A first-in-class antibiotic zoliflodacin is non-inferior to standard of care (SOC) in the treatment of uncomplicated gonorrhea and also shows activity against resistant forms of the infection, a phase 3 clinical trial has shown.
The single-dose oral suspension also had a high microbiological cure rate at urogenital and extragenital sites of infection, and safety was comparable with the standard treatment of ceftriaxone plus azithromycin.
The study was carried out by the nonprofit Global Antibiotic Research and Development Partnership (GARDP), in collaboration with Innoviva Specialty Therapeutics, providing the first example of a successful public-private partnership in the development of a critically needed antibiotic.
“Zoliflodacin is the first new class of antibiotics for Neisseria gonorrhoeae — a World Health Organization [WHO] high-priority pathogen — for 25 years, and this is the largest ever trial conducted in gonorrhea,” Pierre Daram, lead researcher and R&D Drug/Treatment project leader at GARDP, told Medscape Medical News.
He said the successful trial could be a “game changer” for gonorrhea, particularly in Africa where there is a high rate of gonorrhea, and in parts of Asia where there is an alarming rate of resistance.
His colleague Alison Luckey, MD, senior medical lead STI at GARDP, presented the results during this week’s 34th annual European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2024 Global Congress in Barcelona on 30 April.
“Now we have the positive phase 3 results, we want to understand what is the most appropriate use of zoliflodacin bearing in mind patient needs, public health needs, and the need to preserve the lifespan of the drug, and whether it should be for first-line or second-line use,” Daram said.
Largest Trial in Populations With Greatest Need
A total of 930 patients over the age of 12 with uncomplicated gonorrhea were given either a single oral 3-g dose of zoliflodacin or the global SOC — 500-mg intramuscular ceftriaxone plus 1-g oral azithromycin. Nearly 90% of participants were men, around half were Black, and 21% were living with HIV.
The trial had global reach with trial sites in Belgium, the Netherlands, South Africa, Thailand, and the United States. “The large majority of patients came from regions where gonorrhea is a significant threat and new treatments are desperately needed, notably in Africa and Asia,” said Daram. “We know in Cambodia and Vietnam there is already around 10% and 8% resistance to any treatment, respectively. In China, it is probably worse, but numbers are unclear,” he said.
The primary efficacy endpoint was the microbiological response at the urogenital site around 6 days after treatment. Secondary endpoints included microbiological cure at rectal or pharyngeal sites and safety.
The trial met its primary endpoint, with zoliflodacin demonstrating non-inferiority to ceftriaxone plus azithromycin. Zoliflodacin achieved a microbiological cure rate of 90.9%, slightly lower than ceftriaxone and azithromycin, which had a 96.2% cure rate. Microbiological cure rates at extragenital sites were comparable between treatment arms.
The safety profile was comparable between zoliflodacin and the SOC arms, with headache slightly worse with zoliflodacin at 9.9% vs 4.5%, while neutropenia was similar in each group at around 7%. Participants given zoliflodacin reported less nausea and diarrhea than those taking the SOC — 2.4% vs 7.1%.
Across both arms of the study, there was a high rate of ciprofloxacin and tetracycline resistance at around 75%-80%, while azithromycin resistance was around 5% in both arms.
No Resistance
There was no resistance to zoliflodacin detected in the trial. “Since it is a new drug, there is no resistance to it because it has a new mechanism of action,” said Daram. “But we see that it is efficacious against gonorrhea infections that are resistant to other existing drugs, and if only used for gonorrhea and not other infectious diseases, this should prolong effectiveness.”
Daram said there will be a trade-off between meeting the WHO’s ambition of reducing the incidence of gonorrhea by 90% by 2030 through widescale use of new drugs and driving resistance to those drugs. But creative use of resources can help.
“Widescale use of zoliflodacin will wipe out all the infections resistant to current treatments, and later, for anything resistant to zoliflodacin, we can switch back to the old treatments, unless of course there is cross-resistance,” he said. “Sometimes we need to be innovative in our approach because everything we’ve tried so far has failed.”
Carolyn Deal, PhD, from the Enteric and Sexually Transmitted Infections Branch at the National Institute of Allergy and Infectious Diseases, said this is the first antibiotic developed specifically for treating N gonorrhoeae infections, which is an important development. “Most antibiotics we currently use were developed for other indications and were just found to work for Neisseria gonorrhoeae,” she said.
Deal also said the single oral dose is a significant benefit. “Right now, ceftriaxone is an intramuscular injection, and many people fear needles, so an oral drug is an advantage,” she said.
An oral drug could potentially allow healthcare providers to reintroduce patient-delivered partner therapy, in which people diagnosed with gonorrhea are given prescriptions or medications to take home to their partner, she added.
Innoviva Specialty Therapeutics plans to file for registration of zoliflodacin with the US Food and Drug Administration in early 2025 and in Europe soon after. GARDP will file for registration in several low- and middle-income countries starting in South Africa and Thailand.
Daram and Luckey had no relevant financial disclosures. Deal was not involved in the phase 3 study but had some input in the phase 1 study of zoliflodacin.