A new oral antibiotic drug currently in development appears to be effective at treating gonorrhea, an infection for which there is a critical need for new therapeutic options, a study published Wednesday suggested.
The findings are the result of a Phase 2 trial, a small study done to determine if further, larger studies are warranted. Evidence from larger Phase 3 trials would be needed to persuade the Food and Drug Administration or other regulatory agencies to license the one-dose drug, zoliflodacin.
But the data, published in the New England Journal of Medicine, appear to be good news to a field that is overdue for some. Since the dawn of the antibiotic era, Neisseria gonorrhoeae, the bacterium that causes gonorrhea infections, has steamrollered its way through all the drugs that have been placed in its path.
“If the promise of these results is confirmed in Phase 3 studies, then zoliflodacin stands to become a very important drug in gonorrhea treatment worldwide. That’s in the future, but that’s the promise that this study suggests,” said Dr. Hunter Handsfield, a professor emeritus of medicine at the University of Washington’s Center for AIDS and STD. Handsfield was not involved in the study.
The current recommended treatment for gonorrhea is a combination of an injectable antibiotic, ceftriaxone, and another that comes in pill form, azithromycin. Experts hope that the use of two drugs — so-called dual therapy — will slow the development of antibiotic resistance to the drugs.
But these are the last treatments in the antibiotic armamentarium to reliably cure gonorrhea; already there are signs this combination’s power is eroding. Resistance to azithromycin is rising and there have been a few cases of resistance to ceftriaxone reported as well.
Each new case unsettles the cadre of doctors who treat the common sexually transmitted disease, knowing as they do that very hard-to-treat or even untreatable gonorrhea infections may soon loom on the horizon.
Gonorrhea is spread through sexual contact, and infection can occur in the genitals, the rectum, and the throat.
If it is not successfully treated, gonorrhea can cause pelvic inflammatory disease and infertility in women and sterility in men. Babies can contract it from infected mothers during birth, which can leave the infant blind. It increases a person’s risk of contracting HIV and can lead to joint infections in rare cases.
Planning is currently underway for a Phase 3 trial for zoliflodacin; the trial is expected to start in 2019. The Phase 2 trial was financed by the National Institute of Allergy and Infectious Diseases and the Phase 3 will be co-financed by Entasis Therapeutics — which owns the intellectual property — and a nonprofit group called Global Antibiotic Research and Development Partnership, or GARDP.
In exchange for help developing the drug, GARDP will receive an exclusive license to the drug that will allow it to bring it to market at an affordable price in 160 low- and middle-income countries — if it’s approved. Entasis, which is based in Boston, retains the rights in high-income countries.
The Phase 2 results look promising. Zoliflodacin was nearly as effective as ceftriaxone at curing gonorrhea infections in the urethra and in the rectum, though the number of people who had rectal infections was small and therefore the results have to be viewed with some caution.
However, the drug didn’t appear as effective in curing infections in the pharynx — an infection site that has bedeviled other oral antibiotics as well. Even though the trial was small, Handsfield didn’t hold out a lot of hope that a Phase 3 trial would come to a different conclusion.
“I think it will surprise experts in the field if the Phase 3 trial shows strong efficacy for pharyngeal infection. I suspect it will not, based on admittedly small numbers in this trial,” he said.
He and the trial’s principal investigator, Dr. Stephanie Taylor of Louisiana State University Health Sciences Center, didn’t feel that would prevent the drug from being licensed, if the Phase 3 trial shows it is effective against urethral and rectal gonorrhea.
Taylor said a number of other antibiotics that have been the standard of care in the past had similar problems combatting pharyngeal gonorrhea. The belief, she said, is that the oral administration makes it difficult to get a high enough concentration of drug in the throat to quell the bacteria.
But Dr. Lindley Barbee, an assistant professor of infectious diseases at the University of Washington and medical director of the Public Health – Seattle & King County STD Clinic, said having an antibiotic that can’t routinely cure pharyngeal gonorrhea would not be ideal — especially if ceftriaxone fails and the Centers for Disease Control and Prevention needs to recommend zoliflodacin as a first-line therapy.
“I really believe that any regimen that’s going to be recommended at the CDC level needs to be able to eradicate the [bacteria] from the pharynx because the site goes underscreened so often,” said Barbee, who was not involved in the study.
“I do think it’s something we need to think about, thinking on the big picture — the population level. What happens if we put forward a drug — and make it a standard of care — that doesn’t treat one anatomic site and potentially even induces resistance because of that anatomic site?” she asked.
The Phase 2 study involved very few women, a limitation of the work. Taylor said it is hard to enroll women in this type of trial. Research safety rules require that women enrolled must have been on and continue to use effective contraception for the duration of the trial to ensure they are not given an experimental drug while they are pregnant.
“In all other drugs that have ever been studied, the regimens that work well for urethral gonorrhea in men also work well for genital infection in women and generally they work well for rectal infection in women and men having sex with men,” Handsfield noted.
The drug works by a different mechanism than other antibiotics — a feature that experts hope might make it less vulnerable to the development of antibiotic resistance. But Taylor wasn’t ready to count out wily gonorrhea.
“Well, you know, gonorrhea has developed resistance to every drug in the past. So, yes, we’re hopeful,” she said. “But you know, considering historically what has happened we have no idea. We’ll know that answer in a few years.”