GSK's Gepotidacin: First New UTI Antibiotic in 20 Years

On October 16, 2024, GSK, a leading pharmaceutical company, revealed that the US Food and Drug Administration (FDA) has accepted their New Drug Application (NDA) for Gepotidacin, a novel oral antibiotic designed to treat uncomplicated urinary tract infections (uUTI). The FDA's decision to grant the drug priority review underscores its potential as a significant treatment option for female patients and adolescents aged 12 years and older, all weighing at least 40 kg. The expected date for the premarket review, known as the PDUFA date, is set for March 26, 2025.

Gepotidacin represents a breakthrough in antibiotic development as it belongs to a new class of antibiotics. Its unique mechanism of action differs from existing quinolone antibiotics. Gepotidacin’s chemical structure is categorized under triazacenaphthenes, enabling it to effectively hinder bacterial DNA replication. It accomplishes this by selectively and evenly inhibiting bacterial DNA cyclotase (a form of Top II) and Top IV. This dual inhibition mechanism allows Gepotidacin to maintain its efficacy until both Top II and Top IV enzymes in bacteria mutate simultaneously, thus minimizing the risk of bacterial resistance.

The NDA’s acceptance is backed by promising results from two crucial Phase III clinical trials, EAGLE-2 and EAGLE-3. These global, randomized, double-blind, non-inferiority studies recruited a total of 3,136 patients to assess Gepotidacin's effectiveness and safety compared to furantoin, another antibiotic used for uUTI treatment. Patients received either 1500 mg of Gepotidacin or 100 mg of furantoin twice daily. The primary endpoint measured was the therapeutic response—both clinical and microbiological—at a follow-up visit 10 to 13 days post-treatment, referred to as the Test of Cure (TOC).

In the EAGLE-2 trial, 50.6% of patients treated with Gepotidacin achieved "treatment success," slightly higher than the 47.0% success rate in the furantoin group. The EAGLE-3 trial showed even better results, with a 58.5% success rate in the Gepotidacin group compared to 43.6% in the furantoin group. Gepotidacin also demonstrated comparable efficacy to furantoin in high-risk subgroups, including individuals with antibiotic-resistant E. coli infections, those with a history of relapse, and patients over the age of 50.

Regarding safety, the most frequently reported adverse events in the Gepotidacin group were gastrointestinal issues, primarily diarrhea (16%) and nausea (9%). Most of these adverse events were mild (grade 1, 69%) or moderate (grade 2, 28%) in severity.

Uncomplicated urinary tract infections are a widespread concern, affecting more than half of all women at some point in their lives, with over a quarter experiencing recurrent infections. If Gepotidacin is successfully brought to market, it would be the first new oral antibiotic for uUTI in over two decades, offering a novel treatment option. This development could significantly enhance patient outcomes and address ongoing challenges related to antibiotic resistance.