Gepotidacin’s Phase 3 Trial for Gonorrhea Treatment Shows Efficacy

Results were announced from the pivotal EAGLE-1 phase 3 trial, showcasing gepotidacin as a potential oral antibiotic with a mechanism of action aimed at treating uncomplicated urogenital gonorrhea in adolescents and adults. The study achieved its primary efficacy goal, with two 3,000mg oral doses of gepotidacin showing non-inferiority to a standard treatment regimen of 500mg intramuscular ceftriaxone plus 1,000mg oral azithromycin. This is drawn from the primary endpoint, which is the microbiological response, measured as either success or failure, at the Test-of-Cure (ToC) visit occurring 3-7 days following treatment.

Gepotidacin disrupts bacterial DNA replication through a mechanism of action and binding site, effectively inhibiting 2 distinct Type 2 topoisomerase enzymes in a balanced manner. This balanced inhibition contributes to its effectiveness against a wide range of target uropathogens, including E coli, S saprophyticus, and Neisseria gonorrhoeae, even those strains that have developed resistance to existing antibiotics. For resistance to significantly impact gepotidacin’s effectiveness, mutations targeting both enzymes are required, highlighting its action against these pathogens.¹

Main Takeaways

The EAGLE-1 phase 3 trial has substantiated gepotidacin’s clinical equivalence to the established treatment regimen for uncomplicated urogenital gonorrhea.
Gepotidacin introduces a novel approach to bacterial DNA replication inhibition, offering a strategic advantage in the global effort to combat antibiotic-resistant gonorrhea strains.
The development and ensuing success of gepotidacin in clinical trials represent a pivotal response to the escalating public health challenge posed by gonorrhea, particularly strains resistant to current therapies.

When the gepotidacin phase 3 trial clinical program launched in 2019, Hal Baron, MD, chief scientific officer and president of research and development at GSK said in the company’s statement, “Given the increasing rate of antibiotic drug resistance, and gepotidacin’s unique mechanism of action, we believe this drug has the potential to transform the treatment landscape for patients with urogenital gonorrhea who currently have limited therapeutic options.”²

“CDC estimates that approximately 1.6 million new gonococcal infections occurred in the United States in 2018, and more than half occur among young people aged 15-24.1 Gonorrhea is the second most commonly reported bacterial sexually transmitted infection in the United States,” according to the CDC. “Gonorrhea is a sexually transmitted disease (STD) caused by infection with the N gonorrhoeae bacterium. N gonorrhoeae infects the mucous membranes of the reproductive tract, including the cervix, uterus, and fallopian tubes in women, and the urethra in women and men. N gonorrhoeae can also infect the mucous membranes of the mouth, throat, eyes, and rectum.”³

This breakthrough is noteworthy considering the growing concern on the emergence of antibiotic resistance in N gonorrhoeae. This concern is underscored by the identification of the penA 60.001 allele in N gonorrhoeae, a specific genetic variation that contributes to this type of antibiotic resistance. The penA 60.001 allele alters the bacterial response to cephalosporins, a key class of antibiotics for treating gonorrhea.⁴

“Due to high rates of gonorrhea, rapid evolution of N gonorrhea resistance, and increasing case reports of penA 60.001 allele associated with treatment failures, US patients with failed treatment for gonorrhea might be anticipated in the near future. Although ceftriaxone was still effective, these primary care cases are a warning to clinicians and public health officials to scale up clinical awareness, surveillance, and laboratory detection, including culture and gradient strip antimicrobial susceptibility tests and advanced molecular diagnostics, to delay the arrival of extremely drug-resistant gonorrhea until new treatments or vaccines are developed.”⁴

All in all, the safety and tolerability of gepotidacin observed in the EAGLE-1 phase 3 trial aligned with the outcomes from earlier phase 1 and 2 trials of gepotidacin. Comprehensive findings from the EAGLE-1 trial are slated for presentation at a forthcoming scientific conference and will be communicated to health regulatory bodies worldwide.

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