First-in-class oral antibiotic for uncomplicated urogenital gonorrhea clears phase III study

The first-in-class oral bacterial topoisomerase inhibitor zoliflodacin has demonstrated noninferior efficacy versus a combination of ceftriaxone plus azithromycin in the treatment of uncomplicated urogenital gonorrhoea, with favourable safety and tolerability profile.

In a large global, pivotal phase III study, the primary endpoint of microbiological cure as determined by culture from urethral or cervical site at test-of-cure visit (day 6 ±2) was achieved in 90.9 percent of patients on zoliflodacin versus 96.2 percent of those on the combination comparator in the microbiological intention-to-treat (micro-ITT) population, reported lead study investigator Dr Alison Luckey of the Global Antibiotic Research & Development Partnership (GARDP) in Geneva, Switzerland. [ESCMID Global 2024, abstract O1177]

There was a 5.31-percent difference in the microbiological cure rate between the two treatment arms, with the upper limit of 8.85 percent of the 95 percent confidence interval (CI) being within the predefined noninferiority margin of 12 percent, thus establishing the noninferiority of zoliflodacin, Luckey pointed out.

Likewise, in the evaluable population, microbiological cure rates were high and more than 90 percent in both treatment arms (96.8 percent vs 100 percent), with a treatment difference of 3.16 percent (95 percent CI, 1.10–5.14).

Although the study was not powered to assess extragenital infections, zoliflodacin compared favourably with the comparator, with microbiological cure rates being high and very similar at both the pharyngeal and rectal sites in the micro-ITT (pharyngeal: difference, –0.67 percent, 95 percent CI, –20.8 to 16.3; rectal: difference, 1.23 percent, 95 percent CI, –14.4 to 12.6) and evaluable (pharyngeal: difference, 4.35 percent, 95 percent CI, –13.1 to 16.5; rectal: difference, 4.17 percent, 95 percent CI, –7.2 to 11.6) populations, Luckey noted.

Well-balanced AEs

In terms of safety, adverse events (AEs) were well balanced between the zoliflodacin and comparator arms, according to the investigator. The overall rates of AEs were 46.4 percent and 46.8 percent, respectively, of which 18.9 percent and 24.7 percent were deemed related to the corresponding study drug.

Most AEs were mild to moderate, and there was one grade 4 event of low neutrophil count documented in the zoliflodacin arm. In the zoliflodacin arm, more patients had headache (9.9 percent vs 4.5 percent) but fewer had diarrhoea (2.4 percent vs 7.1 percent) than in the comparator arm.

“There were no serious AEs, no [treatment] discontinuations due to an AE, and no deaths,” according to Luckey.

“In summary, this is a large, well conducted global pivotal phase III trial… There was a high microbiological cure rate, which was observed at both urogenital and extragenital sites of infection,” she said.

Low propensity to resistance

Zoliflodacin is a first-in-class antibiotic that acts by interacting with topoisomerase II complex, Luckey noted. Its microbiological potency has been demonstrated against Neisseria gonorrhoeae (MIC₉₀ of 0.12 mg/L), including multidrug resistant strains.

More importantly, the drug has “low propensity to the development of resistance, and no resistance has been observed in any clinical isolates to date,” the investigator said.

A single oral 3-g dose of zoliflodacin, she added, is generally well tolerated, with a comparable safety profile to standard of care. “And this favourable benefit–risk supports progression to a new drug application submission to the FDA.”

The trial included 930 patients ≥12 years of age (mean age 29.7 years, 87.6 percent male, 55.3 percent Black or African American) with signs and symptoms of uncomplicated urethral or endocervical gonorrhoea and/or culture, gram stain, or NAAT positivity for N gonorrhoeae within 14 days prior to screening. These patients were enrolled from countries including South Africa, Thailand, US, the Netherlands, and Belgium.

Randomized treatment allocation was applied, with one group receiving a single, oral 3-g dose of zoliflodacin (n=621) and the other group receiving a single dose each of intramuscular ceftriaxone 500 mg and oral azithromycin 1 g (n=309). The micro-ITT population comprised 744 patients, while the evaluable population consisted of 704 patients.

“Given the public health threat of global transmission of ceftriaxone-resistant N gonorrhoeae, this [study] is a positive milestone in the development of new treatments for uncomplicated gonorrhoea,” Luckey concluded.