PAR-101) against C. difficile.