Gonorrhoea – the current antibiotic pipeline and the need for new drugs

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The WHO has recently published data highlighting a concerning level of antibiotic resistance in strains of gonorrhoea, with over 60% of the 77 surveyed countries reporting resistance to the current last-resort treatment.

In light of this, the WHO has emphasized the relatively empty pipeline for antibiotics against gonorrhoea and has called for new drugs. We, at Infectious Diseases Hub, have taken a closer look at the three antibiotics currently in clinical trials for gonorrhoea, highlighting recent results and next steps.

Zoliflodacin

This first-in-class antibiotic, being developed by Entasis Therapeutics (MA, USA), has recently completed Phase II clinical trials, the data from which was presented at ID Week (LA, USA, 25–30 October 2017) [1].

In this study, the drug, which acts as a DNA gyrase inhibitor, was assessed in 179 gonorrhoea-positive participants who were randomized to receive either 2000 mg zoliflodacin, 3000 mg zoliflodacin or current-treatment ceftriaxone (500 mg intramuscularly) [2].

The team reported ‘microbiological cure’ in 98% of patients receiving 2000 mg zoliflodacin and 100% of those receiving 3000 mg. In addition, they reported that the drug had acceptable minimum inhibitory concentrations among gonorrhoea isolates that were ciprofloxacin- or azithromycin-resistant [2].

Zoliflodacin is currently in line to enter Phase III clinical trials, thanks to a partnership between Entasis Therapeutics and the Global Antibiotic Research and Development Partnership (GARDP). The study will be carried out in several countries including the USA, Thailand and South Africa. Alongside this, non-clinical activities are planned in order to assess the effectiveness of zoliflodacin against recent and geographically diverse strains of gonorrhoea [3].

GARDP Director, Manica Balasegaram, commented: “This partnership with Entasis aims to make sure we are ready as the last resort treatments for gonorrhoea fail, so that the nightmare scenario of untreatable gonorrhoea does not become a reality. Since any new antibiotic must be effectively ‘stewarded’ and accessible to all who need it, we will conduct the additional studies needed not just for registration of zoliflodacin, but to have maximum public health impact – a global approach to a global challenge.”

Gepotidacin

Gepotidacin is another first-in-class antibiotic that has completed Phase II trials. This novel triazaacenaphthylene antibacterial compound is currently being developed by GlaxoSmithKline (London, UK), and has previously demonstrated in vitro activity against Neisseria gonorrhoeae.

The recent trial enrolled 106 patients with urogenital gonorrhoea, who were randomly assigned to receive either a single 1500 mg or 3000 mg oral dose of gepotidacin, with the aim of assessing the efficacy, safety and tolerability of this compound [4]. Results reported that 29 of the 30 participants in the 1500 mg arm achieved bacterial eradication of urogenital N. gonorrhoeae at the test-of-culture visit. In addition, microbiological cure was reported in 37 of the 39 participants receiving a 3000mg oral dose of gepotidacin.

Phase III trials are being planned to further assess this novel antibiotic against not only gonorrhoea, but also skin infections [5].

Solithromycin

This next-generation macrolide is currently being developed by pharmaceutical company Cempra (NC, USA), and has demonstrated activity against a variety of different bacteria. With regards to gonorrhoea, a Phase III trial for solithromycin is underway, including approximately 300 participants [6].

The trial, termed SOLITAIRE-U, will examine the safety and efficacy of solithromycin in patients with urogenital gonorrhoea, compared with the standard-of-care treatment: ceftriaxone and azithromycin. Patients will be randomly assigned to receive 1000 mg solithromycin or 500 mg intramuscular ceftriaxone and 1000 mg oral azithromycin [6].

In initial results, from an original cohort of 262 participants, the antibiotic demonstrated high success rates; after taking the drug, 91.3% of patients with an initially positive baseline culture were negative when they returned for follow-up. In addition, the company reported a 100% success rate for female patients within this population [7].

