GSK antibiotic gepotidacin clears phase 3 gonorrhoea trial

GSK has reported topline results from a phase 3 trial of its novel antibiotic gepotidacin that could spell the end of a decades-long drought in new oral therapies for gonorrhoea.

In the EAGLE-1 trial, two oral doses of gepotidacin proved to be just as effective as standard combination therapy with intramuscular ceftriaxone plus oral azithromycin in resolving uncomplicated urogenital infections with Neisseria gonorrhoeae, the bacteria that causes gonorrhoea.

Gepotidacin was non-inferior to ceftriaxone/azithromycin at achieving a microbiological response at the ‘test-of-cure’ clinical visit, which takes place between three and seven days after treatment starts.

Gonorrhoea was diagnosed in 82 million people in 2020 and, according to World Health Organization (WHO) estimates, ranks high among the agency’s infectious diseases of greatest concern, as it is rapidly becoming resistant to available antimicrobial medicines.

If untreated, gonorrhoea can lead to infertility in both men and women and other sexual and reproductive health complications, as well as increasing the risk of HIV infection. In the US alone, case numbers increased 118% between 2009 and 2021, to reach more than 710,000 - an alarming increase, given that some so-called ‘super-gonorrhoea’ infections have become untreatable with all seven main antibiotic classes.

Gepotidacin is aiming to become the first triazaacenaphthylene antibiotic to reach the market and is also in late-stage testing for uncomplicated urinary tract infections (uUTIs), another indication that has seen a dearth in new oral therapies. Positive data from two phase 3 uUTI studies – EAGLE-2 and EAGLE-2 – were reported last year.

It is one of two novel antibiotics that promise to provide much-needed new options for people with hard-to-treat gonorrhoea, along with Innoviva’s bacterial type II topoisomerase inhibitor zoliflodacin, also chasing a first-in-class approval. In a phase 3 trial reported last year, zoliflodacin was also shown to be as effective as ceftriaxone/azithromycin at achieving microbiological cure.

Gepotidacin inhibits bacterial DNA replication by a novel mechanism of action and binding site, blocking two different type II topoisomerase enzymes, and has shown activity in the lab against multidrug-resistant strains of gonorrhoea and pathogens that cause UTIs, including Escherichia coli and Staphylococcus saprophyticus, according to GSK.

The pharma group, meanwhile, has another iron in the fire for gonorrhoea in the shape of its N. gonorrhoeae vaccine NgG, which is in phase 2 development and was awarded fast-track status from the FDA last year.

There are real concerns that we could be entering a post-antibiotic era, where even minor infections can be enough to kill patients, and by some estimates antimicrobial resistance (AMR) could claim around 1.2 million lives per year globally by 2050 unless new drugs and other measures become available to control infections.

GSK is one of the few remaining big pharma companies carrying out R&D on new antibiotics, after a mass exodus from the category in the last few decades as companies struggled to get a return on R&D investment for drugs typically reserved for use when other therapies have failed.

The UK Government has made an effort to change that dynamic, launching a subscription payment model for new antibiotics that provides developers with a fixed annual access fee, regardless of how much is used to treat patients.