A Phase 1 Study in Healthy Subjects to Investigate Safety, Pharmacokinetics, and Effect on Intestinal Flora of Multiple Ascending Doses of DS-2969b, A Novel Oral DNA Gyrase B Inhibitor for The Treatment of Clostridium difficile Infection

We discovered DS-2969b, a novel oral DNA gyrase B inhibitor, for the treatment of Clostridium difficile infection (CDI), including the life-threatening infection due to the hyper-virulent NAP1/027 strain. DS-2969b showed dose-dependent efficacy in a hamster model of NAP1/027 infection, which was superior to vancomycin or fidaxomicin. DS-2969b proved safe and well tolerated in pre-clinical toxicology studies and in a first-in-human single ascending dose study in healthy subjects, which enabled conducting the multiple ascending dose study reported here to characterize its safety, pharmacokinetics, and effect on intestinal flora in healthy subjects over 14 days of daily administrations. Design: Investigator-blinded, sponsor-unblinded, placebo-controlled, randomized, single-center, sequential cohort study. Participants: 24 healthy male and female subjects (age 18 and 64) in three dose level cohorts of 8 each, randomized 6 to 2 active to placebo. Intervention: Daily oral administration of DS-2969b at the doses of 60, 200, and 400 mg or of placebo for 14 consecutive days. DS-2969b was safe and well-tolerated up to and including the dose of 400 mg. Adverse events were nearly all mild and not drug-related, except for abdominal pain, constipation, and diarrhea observed as mild and drug-related in 3 respective subjects given 400 mg. Systemic exposure was less than dose-dependent and accumulation increased with the dose up to 48%. Plasma half-life was about 15 hours. The major elimination route was urinary excretion. More than two log10 CFU reduction was observed in two bacterial groups in the intestinal flora, i.e., the Clostridium coccoides and the Bifidobacterium groups. No reduction was observed in other groups (Figure 1). Since C. difficile shows higher in-vitro susceptibility to DS-2969b than these two groups (Figure 2), DS-2969b administration seems to have attained at all doses concentrations sufficient for the killing of C. difficile. Preserving the normal intestinal flora is important, as it may deter CDI recurrence. The results of the study support further development of DS-2969b. S. Inoue, Daiichi Sankyo Co., Ltd.: Employee, Salary; R. Gajee, Daiichi Sankyo Inc.: Employee, Salary; N. Masuda, Daiichi Sankyo Co., Ltd.: Employee, Salary; G. Senaldi, Daiichi Sankyo Inc.: Employee, Salary.