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Gepotidacin -- a first-in-class oral antibiotic -- appeared effective and safe for the treatment of uncomplicated urinary tract infections (UTIs) in a pair of large, phase III non-inferiority studies.

In the two trials -- EAGLE-2 and EAGLE-3 -- the therapy was shown to be noninferior to nitrofurantoin, an antibiotic commonly used as a first-line therapy for patients with uncomplicated UTIs, reported Florian Wagenlehner, MD, of the Justus Liebig University in Giessen, Germany, and colleagues.

In EAGLE-2, 50.6% of the 320 patients assigned to gepotidacin and 47.0% of the 287 patients assigned to nitrofurantoin had therapeutic success (adjusted difference 4.3%, 95% CI -3.6 to 12.1).

In EAGLE-3, 58.5% of the 277 patients assigned to gepotidacin and 43.6% of the 264 patients assigned to nitrofurantoin had therapeutic success (adjusted difference 14.6%, 95% CI 6.4-22.8), thus meeting superiority as well as noninferiority criteria.

Both studies were stopped early for efficacy.

"Gepotidacin, therefore, represents a potential new treatment option for uncomplicated urinary tract infections, and addresses an important unmet need for oral agents that are effective against uropathogens resistant to currently available treatments," the researchers wrote in .

Drug developer GSK plans to begin regulatory filings for gepotidacin in the second half of this year, according to a company spokesperson, who added that the therapy "could be the first in a new class of oral antibiotics for uncomplicated UTI in over 20 years," if approved.

In prespecified subgroup analyses, gepotidacin demonstrated efficacy against Escherichia coli -- the most likely culprit in uncomplicated UTIs.

Across the two trials, overall therapeutic success for E. coli was 51.1% and 59.8% for gepotidacin and 45.9% and 44.0% for nitrofurantoin.

Gepotidacin also demonstrated efficacy against drug-resistant phenotypes of E. coli as well as less common uropathogens.

"Because of the increasing worldwide prevalence of antimicrobial resistance, these findings suggest that gepotidacin has potential as a new oral treatment for uncomplicated urinary tract infections caused by common uropathogens resistant to current therapies," the authors observed.

In a accompanying the paper, Ased Ali, MBChB, PhD, of the Mid Yorkshire Teaching NHS Trust in Wakefield, England, and Catriona Anderson, MBChB, of the NHS Primary Care Center in Stoke on Trent, England, said that the prospect of gepotidacin's superiority compared with nitrofurantoin "will probably create much anticipation among clinicians regularly treating patients with uncomplicated urinary tract infections."

"Furthermore," they added, "the shown efficacy against the less common but serious uropathogens such as Proteus mirabilis, which is intrinsically resistant to nitrofurantoin, and Enterococcus faecalis, which is susceptible to a few oral antibiotics, will further enhance the prospects for gepotidacin."

In and , eligible patients were assigned female at birth, non-pregnant, 12 years or older, and weighed 40 kg or more. Eligibility also required two or more symptoms of dysuria, frequency, urgency, or lower abdominal pain along with evidence of urinary nitrite, pyuria, or both.

The mean age of the intent-to-treat population was 52 years in EAGLE-2 and 50 years in EAGLE-3. About 40% of patients had a history of recurrent uncomplicated urinary tract infections.

Therapeutic success was defined as combined clinical success (complete symptom resolution) and microbiological success (reduction of qualifying uropathogens to <10³ colony-forming units/mL) without other systemic antimicrobial use.

According to Wagenlehner and colleagues, the studies were among the first to implement "the stringent inclusion criteria and primary endpoint of combined clinical and microbiological response recommended by the FDA and EMA [European Medicines Agency]."

In the safety population, the percentage of patients having at least one treatment-emergent adverse event in the gepotidacin group was 35% in both trials. In the nitrofurantoin groups, 22-25% of patients had at least one treatment-emergent adverse event.

The most common adverse event was diarrhea with gepotidacin and nausea with nitrofurantoin.

In their editorial, Ali and Anderson suggested that when gepotidacin finally enters regular clinical use and as real-world evidence emerges, "signs of emerging resistance should be closely monitored and health economic analysis should be developed to temper clinical excitement regarding a new antibiotic and to better understand the best use of this new agent in clinical practice."

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