Gepotidacin was non-inferior to nitrofurantoin in both trials and superior in one, with acceptable safety, offering a potential new oral option for uncomplicated UTI.

Background

Uncomplicated urinary tract infections (UTIs) are common in women and are typically treated empirically with oral antibiotics. Rising antimicrobial resistance, contraindications, and limited efficacy of some current options highlight the need for new, effective oral agents. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA gyrase and topoisomerase IV at unique binding sites and retains activity against common uropathogens, including drug-resistant phenotypes.

Patients

• Adolescents and adults assigned female at birth, non-pregnant, aged ≥12 years, weight ≥40 kg.
• ≥2 symptoms (dysuria, frequency, urgency, or lower abdominal pain) beginning within 96 hours of entry; evidence of urinary nitrite, pyuria, or both.
• Key exclusions: symptoms due to other conditions, anatomical/physiological anomalies or complicated UTI, suspected upper UTI, uncontrolled diabetes, known creatinine clearance <60 mL/min (those found after enrollment could continue per investigator), and other safety concerns.
• Primary analysis population: patients with ≥10⁵ CFU/mL qualifying uropathogen(s) at baseline that were nitrofurantoin-susceptible (NTF-S) who received ≥1 dose.
• Enrollment: EAGLE-2 randomized 1531; EAGLE-3 randomized 1605 across 219 centers in 15 countries.

Intervention

Gepotidacin 1500 mg orally twice daily for 5 days.

Control

Nitrofurantoin monohydrate/macrocrystals (Macrobid) 100 mg orally twice daily for 5 days.

Outcome

• Primary: Therapeutic response (success vs failure) at test-of-cure (TOC, day 10–13), defined as both clinical success (complete symptom resolution; score 0) and microbiological success (reduction of qualifying uropathogen(s) to <10³ CFU/mL) without other systemic antibiotic use before TOC.
• Key secondary:
  • Clinical success and microbiological success at TOC and at follow-up (day 25–31; sustained success among TOC successes).
  • Therapeutic response by baseline pathogen (including resistant phenotypes).
  • Safety and tolerability.

Study Design

• Two global, multicenter, randomized (1:1), double-blind, double-dummy, phase 3 non-inferiority trials (margin 10%).
• Stratified by age group and history of recurrent uncomplicated UTI.
• Group-sequential design with a single planned interim analysis; both trials stopped early for efficacy (non-inferiority achieved).
• Primary analysis per FDA/EMA guidance limited to microbiological ITT NTF-S population who reached/should have reached TOC at interim.
• Registrations: NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3).

Level of Evidence

Level 1b (individual randomized controlled trials).

Follow up period

• Test-of-cure: day 10–13.
• Follow-up: day 25–31.

Results

Primary outcome (therapeutic success at TOC; microbiological ITT NTF-S interim set)

• EAGLE-2: 50.6% (162/320) gepotidacin vs 47.0% (135/287) nitrofurantoin; adjusted difference 4.3% (95% CI −3.6 to 12.1). Non-inferior.
• EAGLE-3: 58.5% (162/277) gepotidacin vs 43.6% (115/264) nitrofurantoin; adjusted difference 14.6% (95% CI 6.4 to 22.8). Non-inferior and superior.
  • NNT: 7 to achieve one additional therapeutic success at TOC (based on 14.6% absolute difference).

Secondary outcomes at TOC

• Clinical success:
  • EAGLE-2: 65.6% vs 65.2% (difference 1.2%; 95% CI −6.3 to 8.7).
  • EAGLE-3: 67.9% vs 63.3% (difference 4.4%; 95% CI −3.5 to 12.3).
• Microbiological success:
  • EAGLE-2: 72.5% vs 67.6% (difference 5.2%; 95% CI −2.1 to 12.5).
  • EAGLE-3: 72.2% vs 57.2% (difference 15.0%; 95% CI 7.2 to 22.9).
    • NNT: 7 to achieve one additional microbiological success.

Follow-up (sustained success among TOC successes; complete microbiological ITT NTF-S)

• EAGLE-2: 34.8% vs 31.5% (difference 4.1%; 95% CI −3.1 to 11.3).
• EAGLE-3: 43.2% vs 34.5% (difference 7.6%; 95% CI −0.2 to 15.4).

By pathogen (exploratory)

• Escherichia coli (most prevalent): overall therapeutic success favored gepotidacin in both trials; activity retained against ESBL-producing, fluoroquinolone-resistant, TMP-SMX–resistant, and multidrug-resistant phenotypes.

Safety

• Any treatment-emergent adverse event: 35% (gepotidacin) vs 22–25% (nitrofurantoin).
• Most common events:
  • Gepotidacin: diarrhea 14–18%, nausea 8–11% (mostly mild/moderate).
  • Nitrofurantoin: nausea 4%, diarrhea 3–4%.
• Serious AEs rare; no life-threatening or fatal events. Clostridioides difficile–associated diarrhea <1% with gepotidacin; none with nitrofurantoin.

Limitations

• Trials stopped early at interim after meeting non-inferiority; primary analysis limited to interim data set and NTF-susceptible uropathogens.
• Stringent composite endpoint (complete symptom resolution plus microbiological success) and classification of missing data as failures likely lowered observed success rates vs historical literature.
• Clinician-scored symptom tool (per regulatory guidance) not externally validated; potential subjectivity.
• Discordance between clinical and microbiological components; generalizability may be limited to populations similar to the trial cohort.
• Under-representation of some racial groups.

Funding

GSK and the US Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA). Medical writing support funded by GSK.

Citation

Wagenlehner F, Perry CR, Hooton TM, Scangarella-Oman NE, Millns H, Powell M, et al. Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials. The Lancet. 2024;403:741–755. doi:10.1016/S0140-6736(23)02196-7. Published online Feb 8, 2024.