Gepotidacin as good as current standard treatment for urogenital gonorrhoea

The oral investigational antibiotic gepotidacin is noninferior to the current standard treatment for uncomplicated urogenital gonorrhoea in the randomized, multicentre, phase III EAGLE-1 trial.

Two doses of gepotidacin yielded a 92.6 percent success rate for the primary endpoint of microbiologic response at the test-of-cure visit compared with a 91.2 percent success rate for dual therapy with ceftriaxone and azithromycin.

The adjusted treatment difference between arms was -0.1 percent (95 percent confidence interval [CI], -5.6 percent to 5.5 percent), which was within the prespecified criteria for noninferiority (a lower CI limit above -10 percent).

Neisseria gonorrhoeae, the causative agent of gonorrhoea, has grown resistant to many antimicrobial agents. [Clin Microbiol Rev 2014;27:587–613] Most guidelines recommend dual treatment with ceftriaxone and azithromycin for uncomplicated gonorrhoea. However, sporadic treatment failures have been reported with the regimen.

“Our current options for gonorrhoea are limited. With ceftriaxone, we are already seeing signs of diminishing sensitivity,” said lead investigator Dr Jonathan Ross from the University of Birmingham in Birmingham, UK, at ESCMID Global Congress 2024. “It’s only a matter of time until this obligate human pathogen becomes resistant to our last available therapy. We need novel and better antibiotics.”

Gepotidacin is a first-in-class bactericidal triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes of N. gonorrhoeae. As mutations in both enzymes are required for resistance to develop, researchers believe it may be less likely to happen with gepotidacin.

In the EAGLE-1 study, 406 patients with a clinical suspicion of uncomplicated urogenital gonorrhoea were randomly assigned to receive either two doses of oral gepotidacin (n=202) or intramuscular ceftriaxone in combination with oral azithromycin (n=204). [ESCMID Global 2024; Poster LB030]

The primary outcome was the microbiological response at test-of-cure visits 4–8 days after treatment. Follow-up visits were done between days 14 and 21 to check for sustained treatment response.

None of the 7.4 percent microbiological failures in the gepotidacin group and 8.8 percent in the ceftriaxone-azithromycin group were due to bacteriological persistence.

Of the 622 participants in the safety population (patients who received at least one dose of study treatment), those who received gepotidacin had a substantially higher number of AEs than those treated with dual therapy (519 vs 141 events). Mild-to-moderate gastrointestinal adverse effects, primarily diarrhoea, were frequent in the gepotidacin group. “That is a concern,” said Ross. “It’s hard to get a handle on that until we start using [gepotidacin] in clinical practice.”

Commenting on the study, Dr Anu Hazra from Howard Brown Health in Chicago, US said multidrug-resistant gonorrhoea may not be in the crosshairs or minds of the public, “but for those of us working in sexual health, it’s something that we are truly concerned about.”

“The challenge is [that] the bacteria become resistant to the antibiotic almost as soon as it is released,” Hazra said. “So, I don’t think [gepotidacin] will be our stopgap, but it might be another tool we have. We need to continue to have a robust pipeline of oral agents that will be active against potentially more resistant strains of gonorrhoea.”

Untreated or drug-resistant gonorrhoea can cause sexual and reproductive health complications, including infertility, pelvic pain, and an increased risk of HIV infection.