Zoliflodacin Emerges as a First-in-Class Oral Option Against Drug-Resistant Gonorrhea

As antimicrobial resistance continues to erode the effectiveness of standard gonorrhea therapies, the clinical community is confronting an urgent need for new treatment options that are both effective and accessible.

On Friday, the FDA approved Innoviva Specialty Therapeutics’ zoliflodacin (Nuzolvence), a first-in-class, single-dose oral medication for the treatment of uncomplicated urogenital gonorrhea in adults and pediatric patients 12 years and older weighing at least 35 kg. This approval was based from data of a phase 3 trial, which was published in The Lancet, showing that the antibiotic was noninferior to a combination regimen of ceftriaxone and azithromycin.

Contagion spoke to Innoviva Specialty Therapeutics CMO David Altarac, MD, about zoliflodacin's mechanism of action, global accessibility, and its potential place in the market.

Contagion: What makes zoliflodacin’s mechanism of action distinct from current first-line gonorrhea treatments, and why is this significant in the context of rising antimicrobial resistance?

Altarac: Zoliflodacin, a first-in-class spiropyrimidinetrione, has a distinct mechanism of action. Zoliflodacin disrupts DNA synthesis as an inhibitor of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Zoliflodacin interacts with conserved amino acids in the gyrase B subunit blocking DNA re-ligation.This unique mechanism results in no cross resistance with antibiotics currently used to treat gonorrhea, including first-line therapies and historically used agents such as fluoroquinolones.

Contagion: The phase 3 trial demonstrated non-inferiority to ceftriaxone plus azithromycin. What aspects of the trial design or results do you believe were most critical in establishing confidence in zoliflodacin as a single-dose oral therapy?

Altarac: Confidence in zoliflodacin as a single-dose oral therapy is driven by the robust design and compelling results of the pivotal phase 3 trial. The study enrolled 930 patients across multiple global regions with high gonorrhea burden, ensuring diverse demographic representation and generalizability of findings. A single 3 g oral dose of zoliflodacin demonstrated non-inferiority to the comparator, combination of ceftriaxone plus azithromycin for the treatment of uncomplicated urogenital gonorrhea; no new safety findings emerged. In addition, cure rates at pharyngeal and rectal sites were similar between zoliflodacin and the comparator, reinforcing its effectiveness across challenging anatomical sites. Together, these factors support zoliflodacin as a compliant single-dose oral treatment alternative, addressing a critical need in the fight against antimicrobial resistance.

Contagion: With the FDA reviewing the NDA and a PDUFA action date set, what are the next steps for Innoviva and GARDP to ensure global accessibility—particularly in regions with high prevalence of drug-resistant Neisseria gonorrhoeae?

Altarac: Innoviva Specialty Therapeutics retains commercial rights in major high-income markets (eg, North America, Europe, key Asia-Pacific countries), while GARDP holds rights to register and distribute zoliflodacin across most low- and middle-income countries. This partnership model is designed to balance commercial sustainability with broad public-health access.

Together, our goal is to work with the WHO, CDC, ECDC, and national awareness programs to incorporate zoliflodacin into treatment guidelines, support prescribers and clinic education, and monitor emerging resistance.

Ultimately, our priority is to build a coordinated access and stewardship framework so countries with the highest burden of disease can obtain and use zoliflodacin appropriately.

Contagion: With zoliflodacin getting FDA approved, where do you see its place in the market and how clinicians may be able to prescribe it?

Altarac: Zoliflodacin represents a significant treatment advancement as the first oral, single-dose alternative to injectable ceftriaxone for uncomplicated urogenital gonorrhea. Its unique mechanism and lack of cross-resistance position zoliflodacin as a promising option for outpatient settings, improving access and adherence. By offering an effective oral alternative to injectable therapy, zoliflodacin has the potential to streamline care in outpatient settings and support public health efforts to combat antimicrobial resistance. Zoliflodacin has the potential to expand prescribing options for clinicians and strengthen public health strategies aimed at controlling gonorrhea and preserving the effectiveness of current antibiotics.