Phase 3 data show potential of new oral treatments for gonorrhea
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Gonorrhea is the second most common STI, with more than 82 million new infections globally each year, including 601,319 cases in the United States in 2023.
Neisseria gonorrhoeae , the bacterium that causes these infections, has developed resistance over time to most classes of antibiotics used to for treatment, leaving ceftriaxone as the last recommended treatment.
However, ceftriaxone resistance is now being seen as well, with nine countries in 2023 reporting elevated levels of ceftriaxone resistance ranging from 5% to 40%. This led the CDC to declare drug-resistant N. gonorrhoeae an urgent threat and WHO to call it a high-priority pathogen for which new antimicrobials are needed.
This past year brought some hope in the form of phase 3 clinical trial data for zoliflodacin and gepotidacin as potential new oral treatments for gonorrhea infection, including drug-resistant strains.
Zoliflodacin
Zoliflodacin is the first in the new class of spiropyrimidinetrione antibiotics, which inhibit bacterial type II topoisomerases (GyrB) and DNA biosynthesis, leading to an accumulation of double-strand cleavages. It has binding sites in bacterial gyrase that are distinct from fluroquinolones (GyrA) and lacks cross-resistance to fluroquinolones.
In vitro analysis against 250 reference strains of clinical gonococcal isolates — including those that were multi- or extensively drug-resistant — demonstrated lower minimum inhibitory concentrations (MICs) than most current or prior antimicrobials. The rate of spontaneous resistance mutations to zoliflodacin is low in vitro. Zoliflodacin is being developed only for the treatment of gonorrhea, but does have activity against gram-positive, fastidious gram-negative and atypical organisms.
A phase 2 trial enrolled 179 participants to assess the use of a single oral dose of zoliflodacin (2 g or 3 g) as an oral suspension or a single 500 mg intramuscular dose of ceftriaxone for the treatment of urogenital gonorrhea. The primary outcome was test-of-cure (TOC) in the microbiologic intention-to-treat (micro-ITT) population within 62 days after treatment, and safety was assessed from all participants at 312 days.
Microbiologic cure at urogenital sites was achieved in 96% of participants for both the 2 g and 3 g dose and 100% in the ceftriaxone group. There were 15 rectal infections, all of which were cured regardless of the treatment arm. Pharyngeal infections occurred in 23 participants and were cured in 50%, 82% and 100% of participants in the 2 g, 3 g and ceftriaxone arms, respectively.
Among all microbiologic treatment failures, there was no significant change in pre- or post-treatment MICs, including in pharyngeal isolates, suggesting that poor drug penetration into pharyngeal tissue may have contributed to treatment failures rather than a resistant organism. Zoliflodacin appeared to be well tolerated, and the most common adverse events were gastrointestinal.
Researchers presented the results of a phase 3 noninferiority randomized controlled trial of oral zoliflodacin compared with ceftriaxone plus azithromycin for uncomplicated gonorrhea in at last year’s European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Global Congress. The trial included people aged 12 years or older with uncomplicated gonorrhea. Participants were randomly assigned in a 2:1 ratio to either a single 3 g dose of zoliflodacin (granules for oral suspension) or 500 mg ceftriaxone intramuscularly plus azithromycin in a single 1 g dose. The primary endpoint was microbiological cure at urogenital sites at TOC visit (62 days) and the noninferiority margin was 12%.
Researchers enrolled 930 participants from 15 sites in South Africa, Thailand, the United States, Belgium and the Netherlands. The two groups were well matched: The microbiological cure rate in the micro-ITT population was 90.9% for zoliflodacin compared with 96.2% for ceftriaxone/azithromycin (5.31% difference; 95% CI, 1.38%-8.65%). When limited to evaluable population rates, it was 96.8% and 100% (3.16% difference; 95% CI, 1.1%-5.14%), respectively.
The secondary outcome was microbiological efficacy at extragenital sites. In the evaluable population, cure occurred in 91.3% vs. 95.7% (95% CI, –13.1% to 16.5%) of participants for pharyngeal isolates and 95.8% vs. 100% (95% CI, –7.2 to 11.6) for rectal isolates for zoliflodacin and ceftriaxone, respectively.
Regarding safety, the most common adverse effect for zoliflodacin was headache, with an overall similar rate of adverse effects compared with, ceftriaxone/azithromycin, the majority being mild/moderate.
These data would be expected to be used in a new drug application. If approved, zoliflodacin would offer a new oral single-dose option for the treatment of gonorrhea.
Gepotidacin
Gepotidacin is a new triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interacting in a unique way on the GyrA subunit of bacterial DNA gyrase and the parC subunit of bacterial topoisomerase IV. This is a novel and a distinct binding site from fluoroquinolones.