However, solithromycin didn’t achieve non-inferiority compared with the standard-of-care treatments, causing the company, in collaboration with the National Institute of Allergy and Infectious Disease (NIAID; MD, USA) to propose an expansion to the trial of up to 76 women and adolescents [7]. This expansion is currently still recruiting, but results are hoped to be published in August 2017 [6].

In a company update, Cempra stated: “We believe that the small number of solithromycin treatment failures observed in SOLITAIRE-U could be reduced in an approval-enabling study with an adjustment to the dosing regimen, as we believe the treatment failures were most likely related to the duration of study drug exposure at the site of infection.

“We plan to discuss our next steps with the genitourinary gonorrhoea (GC) program with NIAID and the FDA, as resistance to existing therapies for GC has created an urgent unmet medical need. In SOLITAIRE-U, no GC isolates demonstrated solithromycin resistance at baseline, and there was no emergence of solithromycin resistance in the isolates obtained at follow-up cultures.”

Conclusions

Results from the future trials of these three drugs are of course unknown, meaning success cannot be guaranteed. In addition, developing resistance could require a supply of new drugs that constantly needs to be replenished in order to maintain effective treatment [8].

Director of Antimicrobial Resistance at the WHO, Marc Sprenger, concluded: “To control gonorrhoea, we need new tools and systems for better prevention, treatment, earlier diagnosis, and more complete tracking and reporting of new infections, antibiotic use, resistance and treatment failures. Specifically, we need new antibiotics, as well as rapid, accurate, point-of-care diagnostic tests – ideally, ones that can predict which antibiotics will work on that particular infection – and longer term, a vaccine to prevent gonorrhoea.”

References:
  1. Seña AC, Taylor SN, Marrazzo J et al. Microbiological Cure Rates and Antimicrobial Susceptibility of Neisseria gonorrhoeae to ETX0914 (AZD0914) in a Phase II Treatment Trial for Urogenital Gonorrhea. Program and Abstracts of ID Week 2016, New Orleans, LA, USA, , 25-30 October (Poster 1308)
  2. National Institute of Allergy and Infectious Diseases. Randomized, Open-label Phase 2 Study of Oral AZD0914 in the Treatment of Gonorrhea. https://clinicaltrials.gov/ct2/show/results/NCT02257918 NLM identifier: NCT02257918
  3. Drugs for Neglected Diseases initiative. Entasis Therapeutics and the Global Antibiotic Research & Development Partnership (GARDP) to Develop a New Treatment for Drug-Resistant Gonorrhea. (6th July 2017) dndi.org/2017/media-centre/press-releases/entasis-therapeutics-and-gardp-to-develop-new-treatment-for-drug-resistant-gonorrhea/ (Accessed 7th July 2017)
  4. A Dose-Ranging Study Evaluating the Efficacy, Safety, and Tolerability of GSK2140944 in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria Gonorrhoeae. https://clinicaltrials.gov/ct2/show/results/NCT02294682 NLM identifier: NCT02294682
  5. GSK profiles innovative R&D portfolio to investors (November 2015) http://fr.gsk.com/media/638948/gsk-profiles-innovative-randd-portfolio-to-investors-03_11_15-lse-announcement.pdf (Accessed 7th July 2017)
  6. Cempra Inc. Efficacy and Safety Study of Oral Solithromycin Compared to Intramuscular Ceftriaxone Plus Oral Azithromycin in the Treatment of Patients With Gonorrhea (SOLITAIRE-U). https://clinicaltrials.gov/ct2/show/NCT02210325 NLM identifier: NCT02210325
  7. Cempra Inc. Cempra Provides Corporate Update and Reports Fourth Quarter and Full Year 2016 Financial Results (28th February 2017) http://investor.cempra.com/releasedetail.cfm?ReleaseID=1014807 (Accessed 7th July 2017)
  8. World Health Organization. Antibiotic-resistant gonorrhoea on the rise, new drugs needed (7th July 2017) who.int/mediacentre/news/releases/2017/Antibiotic-resistant-gonorrhoea/en/ (Accessed 7th July 2017)
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