2837. Impact of Regulatory Guidelines on Therapeutic, Clinical, and Microbiological Success Rates in Uncomplicated Urinary Tract Infection: Results from a Two Phase 3 Randomized Controlled Trials of Oral Gepotidacin (EAGLE-2 and EAGLE-3)

BACKGROUND: For noninferiority RCTs in uUTIs, the latest US Food and Drug Administration (FDA; 2019)/European Medicines Agency (EMA; 2018) guidance recommends a primary endpoint of therapeutic response (combined clinical and microbiologic response) with success defined by full symptom resolution plus microbiological eradication from ≥ 10(5) to < 10(3) CFU/mL. Historically, less stringent criteria (clinical or microbiological [not combined], allowing symptom improvement/resolution) and various endpoints were used; success rates of 70–92% have been reported for NTF (Table 1). Gepotidacin, a novel, first-in-class, triazaacenaphthylene, bactericidal ABX has been investigated for uUTI treatment in 2 RCTs, EAGLE-2 (E-2; NCT04020341) and -3 (E-3; NCT04187144) following FDA/EMA guidance. Here, we demonstrate the impact of new endpoint guidance on the RCT results. [Figure: see text] METHODS: E-2 and -3 were global Phase 3, parallel-group, double-blind, noninferiority (10% margin) RCTs comparing the efficacy and safety of oral gepotidacin (1500mg BID, 5 days) vs NTF (100mg BID, 5 days) in female patients (≥ 12 years) with uUTI. Using the complete study dataset, we assessed all patients who received ≥ 1 dose of study drug and had 1–2 qualifying uropathogens (≥ 10(5) CFU/mL) susceptible to NTF. TOC was 10–13 days post first dose, FU was 28 (±3) days. RESULTS: In E-2/-3, the primary endpoint was assessed in 634/567 patients (41/35% of ITT; Table 2). At TOC in E-2/-3, clinical success was 66.7/68.2% for gepotidacin, and 65.8/63.6% for NTF. Microbiological success in E-2/-3 was 72.6/72.9% for gepotidacin, and 66.8/57.5% for NTF. TOC therapeutic success rates (E-2/E-3) were lower than clinical or microbiological rates for both treatments: 51.8/58.9% for gepotidacin, 47.0/44.0% NTF (Table 3). Exploratory analysis replacing clinical ‘resolution’ with ‘near success’ increased TOC therapeutic success rates by 6.2–9.5% (Table 3). Use of non-study ABX for uUTI was substantially lower than the overall rate of therapeutic failure at TOC and FU. [Figure: see text] [Figure: see text] CONCLUSION: In these 2 RCTs using recent regulatory criteria that set a high threshold for uUTI treatment efficacy, therapeutic and clinical success rates were lower than some historic studies. Contemporary study results using new guidance cannot be directly compared with historical studies. DISCLOSURES: Florian Wagenlehner, MD, Achaogen: Advisory Board member, study participation|Astellas: Honoraria|AstraZeneca: Honoraria|AstraZeneca: Advisory Board member|Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Bionorica: Honoraria|Bionorica: Meeting/travel support, study participation|Deutsches Zentrum für Infektionsforschung (DZIF): Study participation|Enteris BioPharma: Study participation|Everest Medicines: Grant/Research Support|German S3 guideline Urinary tract infections: Board Member|Glaxo Smith Kline: Advisor/Consultant|Glaxo Smith Kline: Honoraria|Glaxo Smith Kline: Consulting fees, meeting/travel support, advisory board member, principal investigator in a GSK-sponsored study|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Guidelines European Association of Urology: Infections in Urology: Board Member|Helperby Therapeutics: Study participation|Janssen: Honoraria|Janssen: Advisory Board member|Klosterfrau: Honoraria|LeoPharma: Advisory Board member|MerLion: Advisory Board member|MIP Pharma: Honoraria|MSD: Advisory Board member|OM Pharma/Vifor Pharma: Advisory Board member, study participation|OM-Pharma: Honoraria|Pfizer: Honoraria|Pfizer: Advisory Board member|RosenPharma: Advisory Board member|Shionogi: Advisory Board member, study participation|Speaker research group German research foundation (DFG) Bacterial Renal Infections and Defense (FOR 5427): Study participation|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Consulting fees|University Hospital Giessen and Marburg GmbH, and Justus Liebig University, Germany: Employee|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Consulting fees, Advisory Board member Caroline R. Perry, PhD, GSK: Employee and shareholder Thomas M. Hooton, MD, GSK: Advisor/Consultant Nicole E. Scangarella-Oman, MS, GSK: Employee and shareholder Helen Millns, PhD, GSK: Employee and shareholder Emily Jarvis, MSc, GSK: Employee and shareholder Jeremy Dennison, MD, GSK: Employee and shareholder Amanda Sheets, PhD, GSK: Employee and shareholder Salim Janmohamed, MD, GSK: Employee and shareholder