An important Phase 3 trial has shown that a new drug that targets gonorrhea works as well as the last existing antibiotic to treat the sexually transmitted infection, results that could lead to licensure of the first new treatment for gonorrhea in decades.
The co-developers of the drug, the nonprofit Global Antibiotic Research & Development Partnership, or GARDP, and Innoviva Specialty Therapeutics, a subsidiary of Innoviva Inc., released topline results of the clinical trial on Wednesday. A scientific report outlining full details of the trial will be published later, Manica Balasegaram, executive director of GARDP, told STAT in an interview.
The Phase 3 trial was conducted in areas of high prevalence of gonorrhea in five countries over four continents: Belgium, the Netherlands, South Africa, Thailand, and the United States. A total of 930 people were enrolled, making it the largest clinical trial ever conducted for a new gonorrhea treatment, GARDP said. The trial was successful at reaching its primary endpoint, the partners said, showing the experimental drug, zoliflodacin, was “non-inferior” at treating gonorrhea in urogenital sites compared to a combination of ceftriaxone and azithromycin. Ceftriaxone alone is the current standard of care for gonorrhea.
The infection, which is caused by the bacterium Neisseria gonorrhoeae, is spread through sexual contact. Infection can occur in the genitals, the rectum, and the throat. The World Health Organization estimates that there are more than 80 million new gonorrhea infections every year.
If it is not successfully treated, gonorrhea can cause pelvic inflammatory disease, as well as infertility in women and sterility in men. Babies can contract it from infected mothers during birth, which can lead to blindness. It increases an infected person’s risk of contracting HIV and can lead to joint infections in rare cases.
The arrival of a new drug to combat gonorrhea cannot come too soon. Since the advent of antibiotics, Neisseria gonorrhoeae has developed resistance to each class of antibiotics the medical community has used to combat it, leaving ceftriaxone as the sole remaining drug that can reliably cure gonorrhea. But in the past few years, there have been mounting reports of cases of ceftriaxone-resistant gonorrhea.
“We’re on borrowed time,” said Edward Hook, a professor emeritus at the University of Alabama at Birmingham who was protocol chair for the clinical trial. “Experts in the field … already know that the time for which ceftriaxone will be able to be uniformly effective for gonorrhea is limited. And we know that the World Health Organization has already reported true treatment failures of ceftriaxone in Southeast Asia.”
Under the partnership between GARDP and Innoviva, the nonprofit will bring the drug through the licensure processes in about 160 low- and middle-income countries around the world and line up manufacturers to make the drug for those countries. Pending regulatory approval, Innoviva will commercialize the drug in high-income markets in North and Latin America, the Asia-Pacific, and Europe.
Zoliflodacin is being developed exclusively as a treatment for gonorrhea, an approach people like Hook, who has spent his career studying sexually transmitted infections, hope will slow the bacteria’s ability to develop resistance to the new drug.
“There are good data to show that as gonorrhea inexorably develops resistance to the drugs used to treat it, that what drives that development of resistance is not treatment for gonorrhea but treatment for other infections out in the community,” Hook said in an interview.
“It would be silly to predict that there will never be resistance to zoliflodacin,” he continued. “There has never been an antibiotic used in the treatment of gonorrhea that the bug didn’t become resistant to. I think, though, that the development of resistance in this case hopefully will be a slow process because of the thoughtful approach that has been used in development, and that’s very exciting.”
There are other reasons to be hopeful about the utility of zoliflodacin, Balasegaram said. It is an entirely new drug, not related to existing classes of antibiotics to which gonorrhea has already developed resistance. And a previous study showed that the drug was effective, when tested in a laboratory, against 13,000 drug-resistant gonorrhea isolates.
“This treatment is very well-tolerated, from the studies we’ve done. It’s given as a single dose. It’s an oral treatment, and it has a good cure rate,” Balasegaram said.
The drug is easy to use — easier than ceftriaxone — and does not trigger unpleasant side effects. Zoliflodacin is given in oral form, granules stirred into a liquid suspension.
Ceftriaxone, on the other hand, is injected, which requires syringes for administration and safe disposal of them afterwards. And zoliflodacin doesn’t share some of ceftriaxone’s baggage. The latter is related to penicillin and beta-lactam antibiotics, to which some people are allergic — and to which more mistakenly believe they are allergic, Hook said. In those people, gonorrhea treatment already requires use of non-recommended drugs.
“The success of this study could have a profound effect on how physicians approach gonorrhea infections, as an oral alternative to an injection could improve patient access and compliance, as well as help reduce the increasing spread of antibiotic resistant strains of the disease,” Pavel Raifeld, Innoviva’s chief executive officer, said in a statement.
Zoliflodacin has been in development for a number of years. A Phase 2 trial published in the New England Journal of Medicine in 2018 heralded the promise of the potential new therapy. That earlier study noted that the drug was less effective than ceftriaxone in curing gonorrhea in the throat, but the number of people enrolled with this type of gonorrhea in that earlier study was small. Hook said in the Phase 3 trial, zoliflodacin worked as well as existing drugs at all sites of infection.
In addition to the urgent need for a new treatment for gonorrhea, the zoliflodacin success underscores the possibilities of new development models for antibiotics, a fact highlighted by the National Institute of Allergy and Infectious Diseases in a statement applauding the results.
“NIAID celebrates this exemplary public-private partnership for supporting science to improve the sexual health of people worldwide,” said NIAID Director Jeanne Marrazzo, who was involved in research of zoliflodacin in her prior job as director of the division of infectious diseases at the University of Alabama at Birmingham. “These encouraging results should bolster additional, intersectoral efforts to develop safe and effective therapeutic options for gonorrhea and other bacteria that exhibit antimicrobial resistance.”
With public funding and without a need to generate profits, GARDP was able to take risks a private company might not, Balasegaram said. In return, it was able to ensure that the drug was being developed uniquely for gonorrhea, and would be available in markets that might otherwise not be able to afford what could have been an expensive drug.
“So in terms of [antimicrobial] stewardship, in terms of trying to conserve the treatment, we also said, ‘Look, we’ll help you to do this work. We’ll actually pay for the trials. We’ll actually undertake to sponsor and be responsible for all of this work and generate all this data and information and also develop a pharmaceutical formulation,’” Balasegaram said. “We actually worked on doing that to make it more affordable and something that could be commercialized. But in return, we asked for certain things, including really limiting the use to gonorrhea, to sexually transmitted infections.”
“And of course it’s very exciting we’ve got to this stage,” he said. “But now we have to focus on the next stage, which is how do we bring this successfully to patients around the world and use it responsibly?”