An investigational oral antibiotic called zoliflodacin was well-tolerated and successfully cured most cases of uncomplicated gonorrhoea when tested in a Phase 2 multicentre clinical trial, according to findings. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, sponsored the clinical study.
Gonorrhoea is a common sexually transmitted disease (STD) that affects both men and women, particularly young people ages 15 to 24 years. Gonorrhoea is the second most commonly reported notifiable disease in the US, with more than 550,000 cases reported in 2017. If untreated, gonorrhoea infection can lead to pelvic inflammatory disease, ectopic pregnancy, infertility, and an increased risk of HIV infection. Pregnant women can pass the infection to their babies, who can become blind or develop life-threatening infections as a result.
Gonorrhoea is caused by the bacterium Neisseria gonorrhoeae, which has progressively developed resistance to each of the antimicrobials used to treat it. As a result, in 2015, the US Centres for Disease Control and Prevention revised gonorrhoea treatment guidelines to recommend dual therapy with injectable ceftriaxone and oral azithromycin to reduce the emergence of resistance to ceftriaxone.
Zoliflodacin (formerly known as ETX0914 and AZD0914), developed by Entasis Therapeutics based in Waltham, Massachusetts, represents a new type of oral antibiotic that inhibits DNA synthesis in a different way than currently approved antibiotics.
“The rate of reported gonorrhoea cases in the US has increased 75% since the historic low in 2009, and antibiotic resistance has considerably reduced the number of treatment options for this disease,” said NIAID director Dr Anthony S Fauci. “These encouraging research findings published today suggest that zoliflodacin has the potential to be a useful and easy-to-administer oral antibiotic for treating gonorrhoea.”
The study took place from November 2014 through December 2015 and was led by Dr Stephanie N Taylor, of Louisiana State University Health Sciences Centre in New Orleans. Study investigators recruited patients from sexual health clinics there and in Seattle; Indianapolis, Indiana; Birmingham, Alabama; and Durham, North Carolina.
The trial enrolled 179 participants (167 men and12 non-pregnant women) ages 18 to 55 years with either symptoms of uncomplicated urogenital gonorrhoea, untreated urogenital gonorrhoea or sexual contact with someone with gonorrhoea within 14 days before enrolment. Participants were randomly selected to receive either a single 2 or 3-gram dose of oral zoliflodacin or a 500-milligram (mg) dose of injectable ceftriaxone.
Along the 117 per-protocol participants who were evaluated six days after treatment, 98% (48 of 49 participants) of those who received the 2-gram zoliflodacin dose, 100 percent (47 of 47 participants) of those who received the 3-gram dose, and all (21 of 21) of the participants in the ceftriaxone group were considered cured of their urogenital gonorrhoea based on culture results.
Zoliflodacin cured all rectal gonorrhoeal infections (4 of 4 participants who received the 2-gram dose and 6 of 6 participants who received the 3-gram dose) as did ceftriaxone (3 of 3 participants). However, the investigational drug did not fare as well in treating patients with gonorrhoea infections of the throat (pharyngeal): 67% of volunteers who received the 2- gram dose (4 of 6 participants) and 78% of those who received the 3-gram dose (7 of 9 participants) were cured. All of the participants (4 of 4) in the ceftriaxone group achieved a cure.
The investigational antibiotic was well tolerated with transient gastrointestinal upset the most commonly reported adverse effect. Microbiological evaluation of post-treatment clinical isolates did not demonstrate resistance to zoliflodacin.
In March 2018, NIAID completed a study to evaluate zoliflodacin’s pharmacokinetics, safety and tolerability as a single oral dose to serve as a bridge from the Phase 2 clinical trial formulation to the final formulation for Phase 3 testing. Results from that study have not yet been made public. Additionally, in September 2018 NIAID launched a Phase 1 study to evaluate the investigational drug’s cardiac effects, a standard safety test for new drugs such as this.
Zoliflodacin has been awarded fast track status by the US Food and Drug Administration for development as oral treatment for gonococcal infections. It is expected to begin Phase 3 testing in the Netherlands, South Africa, Thailand and the US next year.
Background: Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea.
Methods: We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 6±2 days after treatment, followed by a safety visit 31±2 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population.
Results: From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal.
Conclusions: The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections.
Stephanie N Taylor, Jeanne Marrazzo, Byron E Batteiger, Edward W Hook III, Arlene C Seña, Jill Long, Michael R Wierzbicki, Hannah Kwak, Shacondra M Johnson, Kenneth Lawrence, John Mueller