1361. Pharmacokinetics and Safety of Ridinilazole (RDZ), a Potential New Therapy for Clostridium difficile Infection (CDI): From Animal Models to Patients

BACKGROUND: CDI is the leading cause of nosocomial diarrhea associated with 29,000 deaths p.a. in the United States. RDZ is a novel oral drug highly selective for C. difficile limiting collateral damage to the gut microbiota. Here we present a combined analysis of all pharmacokinetic (PK) and tolerability data obtained throughout the development of RDZ from animal models to Phase 2, including new human PK data. METHODS: RDZ levels were measured in plasma and in the GI tract of infected hamster after a single oral dose at 25 mg/kg. Quantitative whole-body autoradiography (QWBA) and excretion mass balance studies were performed in rats following a single 50 mg/kg oral dose of (14)C RDZ. In GLP toxicology studies, RDZ was administered orally for 28 days to dogs and rats at 1,000 mg/kg/day. Toxicokinetic, clinical pathology, and histopathology analysis were performed. The Phase 1 study enrolled 56 healthy male subjects receiving single ascending doses from 2 to 2,000 mg, or, 200 or 500 mg BID for 10 days. The Phase 2 enrolled 100 patients assigned 1:1 to 10 days oral RDZ 200 mg BID or VAN 125 mg QID treatment. Both clinical trials quantified RDZ in plasma and feces, and assessed safety and tolerability. RESULTS: In all animal studies, plasma levels of RDZ were below or at the limit of quantification (LOQ, 1.0 ng/mL). In the GI tract of hamsters, RDZ levels were highest in the colon. QWBA and excretion studies showed RDZ accumulated in the cecum and colon, the site of infection; >99% of radioactivity was excreted in feces and no radioactivity was detected systemically. 28 days repeat dosing in dog and rat resulted in no observations from treatment, histopathology or in-life parameters. In Phase 1 and 2 studies, RDZ plasma levels were generally near or below the LOQ (0.1 ng/mL). Concomitant medications, CDI severity, and age had no impact on exposure. In Phase 1, AEs were mild with no dose-dependent relationship, occurring and at a similar incidence to placebo. No significant findings from clinical laboratory, ECGs or other assessment were observed. RDZ was well tolerated in Phase 2 with the incidence of AEs and SAEs similar in both RDZ and VAN groups. CONCLUSION: In both clinical and nonclinical studies to date, RDZ has been well tolerated and associated with low systemic absorption. Further assessment of safety, tolerability, and PK in Phase 3 studies is warranted. DISCLOSURES: E. Duperchy, Summit Therapeutics: Employee, Salary. S. Chowdhury, Summit Therapeutics Inc.: Employee and Shareholder, Salary and Shareholder. R. Vickers, Summit Therapeutics: Employee, Salary and Stock options. N. Robinson, Summit Therapeutics: Consultant, Consulting fee.