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

Abstract

DS-2969b is a novel GyrB inhibitor in development for the treatment of infection (CDI). The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on the 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 subjects received DS-2969b, and two received 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 the maximum concentration of drug in serum () and the area under the concentration-time curve (AUC) increased less than dose proportionally. In all cohorts, sufficient fecal levels of DS-2969a were achieved within 24 h following the administration of the first dose and maintained for at least 17 days. Following treatment with DS-2969b, clear reductions in the populations of and groups were observed. However, populations of three other bacterial groups examined (, , and) were not affected. Data from this study support and encourage the further development of DS-2969b as a novel treatment for CDI.

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

“…Furthermore, DS-2969 demonstrated superior activity against the NAP1/027 strain of C. difficile compared to vancomycin or fidaxomicin [193]. One pharmacological property of potential concern for DS-2969b is its much higher relative oral bioavailability and systemic exposure compared to vancomycin and fidaxomicin, with up to an estimated 70% in an in vivo study featuring cynomolgus monkeys [193,195].…”

“…A more recent 2018 phase I study, evaluating the safety, tolerability, pharmacokinetic and pharmacodynamic properties of daily oral ascending doses of DS-2969b in healthy human adults, demonstrated its safety in all dose cohorts, including 400 mg of oral daily doses for up to 14 days [195]. Plasma half-life of DS-2969b was determined to be approximately 15 h, with mainly renal excretion, but also via faecal routes [195].…”

“…A more recent 2018 phase I study, evaluating the safety, tolerability, pharmacokinetic and pharmacodynamic properties of daily oral ascending doses of DS-2969b in healthy human adults, demonstrated its safety in all dose cohorts, including 400 mg of oral daily doses for up to 14 days [195]. Plasma half-life of DS-2969b was determined to be approximately 15 h, with mainly renal excretion, but also via faecal routes [195]. Drug-related adverse reactions occurred in three subjects given the 400 mg dose [196], with the commonest treatment-emergent adverse events being constipation (1/18, 5.6%), abdominal bloating (1/18, 5.6%), left lower quadrant abdominal pain with hematochezia (1/18, 5.6%), and diarrhoea (1/18, 5.6%), with no dose-effect relationship identified [195,196].…”

“…Plasma half-life of DS-2969b was determined to be approximately 15 h, with mainly renal excretion, but also via faecal routes [195]. Drug-related adverse reactions occurred in three subjects given the 400 mg dose [196], with the commonest treatment-emergent adverse events being constipation (1/18, 5.6%), abdominal bloating (1/18, 5.6%), left lower quadrant abdominal pain with hematochezia (1/18, 5.6%), and diarrhoea (1/18, 5.6%), with no dose-effect relationship identified [195,196].…”

<p>Investigational Treatment Agents for Recurrent <em>Clostridioides difficile</em> Infection (rCDI)</p>

“…44 There have been two studies that evaluated the safety, tolerability, pharmacokinetics and effects of DS-2969b in healthy volunteers. 46,47 One study examined the effects of three sequential ascending dose (60 mg, 200 mg, and 400 mg) cohort with six subjects and placebo groups with 2 subjects every day for 14 days. One study (n=47) evaluated a 14-day regimen of five sequential ascendingdose (6 mg, 20 mg, 60 mg, 200 mg, and 400 mg) cohort with six subjects and placebo groups with 2 subjects.…”