Expert discusses unique mechanism of action of UTI treatment gepotidacin

Ryan Haumschild, PharmD, MS, MBA, CPEL

On March 25, 2025, the FDA approved gepotidacin (Blujepa), a first-in-class oral antibiotic, for treating uncomplicated urinary tract infections (uUTIs) in female adolescents and adults (≥40 kg), GSK announced. The approval marks the first new oral antibiotic for uUTIs in nearly 30 years, according to GSK.¹

Gepotidacin, a triazaacenaphthylene antibiotic, works by inhibiting bacterial DNA replication through a novel mechanism. The approval is based on phase 3 EAGLE-2 and EAGLE-3 trial data comparing gepotidacin to nitrofurantoin, the current standard of care.

EAGLE-2, which included 607 patients, demonstrated non-inferiority of gepotidacin, with therapeutic success in 50.6% vs. 47% of patients receiving nitrofurantoin. EAGLE-3, enrolling 541 patients, showed gepotidacin’s superiority, with success rates of 58.5% vs 43.6% (treatment difference, 14.6%; 95% CI, 6.4% to 22.8%). Gepotidacin also demonstrated higher microbiological success rates (72.2% vs 57.2%).

According to safety data from the trial, gastrointestinal events were the most common adverse effects, including diarrhea (16%) and nausea (9%), with most events mild in nature and serious drug-related adverse events occurring in only 1 patient per arm. According to their approval announcement, GSK plans a US commercial launch in the second half of 2025.

For more on how this approval influences management of uUTI, check out this Q&A with Ryan Haumschild, PharmD, MS, MBA, CPEL, vice president of Pharmacy at Emory Healthcare and Winship Cancer Institute in Atlanta, Georgia.

How significant is the approval of gepotidacin for the treatment of uncomplicated urinary tract infections in female adults and adolescents?

I think the value for uncomplicated UTIs is still really high. We have therapies that we can utilize, such as nitrofurantoin or fluoroquinolones, but at the same time, we've utilized those for a little while, and so individuals’ antibiograms might show some type of resistance and their side effect profiles, specifically with the fluoroquinolones that we may want to avoid. With this recent approval, it gives another option, I think, to infectious disease hospitalists and family medicine to really help identify and treat uncomplicated UTIs. We know this is something that is evident across the board, whether it's in family practice or in the hospitals. There still is a high unmet need. With this approval, we'll have a unique mechanism of action. We'll have another treatment option [with] reduced resistance due to its mechanism of action, and I think that's really going to drive value in the space, especially among the antimicrobials.

How does gepotidacin compare with existing treatment options in terms of efficacy and safety? And, given rising concerns about antibiotic resistance, how do you see gepotidacin fitting into the broader landscape of UTI management?

We talked about the UTI/uncomplicated UTI management landscape. There are therapies approved, but I think this one's a little different. It’s a new MOA [mechanism of action], and that's what's exciting about this treatment. Now, when we look at the clinical trial data, it was non inferior to currently available treatment options, which isn't a isn't a bad thing; it’s actually a positive thing, because now it shows that there is equitable data that gives another option, and a lot of times in the antibiotics, yes, you're looking for superiority, but a lot of times, what's another option that will really impede the resistance that we're seeing across the board? The exciting thing here is we still have nitrofurantoin, we still have fluoroquinolones, but how can we use this new option that might have a different side effect profile and leverage that for specific patient populations, then we can decrease resistance. We can add another option, if patients do progress on therapy or somehow are unresponsive, or if they're worried about Qt prolongation, or if they're worried about some of the fluoroquinolones’ side effects. Now, we have a new option that's available, and so I think this will change the way we look at treatment. I think it gives a different side effect profile available to the clinicians, and I think for patients as well, it provides a better, more durable option over time.

REFERENCE

1. Blujepa (gepotidacin) approved by US FDA for treatment of uncomplicated urinary tract infections (uUTIs) in female adults and paediatric patients 12 years of age and older. News release. GSK. Published online and accessed March 25, 2025. https://www.gsk.com/en-gb/media/press-releases/blujepa-gepotidacin-approved-by-us-fda-for-treatment-of-uncomplicated-urinary-tract-infections/