Positive outcomes from two phase 3 trials suggest that Gepotidacin, an investigational oral antibiotic, holds promise as a groundbreaking, first-in-class medication for managing uncomplicated urinary tract infections (UTIs) in female adolescents and adults.
Clinical Background of UTI
UTIs rank as the most prevalent infections treated on an outpatient basis in the United States, with a lifetime occurrence rate of 50-60% among adult women [1]. Although Southeast Asia reported a low age-standardized incidence rate of 2.5% in 2019 [2], UTIs remain a common infection that becomes more prevalent with age, particularly in women.
Among the various classifications of UTIs, an uncomplicated UTI (uUTI) is characterized by the absence of significant functional or anatomical abnormalities in the urinary tract, no considerable impairment of kidney function, and the absence of concomitant diseases that promote UTIs or pose a risk of developing severe complications [1]. Gram-negative bacteria are the primary causative agents, although gram-positive pathogens may also be involved [3]. Over 95% of uUTIs are monobacterial in nature, with E. coli being the most prevalent pathogen (75-95%), followed by Klebsiella pneumoniae, Staphylococcus saprophyticus, Enterococcus faecalis, group B streptococci, and Proteus mirabilis [3].
UTI Current Treatment Landscape
The treatment objectives for UTIs encompass the eradication of bacterial infection, alleviation of symptoms, and prevention of complications [3]. Currently, first-line antibiotic agents for the standard-of-care treatment of uUTIs include nitrofurantoin, trimethoprim/sulfamethoxazole, and fosfomycin, while fluoroquinolones or beta-lactams serve as second-line options [3].
The selection of treatment is individualized and depends on factors such as previous antibiotic usage, drug allergies, patient compliance and adherence, local practice guidelines, and resistance data [4].
In Asia, resistance rates against trimethoprim/sulfamethoxazole, ciprofloxacin, and ceftriaxone ranged from 33% to 90%, while resistance against nitrofurantoin ranged from 2.7% to 31.4% [5].
Gepotidacin: First-in-class Medicine for Uncomplicated UTI
Gepotidacin (GEP) is an oral investigational antibiotic under evaluation for the treatment of uncomplicated urinary tract infections (uUTIs) in female adolescents and adults. Results from two phase 3 trials have shown promising potential for GEP for this indication [6].
GEP belongs to the novel class of triazaacenaphthylene antibiotics and exerts its antibacterial effects by selectively inhibiting DNA gyrase and topoisomerase IV, acting on the GyrA subunit of bacterial DNA gyrase and the ParC subunit of bacterial topoisomerase IV in E. coli. Gepotidacin binds to similar region of the same target proteins as quinolone antibiotics (e.g., floroquinolones), but gepoticadin recognizes different amino acids and inhibit other stages of the catalytic cycle of target proteins [7]. This unique mechanism of action enables GEP to effectively target a broad range of E. coli and Staphylococcus saprophyticus strains, including those resistant to currently available antibiotics such as fluoroquinolones [4].
Figure 1: Simplified illustration showing binding characteristics of fluoroquinolones, triazaacenaphthylene antibiotics (e.g., gepotidacin), DNA gyrase, and DNA topoisomerase IV.
Two fluoroquinolone molecules bind separate DNA cleavage sites on DNA gyrase and DNA topoisomerase IV, involving Ser84 and Glu88 residues, divalent magnesium ion, and water molecules. This stabilizes double-stranded DNA breaks, posing lethal threat to bacteria if not repaired. Mutations in these binding residues are common in fluoroquinolone-resistant clinical strains. In contrast, gepotidacin selectively binds to a distinct site on DNA gyrase and topoisomerase IV through interactions with Asp83 and water molecules, enhancing formation of lethal single-stranded DNA breaks [7].
In the phase 3 trials, namely EAGLE-2 (NCT04020341) and EAGLE-3 (NCT04187144), GEP demonstrated non-inferiority to nitrofurantoin for the treatment of uUTIs in individuals with confirmed UTI and the presence of a nitrofurantoin-susceptible uropathogen. Notably, the EAGLE-3 trial showed statistically significant superiority of GEP over nitrofurantoin [6].
