The world may soon have a new antibiotic to treat gonorrhoea after a successful phase 3 trial of an oral pill, zoliflodacin, that was led and sponsored by a non-profit organisation.

The results were announced late Wednesday by the Global Antibiotic Research and Development Partnership (GARDP), which conducted the trial in collaboration with Innoviva Specialty Therapeutics.

The gonorrhoea bacteria – Neisseria gonorrhoeae – has slowly grown resistant to many classes of antibiotics, leaving injectable ceftriaxone in combination with oral azithromycin, as the last available recommended treatment for gonorrhoea globally.

In a 2017 World Health Organization (WHO) survey of 77 countries, 97% reported cases of drug resistance to common gonorrhoea antibiotics, while two-thirds reported resistance or decreased susceptibility to the last option for treatment with a single drug. Recent reports of emerging ceftriaxone-resistant gonorrhoea infections have heightened the urgency for new antibiotics.

Zoliflodacin showed “statistical non-inferiority” when compared to the standard regimen – and it is much easier to administer as it’s one pill rather than an injection and a pill.

Meanwhile, previous studies have shown that zoliflodacin is active against multi-drug resistant strains of Neisseria gonorrhoeae, including those resistant to ceftriaxone and azithromycin, with no cross-resistance with other antibiotics. 

“The outcome of this study is a potential game changer for sexual health,” said Professor Edward W Hook III, the study’s protocol chair and Emeritus Professor of Medicine at the University of Alabama in Birmingham, US.

“In addition to the potential benefits for patients with infections with resistant strains of Neisseria gonorrhoeae, the potential lack of cross-resistance with other antibiotics and the oral route of administration will simplify gonorrhoea therapy for clinicians worldwide.”

Non-profit ‘fix’

Gonorrhoea is one of the top three most common sexually transmitted infections with over 82 million new annual infections – mostly in Africa. If left untreated, it can also cause infertility in women, life-threatening ectopic pregnancies, pelvic inflammatory disease and sterility in men.

While the WHO designated gonorrhoea as a “priority pathogen”, no new treatments have been trialled in the past 40 years.

This is the first trial of a priority pathogen led by a non-profit organisation.

“Despite the extremely high public health value, there has been a lack of investment to develop new drugs for gonorrhoea,” said Dr Manica Balasegaram, GARDP’s executive director.

“The zoliflodacin programme demonstrates that it is possible to develop antibiotic treatments targeting multidrug-resistant bacteria that pose the greatest public health threat, and which may not otherwise get developed.”

Meanwhile, Professor Glenda Gray, GARDP board member and President of the South African Medical Research Council (SAMRC), said that “GARDP’s model can play a crucial role in helping to fix the public health failure at the heart of the global AMR crisis and is a significant step forward in the treatment of gonorrhoea”.

The trial involved 930 patients with uncomplicated gonorrhoea and included men, women, adolescents and people living with HIV. Around half the trial participants came from South Africa, with other trial sites in Belgium, the Netherlands, Thailand, and the US.

First-line treatment?

Prof Sinead Delany-Moretlwe, principal investigator for the trial in South Africa, said that the trial had been conducted under difficult circumstances during the height of the COVID-19 pandemic.

“The huge investment in HIV trial infrastructure has really given South African scientists the capacity to do trials in infectious diseases and to yield results that can be submitted to a range of regulatory authorities,” Delany-Moretlwe told Health Policy Watch.

While countries’ medicine regulators still need to grant approval for the drug, parties involved in the trial have discussed an implementation strategy – including whether zoliflodacin should be given as a first-line drug.

“Because it’s an easier drug to administer, if the cost is affordable, it makes sense to implement it [as a first-line treatment],” Delany-Moretlwe, research director of Wits RHI at the University of Witwatersrand in Johannesburg, South Africa.

“And ceftriaxone is not just used to treat gonorrhoea, so it is important to protect a class of drug that is used for more than gonorrhoea in terms of good antibiotic stewardship.”

Another factor in favour of using zoliflodacin for first-line treatment is that it has a unique mechanism that inhibits a crucial bacterial enzyme, which can also help to avoid the emergence of resistance.

Applying for approvals

“GARDP has the right to register and commercialise the product in more than three-quarters of the world’s countries, including all low-income countries, most middle-income countries, and several high-income countries,” according to a GARDP spokesperson. 

However, Innoviva affiliate Entasis Therapeutics has commercial rights for zoliflodacin in the lucrative markets of North America, Europe, Asia-Pacific and Latin America.

“Our aim is to provide sustainable access to an affordable product but we are unable to give further details at this time, as we move into negotiations with commercial partners,” a GARDP spokesperson told Health Policy Watch.

GARDP and Innoviva ST will apply for approval with the US Food and Drug Administration (FDA), and initiate registration activities in South Africa and Thailand shortly after FDA submission. 

“Once approval is obtained in these two countries, we will expand access to zoliflodacin through a process of collaborative approvals within a number of countries,” said GARDP, depending on “the public health need and on the epidemiological situation in each country”.  

Meanwhile, Innoviva CEO Pavel Raifeld said that treatment “could have a profound effect on how physicians approach gonorrhoea 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”.

The GARDP trial was funded with support from the governments of Germany, UK, Japan, the Netherlands, Switzerland and Luxembourg, as well as the Canton of Geneva, the South African MRC, and the Leo Model Foundation. It builds on a phase 2 clinical trial sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID).