GSK Launches Phase III Clinical Program for First-in-Class Oral Antibiotic Gepotidacin Targeting uUTI and Gonorrhea

Compiled by Keke

A novel antibiotic compound is in late-stage clinical development for the treatment of uncomplicated urinary tract infections and urogenital gonorrhea, with a mechanism of action distinct from that of any currently approved antibiotics. For nearly two decades, there have been no new antibiotic agents introduced for these two indications.

On October 28, GlaxoSmithKline (GSK) announced the initiation of a Phase III clinical study evaluating gepotidacin, a potential first-in-class small-molecule therapeutic, for the treatment of uncomplicated urinary tract infections and urogenital gonorrhea.

Gepotidacin (GSK2140944) is a novel antibiotic and the first triazaacenaphthylene topoisomerase inhibitor. Discovered by GSK in 2007, it features a novel dual-targeting mechanism of action and is formulated for oral administration. Its mechanism of action is distinct from that of any currently approved antibiotics. Gepotidacin exerts its effect by selectively interacting with two key bacterial enzymes responsible for DNA replication: DNA gyrase and topoisomerase IV (type II topoisomerases). This novel mechanism confers activity against most target pathogens that have developed resistance to established antibiotics, including fluoroquinolones.

Chemical Structure of Gepotidacin (from Wikipedia)

It is reported that the Phase III clinical program EAGLE, launched recently, comprises two studies and is expected to yield its first results by the end of 2021. The first study, EAGLE-1, plans to enroll approximately 600 patients with urogenital gonorrhea, one of the most common sexually transmitted infections. This study will compare gepotidacin (administered as a single oral dose of 3,000 mg at the baseline visit, followed by a second outpatient oral dose of 3,000 mg 6 to 12 hours after the initial dose) with the guideline-recommended dual therapy consisting of ceftriaxone (500 mg intramuscular injection) plus azithromycin (1 g orally). The study duration is approximately 21 days. The primary endpoint is the bacterial eradication rate of Neisseria gonorrhoeae (NG) in the urogenital tract.

The second study, EAGLE-2, plans to enroll approximately 1,200 female patients with uncomplicated urinary tract infections (UTIs), comparing gepotidacin (1500 mg orally twice daily for 5 days) with the first-line clinical antibiotic nitrofurantoin (100 mg orally twice daily for 5 days). The study duration is approximately 28 days, and the primary endpoint is the treatment response rate in patients with eradication of uropathogens.

The initiation of this Phase III clinical trial stems from the positive results published in 2017 and 2018 from two Phase II studies (NCT02294682 and NCT02045797), which evaluated the efficacy of gepotidacin for the treatment of urogenital gonorrhea and acute bacterial skin and skin structure infections (ABSSSI). Gas chromatography studies indicated that a single oral dose of gepotidacin was effective in curing adult patients with uncomplicated urogenital gonorrhea, achieving a Neisseria gonorrhoeae eradication rate of 95%. Furthermore, the study on ABSSSI demonstrated that two of the three tested doses of gepotidacin met the predefined success criteria for clinical utility in terms of both efficacy and safety.

Uncomplicated urinary tract infections are very common in women, with approximately 11% of women aged 18 years and older experiencing at least one episode annually. The peak incidence occurs among sexually active young women. It is estimated that one-third of adolescent females have experienced at least one uncomplicated urinary tract infection requiring antibiotic treatment by the age of 24. The predominant uropathogen is Escherichia coli (75%–90%), followed by Staphylococcus saprophyticus (5%–15%).

Gonorrhea is the second most common bacterial sexually transmitted infection globally and remains a significant clinical and public health concern worldwide. In 2016, an estimated 87 million new cases of gonorrhea occurred. Over the years, various antibiotics have been employed in clinical practice to treat gonorrhea. However, due to the emergence of resistance to many previously used or first-line agents—including penicillins, narrow-spectrum cephalosporins, tetracyclines, macrolides, and fluoroquinolones—as well as the global spread of the disease, effective treatment options for gonorrhea have rapidly diminished.

As pharmaceutical giants such as Novartis, Pfizer, Sanofi, and AstraZeneca have abandoned their own antibiotic pipelines, GSK stands out as one of the few major pharmaceutical companies still engaged in antibiotic research. In 2013, GSK partnered with the U.S. Biomedical Advanced Research and Development Authority (BARDA) and the Defense Threat Reduction Agency (DTRA) of the U.S. Department of Defense to support the development of multiple antibiotics aimed at combating antibiotic resistance and bioterrorism. Gepotidacin is one of the outcomes of this collaboration.

Reference source: GSK starts a phase III clinical programme for a potential first-in-class antibiotic, gepotidacin