Gepotidacin’s activity for N. gonorrhoeae was evaluated in vitro against 252 strains, including drug-resistant and extensively drug-resistant strains, in a study published in 2018. It showed potent in vitro activity against all strains with no significant cross-resistance. A parC D86N mutation — possibly with additional mutations — which is associated with fluoroquinolone resistance, was associated with increased gepotidacin MICs. In addition to activity for N. gonorrhoeae, gepotidacin has activity against a wide range of gram-positive and gram-negative pathogens and is currently under review by the FDA for uncomplicated UTIs.
A phase 2 randomized controlled trial evaluated a single oral dose of gepotidacin for the treatment of uncomplicated urogenital gonorrhea. Researchers randomly assigned participants to a single dose of either 1,500 mg or 3,000 mg of gepotidacin and evaluated them for microbiological clearance at a TOC visit (4 to 8 days). Of 69 participants in the microbiologically evaluable group, eradication occurred in 97%, 95% and 96% in the 1,500 mg, 3,000 mg and combined groups.
Microbiologic cure occurred in one of two pharyngeal isolates and all three rectal isolates. The three treatment failures all had a baseline isolate with a MIC of 1 g/mL and a pre-existing D86N substitution in the parC gene. High-level resistance emerged in two of the isolates, which was concerning. There were no safety concerns, and gastrointestinal events were the most common.
Researchers determined that 100% eradication occurred when the area under the curve (AUC)/MIC ratio was 48 or more, and all microbiological failures were associated with an AUC/MIC of 24 or less. Additionally, an in vitro hollow fiber model, researchers determined that a total daily dose of 4,500 mg or more would prevent the development of resistance. This resulted in the dose being increased to 3,000 mg for two doses given 10 to 12 hours apart for the phase 3 clinical trial to increase efficacy for isolates with higher MICs and reduce the risk for developing resistance while on therapy.
Researchers presented the results of EAGLE-1, a phase 3, open-label, multicenter, comparator controlled noninferiority study for uncomplicated urogenital gonorrhea at the ESCMID Global Congress in 2024. The trial included 602 participants aged 12 years or older with uncomplicated urogenital gonorrhea who were randomly assigned to either two 3,000 mg doses of gepotidacin 10 to 12 hours apart or ceftriaxone 500 mg intramuscularly plus azithromycin. The primary endpoint was microbiological response at day 4 to 8 TOC visit, with a noninferiority limit of –10% safety evaluated at day 14 to 21 visit.
The microbiological success rate was 92.6% for gepotidacin compared with 91.2% for ceftriaxone/azithromycin. All failures were due to a bacteriological sample not being taken, the participant being lost to follow-up, or no TOC visit, so in the microbiologically evaluable population, the cure rate was 100% in both groups. There was a higher rate of adverse effects in the gepotidacin group, driven by diarrhea and nausea. The study demonstrated noninferiority, but did not meet superiority. There was a reasonable safety profile.
Pending full publications of these data, it seems promising that these two new oral agents may be future options in the armamentarium for treating gonorrhea infections, including drug-resistant strains.
References:
- Branford PA, et al. ACS Infect Dis. 2020;doi:10.1021/acsinfecdis.0c00021.
- CDC. 2019 antibiotic resistance threats report. https://www.cdc.gov/antimicrobial-resistance/data-research/threats/index.html. Accessed Dec. 27, 2025.
- CDC. National overview of STIs in 2023. https://www.cdc.gov/sti-statistics/annual/summary.html. Published Nov. 12, 2024. Accessed Dec. 27, 2024.
- Jacobsson A. et al. J Antimicrob Chemother. 2018;doi:10.1093/jac/dky162.
- Jacobsson S, et al. Antimicrob Agents Chemother. 2014;doi:10.1128/AAC.03090-14.
- Luckey A. et al. Abstract O1177. Presented at: ESCMID Global Congress; April 27-30, 2024; Barcelona.
- New report flags major increase in sexually transmitted infections amidst challenges in HIV and hepatitis. https://www.who.int/news/item/21-05-2024-new-report-flags-major-increase-in-sexually-transmitted-infections---amidst-challenges-in-hiv-and-hepatitis. Published May 21, 2024. Accessed Dec. 27, 2024.
- Perry CR. et al. Infect Dis Ther. 2023;doi:10.1007/s40121-023-00862-6.
- Ross JD. Poster LB030. Presented at: ESCMID Global Congress; April 27-30, 2024; Barcelona.
- Taylor SN. et al. Clin Infect Dis. 2018;doi:10.1093/cid/ciy145.
- Taylor SN. et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1706988.
For more information:
Kelly M. Percival, PharmD, BCPS, BCIDP, is a clinical pharmacy specialist in infectious diseases at the University of Iowa Hospitals & Clinics. Percival can be reached at kelly-percival@uiowa.edu.
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