Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944) in the Treatment of Patients with Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections

Abstract

Gepotidacin is a novel, first-in-class, triazaacenaphthylene antibacterial agent which has in vitro activity against causative pathogens of acute bacterial skin and skin structure infections (ABSSSIs). This phase 2, randomized, 2-part, multicenter, dose-ranging, response-adaptive study with optional intravenous-oral switch evaluated the efficacy and safety of gepotidacin for the treatment of Gram-positive ABSSSIs in 122 adult patients in the United States. The study had a double-blind phase (part 1; intravenous [750 mg or 1,000 mg every 12 h {q12h}]) and an open-label phase (part 2; intravenous [750 mg q12h, 1,000 mg q12h, or 1,000 q8h]). The primary endpoint was a composite of efficacy and safety which consisted of the early cure rate and the withdrawal rate due to drug-related adverse events and utilized a clinical utility index for dose selection. At the early efficacy visit (48 to 72 h after the first dose), the 750-mg q12h and 1,000-mg q8h groups met prespecified success criteria for clinical utility in terms of efficacy and safety; however, the 1,000-mg q12h group did not meet these criteria due to observed lower efficacy rates. The most frequently reported adverse events were nausea (20%) and diarrhea (13%). These encouraging phase 2 results demonstrate the potential for gepotidacin to meet the medical need for novel antibacterial agents to treat ABSSSIs due to drug-resistant pathogens through a unique mechanism of action. (This study has been registered at ClinicalTrials.gov under registration no. NCT02045797.).

Keywords: ABSSSI; antibacterial agent; antimicrobial safety; efficacy; gepotidacin; phase 2 study; skin infections.

FIG 1

Study design. In both part 1 and part 2, at the discretion of the investigator, patients who completed the minimum intravenous dosing duration could be switched to a corresponding unblinded oral dosing regimen (1,500 mg or 2,000 mg twice a day, or 2,000 mg three times a day for part 2) in an outpatient setting to complete 10 days of total treatment. Part 2 was expected to enroll approximately 80 patients by use of an adaptive randomization strategy. A total of 86 patients were enrolled in part 2. Each of the preidentified doses for part 2 were used based on the outcomes of the analyses from part 1. The maximum dose was not to exceed a total daily dose of 4.5 g/day given intravenously or 6.0 g/day given orally.

FIG 2

Adaptive randomization allocation ratios over time following each interim analysis (all-randomized population). The initial randomization bar represents part 1 of the study, where there was 1:1 randomization allocation to the 750-mg q12h and 1,000-mg q12h treatment groups. Interim analysis 5 represents the randomization allocation should the study have continued further.

FIG 3

Clinical response (with 95% confidence interval) by dose group (mITT population). Mean success rates for the early efficacy visit were as follows: 750-mg q12h group, 83%; 1,000-mg q12h group, 72%; and 1,000-mg q8h group, 92%. Mean success rates for the posttherapy visit were as follows: 750-mg q12h group, 90%; 1,000-mg q12h group, 82%; and 1,000-mg q8h group, 84%. Mean success rates for the final follow-up visit were as follows: 750-mg q12h group, 86%; 1,000-mg q12h group, 72%; and 1,000-mg q8h group, 80%.