The US Food and Drug Administration (FDA) late last week approved two novel oral antibiotics for treating uncomplicated gonorrhea infections.

The December 12 approval of zoliflodacin came a day after release of the full results of a pivotal, multinational phase 3 trial that showed a single dose of the first-in-class antibiotic was noninferior to an injection of ceftriaxone and an oral dose of azithromycin—the standard treatment at the time the trial was conducted. Approved for treating uncomplicated urogenital gonorrhea in adult and pediatric patients 12 years of age and older and weighing at least 77 pounds, zolidflodacin will be sold under the brand name Nuzolvence.

On December 11, the FDA approved gepotidacin for treating uncomplicated gonorrhea. Sold under the brand name Bluejepa, the antibiotic was previously approved for treating uncomplicated urinary tract infections last spring but also proved noninferior to ceftriaxone and azithromycin for treating gonorrhea in a phase 3 trial.

With the approval, there are now two new oral antibiotic treatment options for one of the world’s most common sexually transmitted infections, following several years of concern about rising resistance to ceftriaxone, which has been a critical part of gonorrhea treatment for four decades and before last week was the last remaining recommended treatment option. Globally, an estimated 82 million new gonorrhea infections occur every year.

The two new drugs arrive weeks after surveillance data from the World Health Organization (WHO) showed the incidence of multidrug-resistant gonorrhea climbing sharply in some countries. The WHO and the US Center for Disease Control and Prevention have been warning that, without new antibiotics, gonorrhea could become untreatable.

“These approvals mark a significant milestone for treatment options for patients with uncomplicated urogenital gonorrhea,”Adam Sherwat, MD, director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.

A ‘pivotal moment’ for gonorrhea patients 

The first new antibiotic developed solely for gonorrhea in decades, zoliflodacin is a first-in-class antibiotic with a distinct mechanism of action against Neisseria gonorrhoeae, the bacterium that causes gonorrhea. It was developed as part of a public-private partnership between Innoviva Specialty Therapeutics and the nonprofit Global Antibiotic Research and Development Partnership (GARDP).

“The FDA’s approval of Nuzolvence marks a pivotal moment for patients and the broader healthcare community managing gonorrhea infections,” Innoviva Specialty Therapeutics Chief Medical Officer David Altarac, MD, said in a company news release. “For the first time in decades, both patients and their healthcare providers will have a single-dose, oral treatment option for uncomplicated urogenital gonorrhea.” 

Edward Hook, MD, an emeritus professor of medicine at the University of Alabama-Birmingham Medical School and protocol chair of the phase 3 study, which was conducted in five countries across four continents, told CIDRAP News that zoliflodacin will broaden the ability to treat gonorrhea patients in a number of important ways.

These approvals mark a significant milestone for treatment options for patients with uncomplicated urogenital gonorrhea.

For one, the fact that it can be taken orally will make it preferable for patients who don’t like injections, Hook said. Zoliflodacin also doesn’t have to be mixed or refrigerated, which would make it easier to store in low-resource settings. It’s also a suitable alternative for patients who are allergic to ceftriaxone and other beta-lactam antibiotics.

“There are lots of potential advantages over and above the fact that patients just really dread injections,” Hook said.

And while gonorrhea has a history of quickly developing resistance to antibiotics, the hope is that limiting zoliflodacin to gonorrhea infections will minimize excessive use and slow the development of resistance.

“The fact that zoliflodacin, at least at present, is, being used for a single indication, means that it’ll be used in a more limited setting,” Hook said. “And that antibiotic stewardship approach may slow the development of resistance.”

Gepotidacin, developed by GSK, will provide another alternative oral treatment option for gonorrhea patients who don’t like injections. Together, the two new antibiotics should give clinicians confidence in their ability to treat gonorrhea, even in settings where multidrug-resistant infections are rising. 

“The ability of N. gonorrhoeae to develop resistance to currently available options, including standard of care, makes it important to expand the range of effective oral treatments,” GSK Chief Scientific Officer Tony Wood, PhD, said in a company news release.

A milestone for antibiotic development

In addition to being an important advance in gonorrhea treatment, FDA approval of zoliflodacin is a major milestone for GARDP and its efforts to boost antibiotic development and ensure all countries have access to new drugs.

Originally developed by AstraZeneca before it shuttered its antibiotics division, zoliflodacin could have died on the vine. But Entasis Therapeutics (now a subsidiary of Innoviva) saw promise in the drug, and in 2019 GARDP entered into an agreement with the company to run and sponsor the phase 3 trial for zoliflodacin, which was the largest ever conducted for a new gonorrhea treatment.

In return, GARDP received the rights to register and commercialize the drug in more than three-quarters of the world’s countries, including the low- and middle-income countries where prevalence of gonorrhea is high and multidrug-resistance gonorrhea infections are becoming more common. Innoviva remains the marketing authorization holder in the United States and was responsible for filing the new drug application with the FDA.

GARDP hopes that this type of arrangement is one way to address the financial challenges of antibiotic development. Because antibiotics are expensive to develop but don’t bring the same return-on-investment as drugs for chronic conditions, many large pharmaceutical companies have abandoned the space, leaving smaller, cash-strapped biotech companies to pick up the slack. Those companies often need a partner to help them conduct larger clinical trials and bring a new antibiotic to market.

“This approval marks a huge turning point in the treatment of multidrug-resistant gonorrhoea, which until now has been outpacing antibiotic development,” GARDP Executive Director Manica Balasegaram, MRCP, MSc, said in a GARDP news release. “Zoliflodacin shows that a different public-private partnership approach to antibiotic development is possible—one that prioritizes global health needs, strengthens access where the burden is highest and protects the effectiveness of new drugs for the long-term.”

Amesh Adalja, MD, an infectious disease physician and senior scholar at the Johns Hopkins Center for Health Security, told CIDRAP News he thinks this type of public-private partnership could be one way to help ensure that the pipeline for new antibiotics doesn’t run dry.

“Anything that encourages antibiotic development and tries to reflect the unique market characteristics of antibiotics, I think is going to be welcome when you’re trying to deal with these threats,” Adalja said.