Nitrofurantoin

GSK announced positive results from a pivotal phase 3 trial for its potential first-in-class oral antibiotic, gepotidacin, for uncomplicated urogenital gonorrhea in adolescents and adults. The EAGLE-1 non-inferiority trial compared the efficacy and safety of gepotidacin to the current standard of care, ceftriaxone plus azithromycin, in approximately 600 patients with uncomplicated urogenital gonorrhea. In the trial, gepotidacin demonstrated non-inferiority, with a 92.6% success rate compared to a 91.2% success rate for intramuscular ceftriaxone plus oral azithromycin. Gepotidacin, the result of a 2013 public-private partnership between GSK and BARDA, is an investigational bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a novel mechanism of action and binding site and provides well-balanced inhibition of two different type II topoisomerase enzymes. The drug is also in development for uncomplicated urinary tract infections. Last April , GSK presented positive results from two pivotal phase 3 trials.In the EAGLE-2 trial, gepotidacin demonstrated therapeutic success in 50.6% of patients compared to 47% for nitrofurantoin. In the EAGLE-3 trial, gepotidacin demonstrated therapeutic success in 58.5% of patients compared to 43.6% for nitrofurantoin. If approved, gepotidacin would be the first in a new class of oral antibiotics for UTIs in over 20 years. When sharing the trial results, GSK had targeted a June 2023 regulatory filing, but has seemingly delayed the submission, later sharing an expected regulatory decision by 2025.

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.”