Oral Gepotidacin Noninferior to Standard Therapy for Gonorrhea in Phase 3 Trial

Lead author Jonathan D.C. Ross, MD

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An investigational oral antibiotic, gepotidacin, was found to be noninferior to the standard combination of intramuscular ceftriaxone and oral azithromycin for the treatment of uncomplicated urogenital gonorrhea, according to results from a phase 3 clinical trial published in The Lancet.

The EAGLE-1 trial enrolled 628 participants and compared 2 oral doses of gepotidacin (3000 mg, 10–12 hours apart) with a single standard dose of ceftriaxone (500 mg IM) plus azithromycin (1 g PO). In the primary analysis population, culture-confirmed eradication of Neisseria gonorrhoeae from the urogenital site at 4–8 days post-treatment was achieved in 92.6% of participants receiving gepotidacin, compared with 91.2% in the comparator group. The adjusted difference (–0.1%, 95% CI –5.6 to 5.5) met the predefined noninferiority margin of –10%.

While superiority was not established (P = 0.5072), no cases of bacterial persistence were observed in either group.

The findings suggest gepotidacin could offer a convenient oral alternative to injectable therapy for uncomplicated gonorrhea—a benefit for both patients and clinicians in light of rising antimicrobial resistance and declining efficacy of existing regimens.

Gepotidacin, a first-in-class triazaacenaphthylene antibiotic, has a novel dual-target mechanism of action and has shown in vitro activity against drug-resistant strains of N gonorrhoeae, including isolates resistant to ciprofloxacin, tetracycline, and penicillin.

“Gepotidacin is an investigational oral antibiotic with activity and efficacy against N gonorrhoeae, including drug-resistant strains, with an acceptable safety and tolerability profile,” researchers wrote. “The potential introduction of a novel oral antibacterial with proven in-vitro activity and in-vivo efficacy would represent a significant advancement in patient care for uncomplicated gonorrhoea.”

Eradication rates at rectal sites were 100% with gepotidacin in the evaluable population and 80% in the ceftriaxone-azithromycin group. Pharyngeal site clearance was lower with gepotidacin (78%) than with ceftriaxone-azithromycin (94%).

Of note, 12% of isolates carried the ParC Asp86Asn mutation, a known marker of resistance to quinolones and potential contributor to gepotidacin resistance. No isolates had the GyrA Ala92Thr mutation. All urethral isolates remained susceptible to ceftriaxone.

Treatment-emergent adverse events (TEAEs) were more common with gepotidacin (74%) than with the standard regimen (33%), primarily due to gastrointestinal symptoms. Diarrhea (49% vs 10%) and nausea (23% vs 3%) were the most frequently reported events with gepotidacin. Most TEAEs were mild to moderate, and no serious treatment-related adverse events were reported in either group.

EAGLE-1 was a randomized, open-label, sponsor-blinded, multicenter trial conducted across multiple countries between 2019 and 2023. The study was funded by GSK and the US Biomedical Advanced Research and Development Authority (BARDA). Participants were 12 years and older, and most were men (94%) and White (55%).

Reference: Ross JDC, Wilson J, Workowski KA, et al. Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhoea (EAGLE-1): a phase 3 randomised, open-label, non-inferiority, multicentre study. Lancet. Published online April 14, 2025. doi:10.1016/S0140-6736(25)00628-2