Innovative Treatment for Gonorrhea: Phase III Trial Shows Promise for Zoliflodacin

Neisseria gonorrhoeae diplococci bacteria responsible for the sexually transmitted infection gonorrhea.

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Gonorrhea is an ancient disease and is the second most bacterial common sexually transmitted infection. In 2020, an estimated 82.4 million new infections among adults aged 15 to 49 globally, and pharmaceutical companies continue to search for new and better treatments for the disease. Recently, the Phase III zoliflodacin data was presented at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Global held in Barcelona, Spain, from April 27 to 30, 2024.

In an exclusive interview, Infection Control Today^® (ICT^®) learned more about the study’s data from Matt Ronsheim, PhD, president of Innoviva Specialty Therapeutics.

ICT: Would you provide an overview of the Phase 3 trial results for oral zoliflodacin in treating uncomplicated gonorrhea, including the key findings presented at ESCMID Global 2024?

Matt Ronsheim, PhD: The Phase III study data presented at ESCMID Global 2024 by Alison Luckey, MD, GARDP, found that a single oral dose of zoliflodacin is noninferior to a combination of ceftriaxone (administered intramuscularly) and azithromycin (administered orally) for the treatment of uncomplicated urogenital gonorrhea. the trial demonstrated that “zoliflodacin was well tolerated with a favorable safety profile compared to ceftriaxone plus azithromycin.

Key takeaways from the presentation:

• The study was the largest phase 3 registration trial assessing the efficacy and safety of a new investigational product in the uncomplicated gonorrhea indication to date.
• Zoliflodacin is a topoisomerase inhibitor that has a unique mode of binding that is different from that of fluoroquinolones.
• The study demonstrated the noninferiority of zoliflodacin to comparator based on microbiological cure rate at Test of Cure (TOC). High microbiological cure rates were observed at urogenital and extragenital sites of infection.
• The study found that a single oral 3g dose of zoliflodacin was generally well tolerated and had a comparable safety profile to the standard of care. Study results suggested that zoliflodacin has a favorable benefit/risk ratio that supports progression to a new drug application (NDA submission to FDA).

Background Detail:

Innoviva Specialty Therapeutics and our development partner GARDP, sponsored and conducted a global phase 3 pivotal trial of a single oral dose of zoliflodacin, an investigational, first-in-class antibiotic being developed for the treatment of uncomplicated gonorrhea infection. The trial compared zoliflodacin to a globally recommended regimen of 500mg ceftriaxone administered intramuscularly plus 1g azithromycin administered orally).

• The trial was conducted from 2019 to 2023 at 16 sites across 5 countries. A total of 930 patients randomized 2:1 were analyzed overall, making it, to our knowledge, the largest global clinical trial ever conducted for a new treatment against gonorrhea infection.
• The study's primary endpoint was microbiological cure as determined by culture at urethral or cervical sites at TOC (Day 6±2) in the micro-ITT population.
• The trial demonstrated that at TOC, zoliflodacin (a single oral dose of 3 g) was non-inferior to the combination of a single intramuscular injection of 500 mg ceftriaxone with a single oral dose of azithromycin 1 g in the treatment of uncomplicated urogenital gonorrhea based on an upper CI limit of 8.65%, which was within the prespecified NI margin of 12% in the micro-ITT population.
• The microbiological cure rates observed in the zoliflodacin arm and the ceftriaxone-azithromycin arm (micro-ITT population) were 90.9% (460/506) and 96.2% (220/238), respectively, representing a difference of 5.31% (95% CI: 1.38 to 8.65).

ICT: How does the microbiological cure rate achieved by oral zoliflodacin compare to the current global standard of care for gonorrhea treatment, and what implications does this have for future treatment strategies?

MR: The microbiological cure rates observed in the zoliflodacin arm and the ceftriaxone-azithromycin arm (micro-ITT population) were 90.9% (460/506) and 96.2% (220/238), respectively, representing a difference of 5.31% (95% CI: 1.38 to 8.65).

If approved, zoliflodacin will provide a new mechanism of action with no evidence of cross-resistance with other antibiotics. it has shown activity against multidrug-resistant strains, including those resistant to antibiotics typically used to treat gonorrhea, such as ceftriaxone, azithromycin, cefixime, penicillin, ciprofloxacin, and tetracycline. Additionally, zoliflodacin is delivered in a single oral sachet dose suspended in water.

While these cure rates are comparable, resistance to ceftriaxone, the current standard of care, consisting of the combination of ceftriaxone and azithromycin, is on the rise and likely to continue in the near future. New safe and effective agents such as zoliflodacin will be critical to address the medical need.

ICT: Could you elaborate on the significance of the collaborative effort between Innoviva Specialty Therapeutics and GARDP in developing zoliflodacin, particularly in addressing the challenges of antimicrobial resistance?

MR: This is the first collaborative study between industry (IST) and a non-profit organization (GARDP) to address infections associated with World Health Organization high-priority pathogen and CDC urgent threat.

The positive phase III findings offer hope for patients with gonorrhea, particularly in the face of rising antibiotic resistance to current regimens. If approved, zoliflodacin could become the first new antibiotic used solely for treating gonorrhea in decades. It's important to note that the bacterium Neisseria gonorrhoeae has gradually developed resistance to many classes of antibiotics used to treat these infections. As a result, ceftriaxone, given as a single intramuscular injection, has become the last available recommended treatment for gonorrhea globally.

Previous in vitro studies have shown that zoliflodacin is active against multidrug-resistant strains of Neisseria gonorrhoeae, including those resistant to ceftriaxone and azithromycin, with no cross-resistance with other antibiotics.

The World Health Organization estimates that more than 82 million new gonorrhea infections are occurring globally each year. Gonorrhea is the second most common bacterial sexually transmitted infection, affecting both men and women in a manner that can lead to serious and permanent health consequences.