GSK starts a phase III clinical programme for a potential first-in-class antibiotic, gepotidacin

Issued: London, UK

GlaxoSmithKline plc (LSE/NYSE: GSK) today announced that patient dosing has begun in a phase III clinical programme investigating gepotidacin, the first in a new chemical class of antibiotics called triazaacenaphthylene bacterial topoisomerase inhibitors, in patients with uncomplicated urinary tract infection (uUTI, also known as acute cystitis) and urogenital gonorrhoea (GC).

Dr Hal Barron, Chief Scientific Officer and President, R&D, GSK said: “Given the increasing rate of antibiotic drug resistance, and gepotidacin’s unique mechanism of action, we believe this drug has the potential to transform the treatment landscape for patients with uncomplicated urinary tract infection and urogenital gonorrhoea who currently have limited therapeutic options.”

The phase III programme, comprising two studies, will test gepotidacin in two common infections caused by bacteria identified as antibiotic resistant threats by the Centers for Disease Control and Prevention, a division of the US Department of Health and Human Services.^[1]

The first study (EAGLE-1) will compare gepotidacin to ceftriaxone plus azithromycin, a guideline recommended dual therapy approach, in approximately 600 patients with GC, one of the most common sexually transmitted infections.^[2] The second study (EAGLE-2) will compare gepotidacin to nitrofurantoin, a licensed first-line antibiotic, in approximately 1200 patients with uUTI, an infection that is very common in women.^[3] First results are expected by the end of 2021.

The progress into phase III development follows positive results from two phase II studies that evaluated gepotidacin for the treatment of GC, and acute bacterial skin and skin structure infections (ABSSSI). The GC study showed that single, oral doses of gepotidacin were at least 95% effective for bacterial eradication of Neisseria gonorrhoea (NG) in adult participants with uncomplicated urogenital gonorrhoea.^[4] The ABSSSI study showed that two of the three doses of gepotidacin tested met prespecified success criteria for clinical utility in terms of efficacy and safety profile.^[5]

The development of gepotidacin is the result of a successful public-private partnership between GSK, the US government’s Biomedical Advanced Research and Development Authority (BARDA) and Defense Threat Reduction Agency (DTRA). This collaboration was established in 2013 with the aim to support the development of several antibiotics to fight antibiotic resistance and bioterrorism.

As one of the few large pharmaceutical companies still pursuing antibacterial research, GSK also has collaborations and funding partnerships with other companies, academia, and funding bodies such as the Innovative Medicines Initiative, Europe’s largest public-private initiative.

Gepotidacin is currently not approved for use anywhere in the world.

About the EAGLE (Efficacy of Antibacterial Gepotidacin Evaluated) phase III programme

The phase III clinical programme for gepotidacin in adults and adolescents comprises the following two studies:

• Urogenital gonorrhoea study (BTZ116577)

The EAGLE-1 study will compare the efficacy and safety of gepotidacin (3000mg administered orally at the study site during the baseline visit followed by self-administration of a second oral 3000mg dose as an outpatient 6 to 12 hours after the first dose) to a single intramuscular 500mg dose of ceftriaxone plus a single oral 1g dose of azithromycin in approximately 600 patients with uncomplicated GC caused by the bacterium NG. The study duration is approximately 21 days. The primary endpoint will be the culture-confirmed bacterial eradication of NG from the urogenital body site at the Test-of-Cure (TOC) visit.

• Uncomplicated urinary tract infection study (204989)

The EAGLE-2 study will compare the efficacy and safety of gepotidacin (1500mg administered orally twice daily for 5 days) to nitrofurantoin (100mg administered orally twice daily for 5 days) in approximately 1,200 adolescent and adult female patients with uUTI.  The study duration is approximately 28 days. The primary endpoint will be the therapeutic response at the TOC visit in patients with qualifying uropathogens.

This project has been funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, under OTA number HHSO100201300011C.

About gepotidacin

Gepotidacin (GSK2140944) is the first in a new class of antibiotics, called triazaacenaphthylene topoisomerase inhibitors, developed at GSK in 2007 with a novel “dual targeting” mechanism of action (MOA) and oral formulation. Its MOA is distinct from any currently approved antibiotic.

Gepotidacin works by selectively interacting with two key bacterial enzymes, DNA gyrase and topoisomerase IV (type II topoisomerases), responsible for bacterial replication. The novel MOA confers activity against most target pathogens resistant to established antibiotics, including fluoroquinolones.

About uncomplicated urinary tract infections

Uncomplicated urinary tract infections (also known as acute cystitis) are very common in women.  Approximately 11% of women over 18 years of age experience at least one episode of uUTI per year. ^[3] The peak incidence of uUTI occurs in young, sexually active women. ^[3]  An estimated one third of all female adolescents and women experience at least one episode of uUTI, requiring antibiotics by the age of 24 years. ^[6,7] The predominant uropathogens isolated in community-acquired uUTIs are E. coli (75% to 90%) followed by S. saprophyticus (5% to 15%).

About gonorrhoea

Gonorrhoea is the second most prevalent bacterial sexually transmitted infection globally and remains an important clinical and public health problem throughout the world.^[2] In 2016, an estimated 87 million new cases of gonorrhoea occurred. ^[8] A variety of antibiotics have been used over the years for the treatment of gonorrhoea; however, effective treatment options for gonorrhoea have diminished rapidly because of the emergence and worldwide spread of antibiotic resistance to many drugs previously used or considered first line, i.e., penicillins, narrow-spectrum cephalosporins, tetracyclines, macrolides, and fluoroquinolones. ^[9,10]

GSK’s antibiotic heritage

GSK has been active in the discovery, development, manufacturing and commercialisation of antibiotics for over 70 years and we remain firmly committed. Today, GSK and our manufacturing network make approximately 50 antibiotic brands and contribute towards 8% of the global volume.

About GSK

GSK is a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. For further information please visit www.gsk.com/about-us/.

Cautionary statement regarding forward-looking statements

GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D 'Principal risks and uncertainties' in the company's Annual Report on Form 20-F for 2018.

References

[1] Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013/

[2] World Health Organization (WHO). Report on global sexually transmitted infection surveillance, 2018. Geneva: World Health Organization; 2018. License: CC BY-NC-SA 3.0 IGO

[3] Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl J Med 2003; 349(3):259-66.

[4] Taylor SN, Morris DH, Avery AK et al. Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation. Clin Infect Dis. 2018 Aug 1; 67(4): 504–512.

[5] O’Riordan W, Tiffany C, Scangarella-Oman N et al. Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944) in the Treatment of Patients with Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections. Antimicrob Agents Chemother 2017 May 24;61(6). pii e02095-16.

[6] Foxman, B. The Epidemiology of Urinary Tract Infections:  Incidence, Morbidity, and Economic Costs. American Journal of Medicine 2002;113(1A): 5s-13s.

[7] Medina M, Castillo-Pino E. An Introduction to the epidemiology and burden of urinary tract infection. Ther Adv Urol 2019;11:

[8] World Health Organization STD Fact Sheet 2016:  https://www.who.int/en/news-room/fact-sheets/detail/sexually-transmitted-infections-(stis)

[9] Workowski KA, Berman SM, Douglas Jr. JM. Emerging antimicrobial resistance in Neisseria gonorrhoeae: urgent need to strengthen prevention strategies. Ann Intern Med. 2008;148(8):606-13.

[10] Barry PM, Klausner JD. The use of cephalosporins for gonorrhea: the impending problem of resistance. Expert Opin Pharmacother. 2009;10(4):555-77.