Both trials employed a primary efficacy endpoint known as therapeutic success, which included clinical resolution and microbiological eradication of bacteria during the 10 to 13-day follow-up period after initiating treatment. In the EAGLE-2 trial, GEP achieved therapeutic success in 50.6% of individuals in the treatment arm compared to 47% in the nitrofurantoin control group. Similarly, in the EAGLE-3 trial, the respective success rates were 58.5% for GEP and 43.6% for nitrofurantoin [6].
Furthermore, nearly 95% of individuals treated with GEP in both trials did not require additional antibiotics for uUTI during the treatment period up to the 28-day follow-up [6].
Regarding safety, the most common adverse events associated with GEP were gastrointestinal in nature, with diarrhoea being the most frequently reported, followed by nausea. Most adverse events were of mild to moderate severity, consistent with previous trials of the drug [6]. When gepotidacin is administered with drugs that are CYP3A4 inducers or inhibitors, the area under the curve (AUC) exposures of gepotidacin were both increased and decreased by about 50% respectively. However, these interactions may only be clinically significant in the presence of other factors such as renal impairment [8]. Gepotidacin demonstrated weak CYP3A4 inhibition, and may increase the AUC of drugs that undergo this metabolism pathway [8] and thus warrants precaution.
Both the EAGLE-2 and EAGLE-3 trials were stopped for non-inferiority based on predefined success boundaries. Additionally, the EAGLE-3 phase 3 trial met the predefined criterion for demonstrating superiority [6].
GSK plans to apply to the US Food and Drug Administration (FDA) for GEP in the second quarter of 2023 [6].
References
- Medina M, Castillo-Pino E. An introduction to the epidemiology and burden of urinary tract infections. Ther Adv Urol. 2019 May 2;11:1756287219832172. doi: 10.1177/1756287219832172. PMID: 31105774; PMCID: PMC6502976.
- Zeng Z, Zhan J, Zhang K, Chen H, Cheng S. Global, regional, and national burden of urinary tract infections from 1990 to 2019: an analysis of the global burden of disease study 2019. World J Urol. 2022 Mar;40(3):755-763. doi: 10.1007/s00345-021-03913-0. Epub 2022 Jan 23. PMID: 35066637.
- Helen S. L., Jennifer L. Urinary Tract Infections. Pharmacotherapy Self-Assessment Program. 2018. Available at https://www.accp.com/docs/bookstore/psap/p2018b1_sample.pdf [Accessed 21 May 2023]
- Scangarella-Oman NE, Hossain M, Hoover JL, Perry CR, Tiffany C, Barth A, Dumont EF. Dose Selection for Phase III Clinical Evaluation of Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections. Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0149221. doi: 10.1128/AAC.01492-21. Epub 2022 Jan 3. PMID: 34978887; PMCID: PMC8923173.
- Sugianli AK, Ginting F, Parwati I, de Jong MD, van Leth F, Schultsz C. Antimicrobial resistance among uropathogens in the Asia-Pacific region: a systematic review. JAC Antimicrob Resist. 2021 Feb 27;3(1):dlab003. doi: 10.1093/jacamr/dlab003. PMID: 34223081; PMCID: PMC8210283.
- GSK. Gepotidacin’s positive phase III data shows potential to be the first in a new class of oral antibiotics for uncomplicated urinary tract infections in over 20 years. 2023 Apr 15. Available at https://www.gsk.com/en-gb/media/press-releases/gepotidacin-s-positive-phase-iii-data-shows-potential-to-be-the-first-in-a-new-class-of-oral-antibiotics-for-uncomplicated-urinary-tract-infections/ [Accessed 21 May 2023]
- Tiffany C, Dumont EF, Hossain M, Srinivasan M, Swift B. Pharmacokinetics, safety, and tolerability of gepotidacin administered as single or repeat ascending doses, in healthy adults and elderly subjects. Clin Transl Sci. 2022 Sep;15(9):2251-2264. doi: 10.1111/cts.13359. Epub 2022 Jul 13. PMID: 35769034; PMCID: PMC9468557.
- Barth A, Perry CR, Shabbir S, Zamek-Gliszczynski MJ, Thomas S, Dumont EF, Brimhall DB, Nguyen D, Srinivasan M, Swift B. Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug-drug interactions via CYP3A metabolism and transporters. Clin Transl Sci. 2023 Apr;16(4):647-661. doi: 10.1111/cts.13477. Epub 2023 Jan 23. PMID: 36642822; PMCID: PMC10087077.
