BOSTON & GENEVA—A new partnership between the not-for-profit Global Antibiotic Research and Development Partnership (GARDP) and Entasis Therapeutics will bring zoliflodacin, a novel first-in-class oral antibiotic and one of the only treatments in development to address the rapidly growing threat of drug-resistant gonorrhea, to pivotal trials.
According to the World Health Organization (WHO), of 77 countries surveyed across the world, more than 60 percent report resistance to the last-resort treatment for gonorrhea. About 78 million new cases of gonorrhea develop every year. The Neisseria gonorrhoea pathogen creates a potentially serious infection that can cause infertility, ectopic pregnancy, increased risk of HIV infection and pelvic inflammatory disease, among others. Today’s main recommended treatment is an injection of ceftriaxone and an oral dose of azithromycin, but resistance is growing to these treatments.
Entasis and GARDP will co-develop zoliflodacin in a global Phase 3 clinical trial slated to be carried out in countries that include South Africa, the United States and Thailand. The National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, plans to support pharmacological studies on the drug as part of the development program.
“Antimicrobial resistance is of major concern, and this is true for gonorrhea as well as other serious infections,” explained Dr. Manos Perros, CEO of Entasis Therapeutics. “New therapies are needed that address the problem of increasing antimicrobial resistance. For gonorrhea specifically, there are high hurdles for a new treatment, which needs to be effective against bacteria that have developed resistance to every class of antibiotics available for this disease.”
He added, “Zoliflodacin has the potential to stem the spread of drug-resistant gonorrhea by providing a convenient oral cure for patients and their partners. Our collaboration with GARDP demonstrates our commitment to addressing high unmet medical needs through novel antibacterials, while ensuring responsible use and access to our medicines for all patients.”
“As the infection is easily transmitted through sexual contact, new treatments need to be rapidly effective, ideally as a single dose, often administered under direct physician observation; and to enable partner treatment, an oral formulation is highly desirable,” noted Dr. Manica Balasegaram, GARDP director. “Despite the high medical need due to rapidly developing antibiotic resistance, the commercial market for gonorrhea remains challenging, as the majority of patients can still be treated with relatively inexpensive, generic antibiotics. This limits the commercial potential of new drugs in the short term, and as a consequence, all other efforts in discovering new gonorrhea treatments have been as an additional indication for antibiotics which are being primarily developed for other diseases.”
Entasis’ zoliflodacin is the first in a new class of antibiotics and the only new clinical candidate developed specifically to treat gonorrhoea, according to the company. Zoliflodacin demonstrated potent in-vitro activity against Neisseria gonorrhoea, including isolates resistant to fluoroquinolones and extended spectrum cephalosporins, achieving promising efficacy after a single oral dose in a recent Phase 2 clinical study sponsored by NIAID. Zoliflodacin has been designated a Qualified Infectious Disease Product (QIDP) by the U.S. Food and Drug Administration and awarded Fast Track status.
While repurposing or reformulating older drugs and molecules might serve a short-term need in containing rising antimicrobial resistance, Entasis believes that sustainable solutions require scientific innovation. According to the company, zoliflodacin is a first-in-class antibacterial that does not share cross-resistance to other existing antibiotics. As such, it is effective against gonorrhea caused by N. gonorrhoeae strains susceptible and resistant to existing therapies. Unlike other treatments on the market or in clinical development, zoliflodacin has been developed specifically to target gonorrhea pathogens, and Entasis has optimized the microbiology and dosing to effectively and safely cure patients of their infection with a single oral dose. The company demonstrated proof of concept in a Phase 2 clinical trial which was successfully completed last year.
According to Perros, “Our partners at the NIAID are currently performing pre-Phase 3 studies, before starting the pivotal Phase 3 trial with GARDP next year. Our goal is initial submission in the U.S. in 2020, with other territories following shortly thereafter in partnership with GARDP.”
As to commercial potential, zoliflodacin will address the growing market of people infected with gonorrhea. Treatment guidelines drive antibiotic selection and largely depend on changes in gonorrhea resistance. While resistance rates in many countries around the world are already alarmingly high, Zoliflodacin’s commercial potential therefore depends on the speed in which resistance to the current standard of care changes in commercial markets, and how quickly guidelines are adjusted to account for that.
As Perros concluded, “This is a perfect illustration of the conundrum we face in antibacterial development: while resistance is still emerging, there is commercial uncertainty that hampers efforts to invest in developing new treatments. Yet, once resistance is established in the community, a new treatment is needed urgently. The partnerships with NIAID and GARDP have enabled Entasis to move forward with the development of zoliflodacin, so that we can make it available to patients and physicians when they need it.”