Subgroup Analysis of Pooled Phase 3 Efficacy Data from Two Randomized Trials of Gepotidacin Versus Nitrofurantoin in Uncomplicated Urinary Tract Infections (EAGLE-2 and EAGLE-3) including Participants with Uropathogens Not-Susceptible to Nitrofurantoin.

Abstract

Two Phase 3 trials (EAGLE-2 [NCT04020341]/EAGLE-3 [NCT04187144]) demonstrated the efficacy of gepotidacin, a novel, first-in-class triazaacenaphthylene antibacterial, versus nitrofurantoin for the treatment of uncomplicated urinary tract infections (uUTIs). Using pooled data, we assessed gepotidacin efficacy across clinically important subgroups, including participants with nitrofurantoin not-susceptible (NTF-NS; i.e., resistant, intermediate or no interpretation) uropathogens. Female participants aged ≥12 years with uUTI received gepotidacin (1500 mg) or nitrofurantoin (100 mg), both twice daily for 5 days. Therapeutic success at test-of-cure (day 10-13) was defined as combined complete symptom resolution (clinical success) and reduction of baseline qualifying uropathogens from ≥105 to <103 CFU/mL (microbiological success), without other systemic antibacterials. Response rates at test-of-cure were descriptively summarized in the pooled microbiological intent-to-treat (micro-ITT) nitrofurantoin-susceptible (NTF-S) and NTF-NS populations, and across prespecified subgroups. In the micro-ITT NTF-S population, treatment differences (in favor of gepotidacin) [95% confidence interval] for therapeutic, clinical and microbiological success were: 9.6% [4.1, 15.2], 2.8% [-2.4, 8.1], and 10.4% [5.2, 15.6]. Corresponding treatment differences were higher in the micro-ITT NTF-NS population: 20.8% [9.2, 32.4], 10.3% [-1.4, 22.1], 20.7% [9.2, 32.3]. In both of these populations, gepotidacin success rates (all endpoints) were similar to or higher than nitrofurantoin across prespecified subgroups at higher risk for antimicrobial resistant uropathogens (age >50 years, history of recurrent uUTI, diabetes, mild renal impairment, extended-spectrum β-lactamase-producing or fluoroquinolone-resistant uropathogens). Gepotidacin demonstrated efficacy with generally higher therapeutic success rates versus nitrofurantoin in participants with NTF-S and NTF-NS uropathogens, and across a range of key subgroups.