A Phase 1 Study in Healthy Subjects to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Oral Doses of DS-2969b, a Novel GyrB Inhibitor [PublishAheadOfPrint]

DS-2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection (CDI). The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on normal gastrointestinal microbiota of multiple daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled three sequential ascending dose cohorts (60 mg, 200 mg, and 400 mg). In each cohort, subjects received an oral dose of DS-2969b or placebo (six DS-2969b and two placebo) each morning for 14 days. DS-2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS-2969b were mild, and predominantly related to the gastrointestinal tract. DS-2969a (free form of DS-2969b) plasma concentrations increased with increasing doses, however, both C_max and AUC increased less than dose-proportionally. In all cohorts, sufficient fecal levels of DS-2969a were achieved within 24 hours following the administration of the first dose and maintained for at least 17 days. Following treatment with DS-2696b, a clear reduction in Clostridium coccoides and Bifidobacterium groups was observed. However, populations of three other bacterial groups examined (Bacteroides fragilis, Clostridium leptum, and Prevotella) were not affected. Data from this study support and encourage further development of DS-2969b as a novel treatment for CDI.

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