Zoliflodacin study investigator Sarah McLeod, PhD, highlights data presented at IDWeek 2025 in a Q&A.
New subgroup analyses from the global phase 3 zoliflodacin trial highlight the drug’s consistent efficacy against multidrug-resistant Neisseria gonorrhoeae, including ciprofloxacin (CIP)-resistant strains, across all infection sites and patient subgroups. The data were presented at IDWeek 2025 in Atlanta, Georgia.1
Zoliflodacin (ZFD) is a first-in-class spiropyrimidinetrione gyrase inhibitor with a novel mechanism of action, designed to overcome the growing resistance of gonococci to existing therapies. In the pivotal phase 3 randomized controlled trial (NCT03959527), a single oral dose of ZFD demonstrated noninferiority to the current dual therapy standard—ceftriaxone plus azithromycin—for uncomplicated urogenital gonorrhea. Cure rates for pharyngeal and rectal infections were also comparable between treatment arms.1
According to ClinicalTrials.gov, the trial featured patients aged 12 years and older, who weighed at least 35 kg, with signs and symptoms consistent with the following2:
Zoliflodacin was granted the priority review designation by the FDA on June 12, 2025, and was assigned a target action date of December 15, 2025.3
The new subgroup findings examined microbiological cure rates by baseline ZFD minimum inhibitory concentration (MIC) and CIP susceptibility. Among evaluable participants, baseline isolates had ZFD MICs ranging from less than or equal to 0.008 to 0.5 µg/mL. High microbiological cure rates were achieved for isolates with ZFD MICs less than or equal to 0.25 µg/mL—the range covering nearly all samples in the study. There were too few isolates at 0.5 µg/mL (n = 3) to conclude a response at that level.
Microbiological cure rates at urogenital sites of infection were 96.6% among participants infected with CIP-resistant N. gonorrhoeae and 97.4% among those with CIP-susceptible baseline N. gonorrhoeae. High rates of microbiological cure for CIP-resistant N. gonorrhoeae were maintained for pharyngeal and rectal sites of infection, geographical location, and sex at birth.
Key findings:
These results support zoliflodacin’s potential as an effective, single-dose oral therapy—an important advantage for improving access, adherence, and treatment completion compared with injectable regimens. Study authors also note zoliflodacin’s stable potency across years of surveillance, further supporting its long-term potential against resistant N. gonorrhoeae.
Sarah McLeod, PhD, senior director of Clinical Microbiology at Innoviva Specialty Therapeutics in Waltham, Massachusetts, discussed these findings and their clinical implications in the following Q&A with our sister publication, Contemporary Pediatrics.
Contemporary Pediatrics:
The subgroup data showed high cure rates across infection sites and resistance profiles. What do these findings tell us about how zoliflodacin performs against resistant Neisseria gonorrhoeae strains?
Sarah McLeod, PhD:
The rationale for evaluating zoliflodacin in this phase 3 study stems from the urgent global need for new antibiotics to treat gonorrhea, particularly in the face of rising antimicrobial resistance.
Neisseria gonorrhoeae has developed resistance to every class of antibiotics historically used to treat it, and treatment options are becoming increasingly limited.
The phase 3 subset analysis presented at IDWeek highlighted high microbiological cure rates with zoliflodacin across urogenital, rectal, and pharyngeal sites, including against [CIP]-resistant Neisseria gonorrhoeae strains. Among participants with urogenital infections, cure rates were 96.6% for [CIP]-resistant and 97.4% for [CIP]-susceptible strains.
These results were consistent across infection sites and resistance profiles. Zoliflodacin is a first-in-class spiropyrimidinetrione antibiotic with a novel mechanism of action, distinct from currently available therapies. The data reinforce zoliflodacin’s potential as a single-dose oral treatment for uncomplicated gonorrhea, particularly in the face of rising resistance to current therapies.
Contemporary Pediatrics:
Zoliflodacin MIC values were consistent across patient groups. Why is that uniform activity important, and what could it mean for real-world use?
