Nitrofurantoin

Readouts from the EAGLE-2 and EAGLE-3 phase 3 trials last year showed gepotidacin held its own against nitrofurantoin as a UTI treatment. GSK may have pushed back plans to secure approval for gepotidacin as the first new urinary tract infection (UTI) treatment in 20 years, but fresh phase 3 results have lined up the antibiotic for a separate filing to treat gonorrhea. In the late-stage EAGLE-1 trial of around 600 patients, two 3,000-mg daily doses of oral gepotidacin for five days demonstrated noninferiority to the most common treatment for gonorrhea—an injection of the antibiotic ceftriaxone and oral dose of the antibiotic azithromycin—when assessed by microbiological response between three and seven days later. This hit the study’s primary endpoint. The safety and tolerability profile of gepotidacin was consistent with phase 1 and 2 results of the drug, said GSK, which plans to share detailed results “at an upcoming scientific meeting and with global health authorities.” “With rising incidence rates and concern around growing resistance to existing treatments, gonorrhea poses a threat to public health globally,” Chris Corsico, GSK’s senior vice president, development, said in the Feb. 26 release.  Gepotidacin had already turned heads by its ability to show “statistical superiority” as a treatment for uncomplicated UTI compared to the commonly used UTI antibiotic nitrofurantoin in an in-depth readout of the EAGLE-3 phase 3 trial in April 2023, while the late-stage EAGLE-2 trial also showed that gepotidacin held its own against nitrofurantoin. At the time, GSK stated plans to submit gepotidacin for regulatory approval for UTI by June 2023. But the company revealed in its full-year earnings report (PDF) at the end of January 2024 that the deadline has been pushed all the way back to the second half of this year, with an FDA decision now expected in 2025. GSK is currently working with the FDA to provide nonclinical data for review ahead of the submission, a spokesperson told Fierce Biotech this morning. The company is also working in parallel with the FDA to prepare a gonorrhea application in the wake of an approval in UTI. Despite the delayed timeline, today’s gonorrhea data were further affirmation for GSK’s decision to continue to persevere in the antibiotics space even as most Big Pharma peers have long since checked out. Gepotidacin is the first in a new class of chemical antibiotics called triazaacenaphthylene bacterial topoisomerase inhibitors. While the company has been tinkering with the asset since 2007, the story really begins in 2013 with a public-private partnership between the Big Pharma and the U.S. government’s Biomedical Advanced Research and Development Authority to develop new weapons in the fight against antibiotic resistance and bioterrorism. While the relatively low return on investment has deterred plenty of larger drug developers from the space, GSK has continued to weave antibiotics into its business development plans, including paying $66 million upfront in September 2022 to license Spero Therapeutics' tebipenem HBr oral tablets, followed by $90 million to Scynexis in March 2023 to license an FDA-approved antifungal called Brexafemme for the treatment of vulvovaginal candidiasis. GSK's antibiotic for tuberculosis is also set to read out further phase 2 data later this year. Talking to Fierce Biotech a year ago, Melanie Paff, who heads up GSK's hepatitis B program, said antibiotics are “a really hard space to play in because the science and the biology is so difficult.” “When you see the data coming out from gepo[tidacin], for instance—that was hard fought,” she said at the time. “The chemists wouldn't give up, the biologists wouldn't give up, the clinical people wouldn't give up. And I'm really pleased to see that go forward and get the recognition that it deserves.”

Pictured: GSK sign at its headquarters in London/iStock, William Barton GSK is touting results from a Phase III trial of its oral antibiotic gepotidacin in patients with uncomplicated urogenital gonorrhea, the company announced Monday. In the EAGLE-1 trial, GSK’s gepotidacin met its primary endpoint showing non-inferiority to a combination of ceftriaxone and azithromycin, a standard treatment for gonorrhea. According to GSK, the results are based on the primary endpoint of microbiological response at the test-of-cure visit three to seven days post-treatment. However, the exact details of the late-stage results were not disclosed by GSK and will be revealed at an unspecified medical meeting. The company also plans to share the study details with global health regulators. “With rising incidence rates and concern around growing resistance to existing treatments, gonorrhea poses a threat to public health globally. These positive headline results demonstrate the potential for gepotidacin to provide a novel oral treatment option in the face of rising resistance and for patients who cannot take other treatments due to allergies or intolerance,” Chris Corsico, senior vice president of development at GSK, said in a statement. GSK said that the drug’s tolerability and safety pro consistent with what was found in prior trials. Gepotidacin is a potential first-in-class oral antibiotic in the triazaacenaphthylene class with a novel mechanism of action. The drug is designed to bind to a unique DNA gyrase and topoisomerase site to prevent bacterial DNA replication. The company is also investigating gepotidacin in uncomplicated urinary tract infection (uUTI). Two Phase III studies—EAGLE-2 and EAGLE-3—reported positive results last year. In April 2023, gepotidacin succeeded in 50.6% of patients in EAGLE-2, meeting the primary endpoint of non-inferiority to nitrofurantoin. While in EAGLE-3, the drug showed “therapeutic success” in 58.5% of patients, demonstrating statistical superiority. In both trials, 94% of patients who took gepotidacin did not take any additional antibiotic for uUTI. There have been other recent advancements in the potential treatment of gonorrhea. In January 2024, Dutch vaccine biotech Intravacc was awarded $633,000 from non-profit CARB-X to develop a vaccine to prevent the disease. The company announced the vaccine will be developed in its outer membrane vesicle platform. In December 2023, Reece Pharmaceutical posted results for its antibacterial candidate aiming to treat Neisseria gonorrhoeae (N. gonorrhea), which showed that mice treated with its candidate showed a 99.99% reduction in bacterial shedding and positive activity. Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.