In Vivo Efficacy Studies of Clofazimine against CDAD in Hamster Model

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 DESCRIPTION (provided by applicant CDC identified in a 2013 report, C. difficile (CD) associated disease (CDAD) as "urgent public health threat" responsible for at least 14,000 deaths annually. A primary factor for origin of CDAD is exposure to broad spectrum antibiotics causing a disruption of normal intestinal bacterial flora, unchecked growth of CD and its toxins causing serious inflammatory damage to colon wall. Recent emergence and spread of a more virulent strain of CD (NAP1/027/B1) is accompanied by a decrease in efficacy of current drug regimens of metronidazole (MET) and vancomycin leading at times, to fatal conditions. Recent RFI from NIAID (# HHS-NIH-NIAID-BAA-15-037) shows an urgent need for a therapeutic agent that can overcome the re-occurrence problems arising from either emergence of resistant strains of CD and/or from ingestion and growth of new spores in a hospital setting. It is both, incentive and cost prohibitive for major pharmaceuticals to invest in discovery and development of new antimicrobial agents with low return on investment, leaving repurposing of generics as a favorite choice. Based on over 20 yrs of work on tuberculosis (TB) with clofazimine (CFM) antibiotic, the PI tested in detail and found its activity to be excellent against many strains of D including NAP1/027/B1 in culture and not so for a majority of normal flora of the gut. This data led us to examine the properties of CFM to treat CDAD and found to be worth exploring. These are: 1) CFM has over forty years' history of safe use in lepromatous leprosy and multidrug- resistant TB treatment; 2) It has also been used against Crohn's disease, an inflammatory condition of the intestine, as well as other autoimmune conditions; 3) Its bactericidal activity appears to preclude the emergence of resistant mutants of targeted bacteria; 4) It has exhibited promising pharmacological and toxicological data for human use; 5) Half-life of 8-10 days even after a single dose, and upto 70 days after a course of treatment could protect against reinfection with new spores in a hospital. These properties make CFM great candidate to explore its efficacy in a CDAD animal model. To this end, we need non-dilutive SBIR phase I funding to do: 1) Pharmacokinetic study to identify drug formulation and lowest delivery dose that would optimize bioavailability of CFM in the gut lumen; 2) establish conditions of animal model for CDAD in our hands especially to determine minimal amount of CD NAP1/027/B1 spores to kill all clindamycin treated animals; followed by 3) testing 3 pre-selected doses of preselected formulation of CFM on CDAD animals to show improvement in survival. Acceptable data would lead to SBIR phase II study to Optimize Dose, time to treat before or after CD challenge to achieve 100% survival for over 27 days in animal model, a goal to do initial clinical trials during this Phase II period.