McLeod:
Zoliflodacin maintained in vitro activity across diverse patient groups, including women, men who have sex with men, and heterosexual men, regardless of baseline resistance to other antibiotics, reinforcing its potential as a single-dose oral treatment for uncomplicated gonorrhea.
The consistency of cure rates across demographics, including female participants, underscores zoliflodacin’s potential as a treatment option in the face of rising antibiotic resistance.
These findings have important real-world implications, especially for women. Gonorrhea can often be asymptomatic in women but still leads to serious complications such as pelvic inflammatory disease, infertility, and adverse pregnancy outcomes.
Contemporary Pediatrics:
Surveillance data show zoliflodacin’s potency has remained stable over several years. How confident are you that this durability will hold once the drug is in broader clinical use?
McLeod:
Neisseria gonorrhoeae continues to evolve resistance to nearly every antibiotic used against it, especially in parts of Asia and Africa, and we are starting to see resistance in parts of the [US]. This pathogen is one of the most urgent threats identified by global health authorities, including the CDC and [World Health Organization], because of its ability to rapidly develop and spread resistance.
Without new treatment options, we risk returning to an era when gonorrhea could become increasingly difficult to effectively treat, leading to severe reproductive health complications, adverse pregnancy outcomes, and increased HIV transmission.
What makes this phase 3 trial particularly important is that it evaluates zoliflodacin, a novel, first-in-class antibiotic with a different mechanism of action from current therapies. The trial was also designed and conducted with a global perspective, including sites in the [US], Belgium, the Netherlands, Thailand, and South Africa. Many of these countries have high burdens of drug-resistant gonorrhea.
The data generated from the phase 3 study highlight the clinical potential of zoliflodacin and provide valuable insights for both clinical practice and public health strategies aimed at controlling the spread of resistant strains.
In the foreseeable future, we anticipate significant advancements in pathogen-targeted and precision antimicrobial therapies. The traditional one-size-fits-all approach is being replaced by more specific and effective therapies that support antimicrobial stewardship, preserve the microbiome, and potentially help slow down the development of resistance.
This innovation will be supported by rapid diagnostic tools that allow for earlier and more targeted treatments, as well as new therapeutic modalities. Additionally, the development of sustainable models that include public-private partnerships, targeted commercialization, and responsible financing frameworks will be crucial for bringing new antibiotics to the market.
Contemporary Pediatrics:
The phase 3 trial met noninferiority to ceftriaxone plus azithromycin. From a clinical standpoint, what advantages does a single-dose oral therapy offer over the current injectable standard?
McLeod:
In the pivotal phase 3 trial, a multinational, randomized, controlled, open-label, noninferiority trial, zoliflodacin demonstrated noninferiority to the current standard dual therapy of ceftriaxone plus azithromycin for the treatment of uncomplicated urogenital gonorrhea, with both regimens showing comparable safety profiles.
Innoviva Specialty Therapeutics sponsored the study in collaboration with the not-for-profit Global Antibiotic Research & Development Partnership. A total of 930 adolescent and adult participants were enrolled across 16 sites in 5 countries with high gonorrhea prevalence, making it the largest clinical trial to date for a new treatment targeting Neisseria gonorrhoeae.
Participants received either a single, 3 g oral dose of zoliflodacin or the standard regimen of 500 mg intramuscular ceftriaxone plus 1 g oral azithromycin. Zoliflodacin met the prespecified criteria for noninferiority, with a treatment difference of 5.31% (95% CI: 1.38%, 8.65%). It was generally well tolerated, with adverse events comparable across both treatment groups, and no serious adverse events were reported.
Having a new, single-dose oral treatment shown to be effective across all anatomical sites and resistant strains has the potential to simplify treatment and improve adherence, particularly in settings where follow-up may be difficult.
For ob/gyns, this represents a promising step toward more accessible and effective care for women affected by gonorrhea.
This article was originally published by our sister publication, Contemporary Pediatrics.
References
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