P31 Efficacy and safety of oral gepotidacin in the treatment of uncomplicated urinary tract infection: results of two randomized, multicentre Phase 3 trials (EAGLE-2 and EAGLE-3)
Authors: Wagenlehner Florian , Perry Caroline R , Hooton Thomas M , Scangarella-Oman Nicole E , Millns Helen , (Ed) Feng Hwa-ping , Powell Marcy , Jarvis Emily , Dennison Jeremy , Sheets Amanda , Butler Deborah , Breton John , Janmohamed Salim 
Published: August 2023

Abstract

Background
Uncomplicated urinary tract infections (uUTIs) are among the most prevalent infections worldwide. Currently, treatments are limited by antimicrobial resistance and antibiotic allergy/intolerance. There is an unmet need for new oral antibiotics active against uropathogens resistant to current treatments. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and binding site and provides well-balanced inhibition of two Type II topoisomerase enzymes. Gepotidacin is under investigation for treatment of uUTI.

Methods
EAGLE-2 (NCT04020341) and EAGLE-3 (NCT04187144) were near-identical global Phase 3, randomized, parallel-group, double-blind, non-inferiority (10% margin) studies comparing the efficacy and safety of oral gepotidacin (1500 mg twice daily, 5 days) to nitrofurantoin (100 mg [Macrobid] twice daily, 5 days) for the treatment of uUTI. Eligible female patients were aged ≥12 years with ≥2 uUTI symptoms and urinary nitrite or pyuria (Figure 1). Per latest US FDA guidance, the primary endpoint, therapeutic response at test-of-cure (Days 10–13), was evaluated in patients with qualifying uropathogen(s) (≥105 cfu/mL) susceptible to nitrofurantoin. Therapeutic success was combined clinical success (complete resolution of symptoms) and microbiological success (reduction of uropathogen[s] to &lt;103 cfu/mL) without additional systemic antimicrobials. Data below are from a predefined interim analysis (IA) with efficacy/futility stopping criteria, conducted by an Independent Data Monitoring Committee (IDMC).

Results
A total of 2986 randomized patients (EAGLE-2: N=1474; EAGLE-3: N=1512) were included in the IA. See Table 1 for key efficacy results available to IDMC that led to their recommendation to stop both studies for efficacy (non-inferiority) with no concerning safety findings. Table 1.Therapeutic, clinical, and microbiological response at test-of-cure (data available to IDMC)EndpointGepotidacin 1500 mg BIDNitrofurantoin 100 mg BIDTreatment difference (gepotidacin – nitrofurantoin) (95% CI)aEAGLE-2N=320N=287 Therapeutic success162 (50.6%)135 (47.0%)4.3% (−3.6%, 12.1%) Clinical success210 (65.6%)187 (65.2%)1.2% (−6.3%, 8.7%) Microbiological success232 (72.5%)194 (67.6%)5.2% (−2.1%, 12.5%)EAGLE-3N=277N=264 Therapeutic success162 (58.5%)115 (43.6%)14.6% (6.4%, 22.8%) Clinical success188 (67.9%)167 (63.3%)4.4% (−3.5%, 12.3%) Microbiological success200 (72.2%)151 (57.2%)15.0% (7.2%, 22.9%)Study success rules were based on pre-defined interim analysis rules. Both studies were stopped for non-inferiority as the observed Z statistics of 3.5554 (EAGLE-2) and 5.8838 (EAGLE-3) were greater than the non-inferiority boundaries of the respective studies (2.065 for EAGLE-2 and 2.098 for EAGLE-3). Following pre-specified hierarchical testing strategy, superiority was then demonstrated in EAGLE-3 (observed one-sided P value of 0.0003 less than the superiority boundary [0.018]).Calculated using Miettinen–Nurminen test adjusting for age and recurrence history.These endpoints were evaluated in patients with all qualifying uropathogens determined to be susceptible to nitrofurantoin.BID, twice daily.

Conclusions
In two large Phase 3 trials using the latest, stringent, FDA efficacy endpoint, gepotidacin demonstrated non-inferiority in one trial and superiority in the other versus nitrofurantoin in the treatment of uUTI with an acceptable safety and tolerability profile. These data will be further described. Gepotidacin has the potential to be a useful oral antibiotic to treat uUTI and its evaluation in Phase 3 trials is an important step in addressing a significant unmet need.