The FDA has accepted GSK's New Drug Application (NDA) for gepotidacin, an investigational oral antibiotic, and granted it Priority Review for the treatment of uncomplicated urinary tract infections (uUTIs) in female adults and adolescents. This decision, with a Prescription Drug User Fee Act (PDUFA) action date of March 26, 2025, could mark the introduction of the first new class of oral antibiotics for uUTIs in over two decades, addressing a critical need due to rising antibiotic resistance.
Clinical Trial Data
The NDA is based on positive results from the Phase III EAGLE-2 and EAGLE-3 trials. These studies compared the efficacy and safety of gepotidacin (1500 mg orally twice daily for five days) to nitrofurantoin (100 mg orally twice daily for five days) in female adults and adolescents with uUTIs.
In EAGLE-3, gepotidacin demonstrated statistically significant superiority versus nitrofurantoin, achieving therapeutic success in 58.5% of participants compared to 43.6% for nitrofurantoin. EAGLE-2 showed therapeutic success in 50.6% of participants treated with gepotidacin compared to 47.0% with nitrofurantoin, demonstrating non-inferiority.
Mechanism of Action
Gepotidacin is a bactericidal, first-in-class triazaacenaphthylene antibiotic. It inhibits bacterial DNA replication by binding to a distinct site on bacterial type II topoisomerase enzymes. This novel mechanism of action provides activity against common uropathogens, including those resistant to current antibiotics.
The Need for New Treatments
Over half of all women are affected by uUTIs in their lifetime, with approximately 30% experiencing recurrent infections. The increasing number of uUTIs caused by drug-resistant bacteria is leading to higher treatment failure rates, underscoring the urgent need for new treatment options. Chris Corsico, Senior Vice President of Development at GSK, stated that gepotidacin, if approved, will offer a much-needed additional oral treatment option for patients at risk of treatment failure associated with resistance or recurrence of uUTI.
Safety and Tolerability
The safety and tolerability profile of gepotidacin in the EAGLE-2 and EAGLE-3 trials was consistent with previous trials. The most commonly reported adverse events were gastrointestinal, with diarrhea (16%) and nausea (9%) being the most frequent. The majority of these events were mild to moderate in severity.
Expert Commentary
Florian Martin Erich Wagenlehner, MD, principal investigator for the EAGLE-2 trial, noted that gepotidacin is the first antibiotic to meet contemporary regulatory criteria, which set a high threshold for the efficacy of treatments in uncomplicated urinary tract infections. He added that gepotidacin has the potential to offer healthcare professionals another oral option to treat this common community infection.
