medwireNews: In people with uncomplicated urogenital gonorrhea, the first-in-class antibacterial gepotidacin is noninferior to the standard first-line option with respect to microbiological cure at the urogenital site, show phase 3 trial data presented at ESCMID Global 2025 in Vienna, Austria.
Writing in a simultaneous publication in The Lancet, the EAGLE-1 researchers note that “the safety and tolerability profile of gepotidacin was consistent with previous studies, with no new safety concerns identified.”
They continue: “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.”
The authors of an accompanying commentary say that “EAGLE-1 is important, as no new antimicrobials have been introduced for gonorrhoea treatment since the extended-spectrum cephalosporins in the 1990s.”
The trial – conducted in 49 centers across Australia, Germany, Mexico, Spain, the UK, and the USA – recruited 628 participants aged 12 years or older with a clinical suspicion of urogenital gonococcal infection, a positive laboratory test for Neisseria gonorrhoeae, or both.
Caroline Perry (GSK, Collegeville, Pennsylvania, USA) and co-investigators explain that the primary outcome was assessed in the microbiological intention-to-treat (micro-ITT) population comprising the 406 participants who received at least one dose of their allocated study treatment and “had confirmed ceftriaxone-susceptible N gonorrhoeae isolated from the baseline culture of their urogenital specimen.”
The micro-ITT population was aged an average of 33 years, the majority were men (92%) and White (74%), and there was a higher proportion of men who have sex with men (71%) than men who have sex with women (20%).
The primary outcome analysis revealed that microbiological success at the urogenital body site, defined as culture-confirmed bacterial eradication at the test-of-cure visit at day 4–8, was achieved by 92.6% of the 202 participants who were randomly assigned to receive two doses of oral gepotidacin 3000 mg administered 10–12 h apart, and by 91.2% of the 204 patients who instead received a single dose of intramuscular ceftriaxone 500 mg plus oral azithromycin 1 g.
The adjusted between-group difference was –0.1%, and the lower limit of the two-sided 95% confidence interval was above the noninferiority margin of –10.0%, but as it was not above 0.0%, the criteria for superiority of gepotidacin over ceftriaxone plus azithromycin were not met, report Perry et al.
The microbiological success rates for gepotidacin versus the control at the rectal body site were 100% and 80%, respectively, with corresponding rates at the pharyngeal site of 78% and 94%.
“While the sample sizes were small for these body sites, the numerically lower microbiological success rate observed for pharyngeal gonorrhoea compared with other body sites is consistent with studies evaluating other treatments, which have reported the pharyngeal site as a frequent location of treatment failures,” observe the study authors.
Turning to the safety, they highlight that although “adverse events [AEs] were reported more frequently in the gepotidacin group than the ceftriaxone plus azithromycin group, the frequency was predominantly driven by mild-to-moderate gastrointestinal adverse events.”
Specifically, treatment-emergent AEs occurred in 74% of gepotidacin-treated patients and 33% of those given the control regimen, but all were of grade 1 or 2, with the exception of one grade 3 AE in each group, neither of which was considered related to study treatment.
Discussing future steps, Perry and colleagues say that “[t]he prevalence of pharyngeal infections warrants further investigation in larger, body site-specific cohorts, in addition to studying the efficacy of gepotidacin in the treatment of pharyngeal gonorrhoea cases.”
They add: “It will also be important to investigate the efficacy of gepotidacin in less-represented populations in this trial, especially women, adolescents, and non-White populations; and also in combination with other antimicrobials that are often used to treat co-infections of M genitalium or C trachomatis, as well as the potential for drug interactions between these treatments.”
The commentators Magnus Unemo (Örebro University, Sweden) and Teodora Wi (WHO, Geneva, Switzerland) say that “gepotidacin is promising for the treatment of gonorrhoea, but the challenges to retain gonorrhoea as a treatable infection will continue.”
And they conclude: “Due to the inherent ability of gonococci to develop resistance, difficulties in increasing the gepotidacin dose due to adverse events, and the lack of other treatment options, preclinical and clinical development of additional gonorrhoea treatments remains important.”
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ESCMID Global 2025; Vienna, Austria: 11–15 April
Lancet 2025; doi:10.1016/S0140-6736(25)00628-2
Lancet 2025; doi:10.1016/S0140-6736(25)00680-4