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Gepotidacin shows promise against gonorrhea in phase 2 trial
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Phase 2 data recently published in Clinical Infectious Diseases showed that oral gepotidacin was more than 95% effective against uncomplicated urogenital gonorrhea.
These results suggest that gepotidacin (GlaxoSmithKline) — a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor — could serve as an alternative treatment option for Neisseria gonorrhoeae (NG), according to Stephanie N. Taylor, MD, infectious disease specialist at Louisiana State University Health Sciences Center in New Orleans, and colleagues.
“Over the past few decades, NG has demonstrated the ability to develop resistance to most antibiotics recommended or used for treatment, suggesting the possibility of untreatable gonorrhea in the future,” the researchers wrote.
Last year, WHO officials warned that the number of countries reporting drug-resistant gonorrhea infections has increased between 2009 and 2014. Of 77 countries surveyed by WHO, 66% detected gonococcal isolates with decreased susceptibility or resistance to extended-spectrum cephalosporins, and 81% reported isolates resistant to azithromycin. Recently, health officials in England identified the first reported case of a gonorrhea infection that is resistant to both ceftriaxone and azithromycin, which are widely recommended for treatment.
For the phase 2 trial, Taylor and colleagues evaluated the safety, tolerability and efficacy of gepotidacin in 69 patients with uncomplicated urogenital NG. The participants were enrolled at one of 12 sites in the United States (n = 11) and the United Kingdom from April 2015 to August 2016. They were randomly assigned in a 1:1 ratio to receive 1,500 mg (n = 30) or 3,000 mg (n = 39) of oral gepotidacin. Only two women were included in the microbiologically evaluable analysis, including one in the 1,500 mg (low-dose) group and one in the 3,000 mg (high-dose) group.
Microbiological eradication was achieved in 97% of participants in the low-dose group and 85% of participants in the high-dose group at the test-of-cure visit, which was 4 to 8 days after treatment. The combined efficacy of both doses was 96%.
Fifty-two percent of participants in the low-dose group and 64% in the high-dose group reported adverse events, mostly diarrhea (27%), flatulence (23%), abdominal pain (15%) and nausea (13%). None of these events led to treatment discontinuations, and no deaths or serious adverse events were reported. However, one participant with no underlying cardiovascular history developed mild tachycardia, which the researchers said was possibly related to the study drug.
In vitro susceptibility testing revealed that 33% of isolates were resistant to ciprofloxacin, 28% were resistant to penicillin and 20% were resistant to tetracycline. All isolates were susceptible to cefixime, ceftriaxone and spectinomycin.
Microbiological failure occurred in two participants in the high-dose group and one in the low-dose group, all of whom were subsequently treated with ceftriaxone and azithromycin. NG isolates obtained from these three participants had a common gene mutation that is known to disrupt gepotidacin binding, according to the researchers. Gepotidacin resistance emerged in two of the treatment failures.
“Emergence of high-level resistance in two of three treatment failures is a concern,” Taylor and colleagues wrote. “However, new therapies for drug-resistant NG are urgently needed.”
According to WHO, gepotidacin is one of only three drug candidates in the antibiotic pipeline for gonorrhea. The other candidates are solithromycin (Cempra) and zoliflodacin (Entasis), both of which are currently in phase 3 development.
“To maintain the efficacy of gepotidacin and to help preserve the efficacy of other antibacterials, different dosing strategies for gepotidacin, including dual-agent therapy, may ultimately be needed,” the researchers wrote. – by Stephanie Viguers
Disclosures: The trial was sponsored by GlaxoSmithKline. Taylor reports receiving research support from AstraZeneca, Beckman Coulter, Becton Dickinson, Cepheid, GlaxoSmithKline, Hologic, Melinta and Roche Molecular. She also severed as a consultant and on a scientific advisory board for GlaxoSmithKline. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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The threat of untreatable gonococcal infections becomes more real every day. Recently, Public Health England reported a case of dually ceftriaxone- and azithromycin-resistant N. gonorrhoeae, which failed empiric treatment with 1g ceftriaxone and was treated with ertapenem. New antimicrobials are urgently needed; the present study offers hope. In this small phase 2 study, gepotidacin, a novel triazaacenaphthylene type II topoisomerase inhibitor, cured 96% (lower bound of 95% CI, 89.1%) of 69 subjects with urogenital gonorrhea. Moreover, it was safe and tolerable. However, there are at least two issues that require further evaluation before this drug is ready for prime time. First, this study included only two cases of pharyngeal gonorrhea, which is notoriously difficult to treat. Although we cannot draw conclusions from two cases, only one was cured. Future gonococcal treatment recommendations need to ensure pharyngeal eradication because too often infection at this anatomic site is missed, leading to continued N. gonorrhoeae transmission. Secondly, among the three urogenital treatment failures, two exhibited evidence of induced resistance following exposure to gepotidacin, with MIC increasing from 1 μg/mL to 32 μg/mL or higher. Determining how to prevent the development of gepotidacin-resistant N. gonorrhoeae if gepotidacin were to become widely used will be key before this can be a recommended agent.
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