Zoliflodacin noninferior to dual therapy for uncomplicated urogenital gonorrhoea

Zoliflodacin was noninferior to ceftriaxone plus azithromycin in achieving microbiological cure at the urogenital site in patients with uncomplicated gonorrhoea, according to a study presented at ESCMID 2024.

Zoliflodacin is an investigational, first-in-class oral antibiotic bacterial topoisomerase inhibitor with potent in vitro activity against Neisseria gonorrhoeae (N. gonorrhoeae), including multidrug-resistant strains, being developed as a single oral dose for the treatment of uncomplicated gonorrhoea.

The global infection rate of gonorrhoea is on the rise, with approximately 82 million new cases being reported annually and limited treatment options due to antimicrobial resistance. [https://gardp.org/gardp-and-innoviva-specialty-therapeutics-announce-completion-of-patient-recruitment-for-registrational-phase-3-gonorrhoea-treatment-trial/]

Antimicrobial resistance in N. gonorrhoeae, a gonorrhoea bacterium, has increased rapidly in recent years and reduced treatment options. [https://www.who.int/news-room/fact-sheets/detail/multi-drug-resistant-gonorrhoea]

“Developing new treatments for multidrug-resistant N. gonorrhoeae is a critical public health priority,” said Dr Alison Luckey from the Global Antibiotic Research & Development Partnership in Geneva, Switzerland.

Hence, Luckey and her team conducted a phase III, parallel-group, open-label (sponsor-blinded), noninferiority trial involving 930 patients with uncomplicated gonorrhoea (mean age 29.7 years, 87.6 percent male) in South Africa, Thailand, and the US. Participants were randomized in a 2:1 ratio to receive oral zoliflodacin 3 g (n=621) or intramuscular ceftriaxone 500 mg plus oral azithromycin 1 g (n=309). All medications were administered in a single dose. 

Of the 744 participants in the micro-ITT urogenital population, 506 received zoliflodacin, while 238 received ceftriaxone plus azithromycin.

The trial met its primary endpoint of achieving a statistical noninferiority of microbiological cure at the urogenital site with zoliflodacin compared with the combination treatment of ceftriaxone and azithromycin, said Luckey.

At the test-of-cure visit (6 days post-treatment), a microbiological cure rate at the urogenital site was achieved by 90.9 percent in the zoliflodacin arm and 96.2 percent in the ceftriaxone plus azithromycin arm (treatment difference, 5.31 percent, 95 percent confidence interval, 1.38–8.65), which was within the predefined noninferiority margin of 12 percent. “Therefore, noninferiority was declared,” Luckey mentioned. [ESCMID 2024, abstract O1177]

As a secondary endpoint, microbiological efficacy at extragenital sites was assessed. The microbiological cure rates were similar between the zoliflodacin and combination regimen arms at both the pharyngeal (79.2 percent vs 78.6 percent; treatment difference, -0.67 percent) and rectal sites (87.3 percent vs 88.6 percent; treatment difference, 1.23 percent).

In terms of safety, the overall rates of adverse events (AEs) were comparable between the zoliflodacin and ceftriaxone plus azithromycin arms (46.4 percent vs 46.8 percent). There were no deaths or serious AEs observed in either treatment arm.

Luckey noted that zoliflodacin was generally well tolerated, and its safety profile was comparable to the standard of care.

Overall, “there was a high microbiological cure rate, which was observed at both the urogenital and extragenital sites of infection,” said Luckey. “The favourable benefit/risk supports progression to a new drug application submission to FDA.”

“This is the largest global phase III trial for N. gonorrhoeae, … and presenting these findings to the scientific community for the first time is a significant milestone in the journey of this important antibiotic in the fight against N. gonorrhoeae, a World Health Organization priority pathogen,” said Luckey.