At IDWeek, 2025, held on 19–22 October, Dr Sarah McLeod from Innoviva Specialty Therapeutics presented subgroup analyses from a global Phase III noninferiority randomised controlled trial which evaluated the safety and efficacy of zoliflodacin compared to the dual therapy of ceftriaxone plus azithromycin for uncomplicated gonorrhoea.
Gonorrhoea, caused by the bacterium Neisseria gonorrhoeae, is one of the most prevalent sexually transmitted infections worldwide. According to GlobalData epidemiologists, there were an estimated 2.73 million diagnosed incident cases of gonorrhoea in 2024 across 16 major markets (Australia, Brazil, Canada, China, France, Germany, India, Italy, Japan, Mexico, Russia, South Africa, South Korea, Spain, the UK, and the US). This is expected to increase to 2.81 million diagnosed incident cases by 2029.
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Uncomplicated gonorrhoea refers to infections localised to mucosal surfaces such as the urethra, cervix, rectum, or pharynx whereas complicated gonorrhoea occurs when the infection spreads beyond these sites and may lead to complications such as pelvic inflammatory disease. However, both complicated and uncomplicated gonorrhoea can be antibiotic-resistant. The emergence and worldwide spread of antimicrobial resistance (AMR) to many antibacterials previously used as first-line therapies has effectively diminished the treatment options for this infection. Hence, there is an urgent unmet need for novel therapeutics.
Innoviva’s zoliflodacin is a first-in-class, single-dose, oral spiropyrimidinetrione antibiotic currently under regulatory review by the FDA for the treatment of uncomplicated gonorrhoea. Zoliflodacin has bactericidal activity through the inhibition of DNA replication. Its primary target is the B subunit of DNA gyrase, and this unique mode of inhibition has not been associated with cross-resistance to other antibiotics. Zoliflodacin has demonstrated activity against N. gonorrhoeae in vitro, including multi-drug resistant strains, and has demonstrated a low propensity to develop resistance in vitro.
This Phase III trial was the largest that has been conducted for uncomplicated gonorrhoea. In the trial, participants with urogenital gonorrhoea were randomised in a 2:1 ratio to receive either 3g zoliflodacin administered as a single oral dose or 500mg ceftriaxone administered intramuscularly in combination with 1g azithromycin administered orally (ceftriaxone/ azithromycin). The primary efficacy endpoint was microbiological cure at the urogenital (urethral or cervical) site of infection at the test-of-cure (TOC) visit on day six in the microbiological intent-to-treat (micro-ITT) population. Microbiological cure was determined based on a culture that was positive for N. gonorrhoeae at baseline and negative for N. gonorrhoeae at the TOC visit. Zoliflodacin met its primary efficacy endpoint of non-inferiority compared to ceftriaxone/azithromycin with urogenital microbiological cure rates of 90.9% and 96.2% observed, respectively. Key secondary analyses were also comparable between the zoliflodacin and ceftriaxone/azithromycin treatment arms. At the TOC visit in the micro-ITT population, microbiological cure rates were 79.2% and 78.6%, respectively, at the pharyngeal site, and 87.3% and 88.6%, respectively, at the rectal site. In addition, for subjects in the zoliflodacin arm who had ciprofloxacin-resistant infections at baseline, microbiological cure rates were high, and this effect was consistent across urogenital, pharyngeal, and rectal sites of infection. Zoliflodacin was also generally well tolerated with an overall safety profile comparable to ceftriaxone/azithromycin.
Overall, zoliflodacin represents a highly promising drug candidate with a strong safety and efficacy profile, and a convenient oral route of administration. If approved, it will likely compete with GSK’s gepotidacin, a first-in-class orally administered triazaacenaphthylene antibiotic that is also under regulatory review for uncomplicated gonorrhea by the FDA. Both zoliflodacin and gepotidacin have been granted priority review status and have Prescription Drug User Fee Act (PDUFA) target action dates of December 2025. Therefore, after decades of stagnation in which no new antibiotics have been approved for gonorrhoea, two novel orally administered therapies with distinct mechanisms of action are likely to launch on the US market in 2026, making this an exciting time for clinicians in the field.
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