Further Phase 3 Study Insights for Newly Approved Gepotidacin for Gonorrhea

Yesterday, the FDA approved gepotidacin (Blujepa) for the treatment of uncomplicated urogenital gonorrhea in patients 12 years or older (weighing ≥ 45 kg [99.2 lb]).

This approval was based from data of the EAGLE-1 phase 3 trial results, which were published in The Lancet. The results showed that gepotidacin (was noninferior, with a 92.6% success rate at urogenital site when compared with a 91.2% success rate for intramuscular ceftriaxone (500 mg) plus oral azithromycin (1000 mg) combined therapy.¹

Contagion spoke to GSK VP Head of Infectious Disease Research David Payne, PhD, who offered more information about the study including its safety profile, efficacy results, and the importance of the lack of bacterial persistence at the urogenital site.

Contagion: How did the design of the EAGLE-1 phase 3 noninferiority trial support confidence in comparing oral gepotidacin with the standard ceftriaxone-plus-azithromycin regimen for uncomplicated urogenital gonorrhea?

Payne: The EAGLE 1 phase 3 trial showed that gepotidacin (oral, two doses of 3,000mg) was non-inferior with 92.6% success rates (187/202 [95% CI 88–95.8]) at urogenital site when compared to 91.2% success rates (186/204 [95% CI 86.4–94.7]) for intramuscular ceftriaxone (500mg) plus oral azithromycin (1,000mg) combined therapy, a leading combination treatment regimen for gonorrhea. The study additionally found that there were no failures at the urogenital site due to bacterial persistence of N gonorrhoeae in either treatment arms.

The safety and tolerability profile of gepotidacin in the EAGLE-1 trial was consistent with results seen in previous clinical trials, with no serious drug related AEs observed in either the gepotidacin arm or the comparator arm. The most commonly reported AEs in gepotidacin subjects were GI. All AEs were mild (45% Grade 1) or moderate (29% Grade 2) except for one severe (<1% Grade 3), unrelated event in each treatment arm and one unrelated serious event in the gepotidacin arm.

The approval is supported by these data—making Blujepa the first in a new antibiotic class for the treatment of gonorrhea approved in over three decades, and a new oral option for US patients with gonorrhea currently relying on injectable treatments. Gepotidacin maintained efficacy against isolates of N gonorrhoeae that were resistant or non-susceptible to existing antibacterials, a crucial factor given the rising threat of AMR to current available treatments. The ability of N gonorrhoeae to develop resistance to currently available options, including standard of care, makes it important to expand the range of effective oral treatments.

Contagion: What is the clinical significance of gepotidacin achieving a 92.6% urogenital cure rate and demonstrating noninferiority within the prespecified –10% margin compared with the current standard of care?

Payne: The standard of care treatment for gonorrhoea includes an intramuscular injection of ceftriaxone, a highly effective antibiotic with low resistance recorded in the US. However, efficacious alternatives are needed in cases where the current standard of care may not be suitable (eg, patient allergies, intolerances, or needle-phobia) or should resistance increase in the US as is already the case in other parts of the world.

Contagion: How do the safety and tolerability findings from EAGLE-1—particularly the absence of serious drug-related adverse events—inform the potential role of gepotidacin as a future oral treatment option?

Payne: The safety and tolerability profile of gepotidacin in the EAGLE-1 trial was consistent with results seen in previous clinical trials, with no serious drug related adverse events (AEs) observed in either the gepotidacin arm or the comparator arm. The most commonly reported AEs in gepotidacin subjects were GI. All AEs were mild (45% Grade 1) or moderate (29% Grade 2) except for one severe (<1% Grade 3), unrelated event in each treatment arm and one unrelated serious event in the gepotidacin arm.

In the US, the standard of care treatment for gonorrhea includes an intramuscular injection of ceftriaxone, a highly effective antibiotic with low resistance recorded in the US. However, efficacious alternatives are needed in cases where the current standard of care may not be suitable (eg, patient allergies, intolerances, or needle-phobia) or should resistance increase in the US as is already the case in other parts of the world.

 With this approval, Blujepa is now available to US patients for the treatment of uncomplicated urogenital gonorrhoea when appropriate. For the treatment of uUTI, gepotidacin has been available in the US since October with commercial launch planned for Q1 2026.

Contagion: Why is the lack of bacterial persistence of Neisseria gonorrhoeae in both treatment arms an important outcome, and how might this influence future antimicrobial stewardship or treatment guidelines?

Payne: The study found that there were no failures at the urogenital site due to bacterial persistence of N gonorrhoeae in either treatment arms. Gepotidacin maintained efficacy against isolates of N gonorrhoeae that were resistant or non-susceptible to existing antibacterials, which is a crucial factor given the rising threat of AMR to current available treatments. Lack of bacterial persistence at the urogenital site means a ‘microbiological cure’ or absence of persisters and therefore reduced likelihood of relapse of current infection and transmission to others. Lack of persistence thus confirms efficacy and absence of resistance GC.

Robust stewardship measures are essential to preserve the effectiveness of anti-infectives. All medical education activities on Blujepa will be pursued in alignment with stewardship principles and within the confines of the FDA indication.

Contagion: With gepotidacin getting FDA approved, where do you see its place in the market and how clinicians may be able to prescribe it?

Payne: With this approval, Blujepa is now available to US patients for the treatment of with uncomplicated urogenital gonorrhea in alignment with the FDA’s label. For the treatment of uUTI, gepotidacin has been available in the US since October with commercial launch planned for Q1 2026.

Reference

1. Ross JDC, Wilson J, Workowski KA, et al. Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhea (EAGLE-1): a phase 3 randomised, open-label, non-inferiority, multicentre study. Lancet. 2025;405(10489):1608-1620. doi:10.1016/S0140-6736(25)00628-2