Originally published by our sister publication Infectious Disease Special Edition
The FDA approved gepotidacin (Blujepa, GSK) for the treatment of female adults (≥40 kg) and children (≥12 years of age, ≥40 kg) with uncomplicated urinary tract infections (uUTIs) caused by susceptible organisms. This is the first new class of antibiotic for UTIs in nearly three decades.
It is indicated for uUTIs caused by Citrobacter freundii complex, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae and Staphylococcus saprophyticus.
Gepotidacin is a first-in-class oral bactericidal triazaacenaphthylene antibiotic with a novel mechanism of action. Gepotidacin works by inhibiting bacterial DNA replication by a distinct binding site, a novel mechanism of action and for most pathogens, provides well-balanced inhibition of two different Type II topoisomerase enzymes. This provides activity against most target uropathogens (e.g., E. coli and S. saprophyticus) and Neisseria gonorrhoeae, including isolates resistant to current antibiotics. Due to the well-balanced inhibition for most pathogens, gepotidacin target-specific mutations in both enzymes are needed to significantly affect susceptibility to gepotidacin. Therefore, a lower potential for developing resistance is expected.
The approval is based on positive results from the pivotal phase 3 EAGLE-2 and EAGLE-3 trials, which compared the efficacy and safety of gepotidacin (1,500 mg administered orally twice daily for five days) versus nitrofurantoin (100 mg administered orally twice daily for five days) with 1,531 and 1,605 female adults and pediatric patients with uUTIs, respectively. Across both trials, follow-up for participants was approximately 28 days, and the primary end point, a stringent composite measure of efficacy, was the combined clinical and microbiological response at the test-of-cure visit (days 10-13) in patients with qualifying uropathogens susceptible to nitrofurantoin.
The results demonstrated noninferiority to nitrofurantoin, one of the current standard-of-care options for uUTIs, in female adults (≥40 kg) and children (≥12 years, ≥40 kg) with a confirmed uUTI. In EAGLE-2, gepotidacin demonstrated noninferiority in therapeutic success, which occurred in 50.6% (162/320) of participants compared with 47.0% (135/287) for nitrofurantoin (covariate-adjusted treatment difference, 4.3%; 95% CI, –3.6% to 12.1%). In EAGLE-3, gepotidacin demonstrated statistically significant superiority versus nitrofurantoin (one-sided P=0.0003). Therapeutic success occurred in 58.5% (162/277) of participants compared with 43.6% (115/264) for nitrofurantoin (covariate-adjusted treatment difference, 14.6%; 95% CI, 6.4%-22.8%).
EAGLE-1 (noninferiority uncomplicated urogenital gonorrhea trial) compared the efficacy and safety of gepotidacin with ceftriaxone plus azithromycin in 628 patients with uncomplicated urogenital gonorrhea caused by N. gonorrhoeae.
The safety and tolerability profile of gepotidacin in the EAGLE-2 and EAGLE-3 phase 3 trials was consistent with previous studies. The most commonly reported adverse events (AEs) in gepotidacin participants were gastrointestinal. Diarrhea was the most common, followed by nausea. Of the participants who reported GI AEs in the gepotidacin group, the most common maximum severity was mild (69% grade 1) and moderate (28% grade 2). Participants with grade 3 GI events accounted for 3% of all patients with GI events and occurred in less than 1% of all participants. There was one drug-related serious AE in each treatment arm (gepotidacin and nitrofurantoin) across the two trials. The U.S. prescribing information is available here.
Uncomplicated UTIs are the most common infection in women, affecting up to 16 million in the United States annually (Infect Dis Clin North Am 2014;28[1]:1-13). More than half of all women experience a uUTI in their lifetime (Prz Menopauzalny 2021;20[1]:40-47), with approximately 30% suffering from at least one recurrent episode that can cause significant patient burden, including discomfort and restriction of daily activities (BMJ 2010;340:b5633).
“For many, uUTIs can be a burden that severely impacts daily life. With an increasing number of patients experiencing recurrent infections, there remains a clear need for continued research of antimicrobials to help address ongoing patient challenges and the strain on healthcare systems,” said Thomas Hooton, MD, a professor of clinical medicine at the University of Miami Miller School of Medicine.
The new medication should be available in the United States in the second half of 2025.
The development of gepotidacin was funded in part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under Other Transaction Agreement number HHSO100201300011C; and with federal funds awarded by the Defense Threat Reduction Agency under agreement number HDTRA1-07-9-0002.