A new type of antibiotic to treat urinary tract infections could also work against gonorrhoea infections, a study has suggested, possibly launching the medication – gepotidacin – as the first new antibiotic for gonorrhea since the 1990s, according to the researchers.
“Gepotidacin is a novel oral antibacterial treatment with the potential to become an alternative option for the treatment of gonococcal infections, supported by an acceptable safety and tolerability profile,” they wrote in The Lancet, adding that the drug “could mark a meaningful advancement in patient care”.
As an antibiotic, gepotidacin works by inhibiting bacteria from replicating in the body. CNN reports that in March, it was approved by the US Food and Drug Administration to treat uncomplicated urinary tract infections in women and girls aged 12 and older.
Recurrent UTIs have become a bigger problem as the bacteria that cause them have become more resistant to the antibiotics available to treat them.
Now, there is new hope that gepotidacin may help fight drug-resistant gonorrhoea.
“Having additional treatment options for gonorrhoea is fantastic,” said Dr Jason Zucker, an infectious disease and sexually transmitted infections expert and assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, who was not involved in the study.
Effective treatments for gonorrhoea have become increasingly limited in recent years due to the global rise of antimicrobial resistance in Neisseria gonorrhoeae, the bacteria that cause gonorrhoea, rendering many previously used first-line antibiotics ineffective.
The current standard of care involves an intramuscular injection of the antibiotic ceftriaxone, and requires a visit to a care facility.
A key benefit of gepotidacin is that it would not involve an injection at the doctor’s office, which could make treating gonorrhoea more convenient for patients, Zucker said.
Gonorrhoea can lead to serious health problems if left untreated, and though rare, can even spread to the blood or joints. Among women, if untreated, it can cause pelvic inflammatory disease, which can lead to a greater risk of pregnancy complications and infertility. In men, gonorrhoea also can lead to infertility in rare cases.
In the United States, gonorrhoea and other sexually transmitted infections or STIs have become more common. Reported cases of three nationally notifiable STIs – chlamydia, gonorrohea and syphilis – were up 90% in 2023 compared with about two decades, according to data released last year by the US Centres for Disease Control and Prevention. More than 2.4m cases of STIs were reported in 2023 nationally.
Race to treat gonorrhoea
The phase 3 trial, conducted between October 2019 and October 2023, included more than 600 people aged 12 and older, diagnosed with gonorrhoea in the urogenital area, across six countries: Australia, Germany, Mexico, Spain, the United Kingdom and the United States.
The study was funded by pharmaceutical company GSK, which developed the antibiotic, and the development of gepotidacin was funded in part with federal funds from the US Department of Health and Human Services, Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority, and the Defence Threat Reduction Agency.
About half of the study participants were treated with a gepotidacin regimen of two oral doses administered about 10 to 12 hours apart, at 3 000mg per dose. The other participants were provided with the current standard treatment of administering a single dose of the antibiotic ceftriaxone as an injection paired with orally taking the antibiotic azithromycin.
The trial data, which is being presented at the European Society of Clinical Microbiology and Infectious Diseases conference (ESCMID 2025, showed that gepotidacin was as effective as the current leading combination treatment, and also effective against treatment-resistant infections.
The gonorrhoea infections were cured among 92.6% of the study participants who were administered gepotidacin compared with 91.2% of participants who were treated with ceftriaxone plus azithromycin.
Among the 7.4% of participants in the gepotidacin group who were not successfully treated, they all were due to missing data, according to GSK, which added that “in participants with complete data, there was no bacterial persistence at the urogenital body site”.
While the study primarily assessed gepotidacin as a treatment for urogenital gonorrhoea, some participants with rectal and throat infections were evaluated. Of those with complete data, the study showed that it was more difficult to treat gonorrhoea in the throat compared with other body sites, as 14 out of 16 people with throat gonorrhoea and complete data – 88% – were successfully treated.
The researchers wrote that the prevalence of throat infections “warrants further investigation” in a larger group of participants, as does studying the efficacy of geptodiacin in the treatment of gonorrhoea in the throat.
“Pharyngeal gonorrhoea is notoriously harder to treat and plays a key role in silent transmission and resistance development, so having reliable oral options at all anatomical sites is critical,” Zucker, said.
The international team of researchers found no life-threatening nor fatal side effects associated with either treatment approach used in the study, but the gepotidacin group had higher rates of side effects compared with the ceftriaxone-plus-azithromycin group, which were mostly gastrointestinal, such as diarrhoea and nausea, and almost all were mild or moderate, according to the study.
“One of the challenges is that a lot of oral antibiotics have GI side effects,” Zucker said.
The researchers said it would be important to investigate the efficacy of gepotidacin for treating gonorrhoea in groups not primarily represented in the study, especially women and black and brown communities, as 92% of participants in the study were men, 74% were white and 71% were men who have sex with men.
Bluejepa, the brand name for the version of gepotidacin approved in the United States to treat UTIs, is expected to be available in the second half of 2025.
