麻豆传媒

Gepotidacin, an investigational antibiotic, proved noninferior to dual therapy for the treatment of uncomplicated urogenital gonorrhea, according to results of the phase III .

The microbiological success rate was 92.6% with oral gepotidacin compared with 91.2% with ceftriaxone plus oral azithromycin, reported Jonathan Ross, MD, of the University of Birmingham in England, at the , held this year in Barcelona.

The adjusted treatment difference between the gepotidacin and dual-therapy groups was -0.1% (95% CI -5.6% to 5.5%), falling within prespecified criteria for noninferiority (a lower CI limit above -10.0%). Adverse event (AE) rates, along with drug-related AEs, were higher in the gepotidacin arm.

"There is a need for antibiotics for gonorrhea because the current options we have are very limited," Ross told 麻豆传媒. "We have one [oral] antibiotic left -- ceftriaxone."

"We've learned over the last 20 to 30 years that we lose antibiotics over time. Already we see signs that sensitivity to ceftriaxone is diminishing," he said. "Therefore it's a question of when, rather than if, we lose that last antibiotic."

Gepotidacin is a first-in-class triazaacenaphthylene, a bactericidal antibiotic that inhibits bacterial DNA replication by of the Neisseria gonorrhoeae bacterium. Researchers believe that N. gonorrhoeae may be less likely to become resistant to gepotidacin than other antibiotics because mutations in both enzymes would likely be necessary for resistance to develop.

"Multi-drug resistant gonorrhea ... is a major public health threat," Anu Hazra, MD, of Howard Brown Health in Chicago, told 麻豆传媒. "It may not be at the crosshairs or in the minds of the general public, but for those of us that work in sexual health, it's something that we are truly concerned about."

"The challenge with antibiotic development is bacteria become resistant to the antibiotic almost as soon as it is released," Hazra said. "So I don't think [gepotidacin] is going to be our stopgap, but at least it might be another tool that we have. I think we need to continue to have a robust drug pipeline to continue to offer us oral agents that will be active against potentially more resistant strains of gonorrhea."

According to the , in 2020 there were an estimated 82.4 million new gonorrhea infections among adults across the globe. If left untreated, gonorrhea can cause a variety of sexual and reproductive health complications, including infertility in both men and women. It also increases the risk of HIV infection.

Hazra also pointed out that the EAGLE-1 trial only looked at the efficacy of gepotidacin against urogenital gonorrhea. "The major threat that we have with multi-drug resistant gonorrhea has actually been with oropharyngeal gonorrhea," he said. "So I think this is a great first step, but I will want to see further studies of efficacy of this drug against gonorrhea at other sites as well."

Ross concurred that more studies of the drug are needed, but noted that it was not the aim of the trial to evaluate gepotidacin in patients with oropharyngeal gonorrhea. However, a small number of patients enrolled in EAGLE-1 also had pharyngeal and/or rectal gonorrheal infections in addition to urogenital infections, he said. All of these patients achieved a microbiologic cure. "I think we can say cautiously that [gepotidacin] seems to work for pharyngeal infections but that's an important question that remains to be answered," he said.

Gepotidacin has also been evaluated in the EAGLE-2 and EAGLE-3 trials for efficacy and safety in the treatment of uncomplicated urinary tract infections (UTIs). Those trials found gepotidacin to be noninferior to nitrofurantoin, an antibiotic commonly used as a first-line therapy for the treatment of uncomplicated UTIs.

The current trial included 406 male and female adolescent and adult participants in the primary analysis population with a clinical suspicion of uncomplicated urogenital gonorrhea. Participants were randomized to receive either two 3-g doses of gepotidacin (n=202) or an intramuscular injection of ceftriaxone 500 mg plus 1 g of oral azithromycin (n=204).

The primary endpoint of the trial was microbiological response at a test-of-cure visit 4 to 8 days after treatment. Participants also had a follow-up visit between days 14 to 21 to confirm sustained response to treatment.

Among the study population that underwent microbiological evaluation, of the 7.4% of microbiological failures in the gepotidacin group and the 8.8% in the ceftriaxone/azithromycin group, none of the failures were due to bacteriological persistence. All failures were due to researchers being unable to determine outcomes, for example, in cases where no sample was taken for culture, the sample was lost, or a scheduled visit did not occur.

Among the 622 participants in the safety population -- all randomized patients who received at least one dose of study treatment -- those who received gepotidacin reported a substantially higher number of AEs than those in the dual therapy arm (519 vs 141 events). Mild-to-moderate gastrointestinal adverse effects -- primarily diarrhea -- were frequent in the gepotidacin group, Ross said. "That is of concern," he acknowledged. "It's hard to get a handle on that until we start using [gepotidacin] in clinical practice -- how important is that to patients."

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