‘A true advance’
The study was “very well-done” with “rigorous data”, and having more options to treat gonorrhea is critical for slowing down the bacteria’s drug resistance, said Dr Jeffrey Klausner, a clinical Professor of Public Health at the University of Southern California’s Keck School of Medicine in Los Angeles, who was not involved in the trial.
“Having more options to treat gonorrhoea means doctors do not have to use the same drug over and over again, which is a recipe for disaster and more resistance.” Klausner said. “If gepotidacin is approved and recommended, that will greatly help efforts to slow down drug resistance in gonorrhoea.”
In the study, researchers noted that using gepotidacin as an oral treatment option, not an injection, may be more efficient and reduce the risk of persistent, drug-resistant infections.
Yet there is some concern that strains of gonorrhoea may eventually develop resistance to gepotidacin, according to a comment paper accompanying The Lancet study.
“In our opinion, N gonorrhoeae will also develop gepotidacin resistance when the selective pressure increases and where compliance to the dual-dose regimen is suboptimal,” Magnus Unemo of Örebro University in Sweden and Teodora Wi of the World Health Organisation in Switzerland wrote in the paper.
“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,” they wrote. “In conclusion, gepotidacin is promising for the treatment of gonorrhoea, but the challenges to retain it as a treatable infection will continue.”
Study details
Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhoea (EAGLE-1): a phase 3 randomised, open-label, non-inferiority, multicentre study
Jonathan Ross, Janet Wilson, Kimberly Workowski et al.
Published in The Lancet on 14 April 2025
Summary
Background
Gepotidacin, a first-in-class, bactericidal, triazaacenaphthylene antibacterial that inhibits bacterial DNA replication, was shown to be efficacious and well tolerated in the treatment of uncomplicated urinary tract infections. We evaluated the efficacy and safety of gepotidacin for the treatment of uncomplicated urogenital gonorrhoea.
Methods
EAGLE-1 (NCT04010539) was a phase 3, open-label, sponsor-blinded, multicentre, non-inferiority study evaluating oral gepotidacin (two 3000 mg doses administered 10–12 h apart) compared with 500 mg intramuscular ceftriaxone plus 1 g oral azithromycin for the treatment of gonorrhoea. Eligible participants were aged 12 years and older, had a bodyweight over 45 kg, and had suspected uncomplicated urogenital gonorrhoea (including mucopurulent discharge), a positive laboratory test for Neisseria gonorrhoeae, or both. Participants were randomly allocated in a 1:1 ratio to each treatment group, stratified by sex (original urogenital anatomy at birth) and sexual orientation (men who have sex with men [MSM], men who have sex with women [MSW], and female) in combination, and age group (age <18 years, ≥18 to 65 years, or >65 years). The primary efficacy endpoint was microbiological success, defined as culture-confirmed bacterial eradication of N gonorrhoeae from the urogenital body site at test-of-cure (days 4–8). The non-inferiority margin was prespecified at –10%. The primary outcome was assessed in the microbiological intention-to-treat (micro-ITT) population, all participants randomly allocated to a study treatment who received at least one dose of their study treatment and had confirmed ceftriaxone-susceptible N gonorrhoeae isolated from the baseline culture of their urogenital specimen. The safety population comprised all participants who received one or more doses of any study treatment.
Findings
Between Oct 21, 2019, and Oct 10, 2023, 628 participants were randomly allocated (314 allocated to each treatment group). Overall, 39 (6%) of 628 participants discontinued the study prematurely (20 in the gepotidacin group and 19 in the ceftriaxone plus azithromycin group), with the primary reason being lost to follow-up. The micro-ITT population included 406 participants (202 in the gepotidacin group and 204 in the ceftriaxone plus azithromycin group). Most participants in the micro-ITT population were male (372 [92%] vs 34 [8%] female), and there was a higher percentage of participants who were MSM (290 [71%]) compared with participants who were MSW (82 [20%]). Participants were predominantly white (299 [74%]) or black or African American (61 [15%]), with 70 (17%) identifying as Hispanic or Latino. Results of the primary analysis of microbiological response at test-of-cure demonstrated microbiological success rates of 92·6% (187 of 202 [95% CI 88·0 to 95·8]) in the gepotidacin group and 91·2% (186 of 204 [86·4 to 94·7]) in the ceftriaxone plus azithromycin group (adjusted treatment difference –0·1% [95% CI –5·6 to 5·5]). Gepotidacin was non-inferior to ceftriaxone plus azithromycin. No bacterial persistence of urogenital N gonorrhoeae was observed at test-of-cure for either group. The gepotidacin group had higher rates of adverse events and drug-related adverse events, mainly due to gastrointestinal adverse events, and almost all were mild or moderate. No treatment-related severe or serious adverse events occurred in either group.
Interpretation
Gepotidacin demonstrated non-inferiority to ceftriaxone plus azithromycin for urogenital N gonorrhoeae, with no new safety concerns, offering a novel oral treatment option for uncomplicated urogenital gonorrhoea.
See more from MedicalBrief archives:
Concern as ‘super-strength’ gonorrhoea gets more drug resistant
First new gonorrhoea drug in 40 years offers promise
Declining susceptibility to azithromycin found in German gonorrhoea samples
Throat a major source of gonorrhoeal infection in MSM