REG - GSK PLC - IDMC recommends gepotidacin early efficacy stop

GSKAnnouncement

03/11/2022 07:00

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RNS Number : 1968F  GSK PLC  03 November 2022

Issued: 3 November 2022, London UK

 

EAGLE-2 and EAGLE-3 phase III trials for gepotidacin stopped early for
efficacy following pre-planned interim analysis by Independent Data Monitoring
Committee

 

·   Gepotidacin could be the first new novel oral antibiotic treatment for
uncomplicated urinary tract infections in over 20 years

·   GSK plans to submit a New Drug Application for gepotidacin to the US
Food and Drug Administration (FDA) in H1 2023

 

 

 

GSK plc (LSE/NYSE: GSK) today announced that the pivotal phase III EAGLE-2 and
EAGLE-3 trials evaluating gepotidacin, an investigational treatment for
uncomplicated urinary tract infection (uUTI) in female adults and adolescents,
will stop enrolment early for efficacy following a recommendation by the
Independent Data Monitoring Committee (IDMC). This decision was based on a
pre-specified interim analysis of efficacy and safety data in over 3000
patients across the trials.

 

Chris Corsico, SVP, Development, GSK, said: "Uncomplicated urinary tract
infections (uUTI) are the most common outpatient infection with over half of
all women developing a uUTI during their lifetime and more than a quarter of
women suffering from recurrent uUTIs. There has been no new class of oral
antibiotics for uUTI for over 20 years. With the number of uUTIs caused by
resistance bacteria increasing, new antibiotic treatments are necessary. The
IDMC's recommendation to stop the EAGLE-2 and 3 trials early for efficacy
provides GSK with the opportunity to engage regulatory authorities as we work
together to bring a new class of antibiotics to patients with uUTIs."

 

The EAGLE-2 and EAGLE-3 trials met the primary efficacy endpoint of combined
clinical and microbiological resolution following treatment at the
Test-Of-Cure (TOC) visit for gepotidacin versus nitrofurantoin in patients
with a confirmed uUTI and a uropathogen sensitive to nitrofurantoin. The IDMC
review did not identify any safety concerns.

The EAGLE-2 and 3 trials are now closed for recruitment, with final study
visits and data collection anticipated during the first quarter of 2023. GSK
will work with regulatory authorities to commence regulatory filings for
gepotidacin in H1 2023. The full results will also be submitted for
presentation at a scientific congress and for publication in a peer-reviewed
journal in 2023.

The development of gepotidacin is the result of a public-private partnership
between GSK, the US government's Biomedical Advanced Research and Development
Authority (BARDA), part of the Administration for Strategic Preparedness and
Response at the U.S. Department of Health and Human Services, and Defense
Threat Reduction Agency (DTRA) within the Department of Defense. The
collaboration with BARDA was established in 2013 with the aim to support the
development of antibiotics to fight antibiotic resistance and bioterrorism
under contract number HHSO100201300011C.

 

uUTIs are one of the most common infections in the community(1). The annual
incidence of uUTI (or acute cystitis) in women is 12% and c.˜20% in women
over 65; 30-44% of uUTI episodes are recurrent 1  (#_edn1) (, 2  (#_edn2) , 3 
(#_edn3) ). Escherichia coli (e. coli) bacteria are the main cause of uUTI(1)
but it is showing increasing resistance to antibiotics currently used 4 
(#_edn4) (, 5  (#_edn5) ), leaving healthcare professionals with fewer oral
options to treat their patients 6  (#_edn6) . As a result, there is a need to
develop new oral antibiotics that may help treat uUTIs and potentially combat
antimicrobial resistance (AMR) in the community, particularly given that there
has not been a new class of oral antibiotics for uUTI for over 20 years.(2, 7 
(#_edn7) )

 

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

The phase III clinical programme for gepotidacin in adults and adolescents
comprises three trials:

 ●    EAGLE-2 (non-inferiority uUTI trial, 204989) compares the efficacy and safety
      of gepotidacin (1500mg administered orally twice daily for 5 days) to
      nitrofurantoin (100mg administered orally twice daily for five days). The
      trial duration for participants is approximately 28 days. The primary endpoint
      is the combined clinical and microbiological response at the TOC visit in
      patients with qualifying uropathogens.
 ●    EAGLE-3 (non-inferiority uUTI trial, 212390) compares the efficacy and safety
      of gepotidacin (1500mg administered orally twice daily for 5 days) to
      nitrofurantoin (100mg administered orally twice daily for 5 days). The trial
      duration for participants is approximately 28 days up until follow-up. The
      primary endpoint is the combined clinical and microbiological response at the
      TOC visit in patients with qualifying uropathogens.
 ●    EAGLE-1 (non-inferiority urogenital gonorrhoea trial, BTZ116577) compares the
      efficacy and safety of gepotidacin (3000mg administered orally at the trial
      site during the baseline visit followed by self-administration of a second
      oral 3000mg dose as an outpatient 10 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 trial duration is approximately 21 days. At the TOC visit,
      the primary endpoint is the culture-confirmed bacterial eradication of NG from
      the urogenital body site. The EAGLE-1 trial which is investigating gepotidacin
      for the treatment of uncomplicated urogenital gonorrhoea is ongoing.

EAGLE-2 and 3 are similar trials and together provide substantial clinical
evidence, with EAGLE-2 providing additional pharmacokinetic data and EAGLE-3
including an on-treatment ECG test. Trial enrolment overlapped with the
COVID-19 pandemic (the EAGLE-2 trial started in October 2019, and the EAGLE-3
trial began in May 2020), and trial sites are located across 12 countries,
each with different infection and resistance patterns.

About gepotidacin

Gepotidacin is a novel, investigational bactericidal, first-in-class
triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a
distinct mechanism of action 8  (#_edn8) (, 9  (#_edn9) ) and equally and
independently binds to two different Type II topoisomerase enzymes 10 
(#_edn10) . This provides activity against most strains of E. coli and S.
saprophyticus, including isolates resistant to current antibiotics 11 
(#_edn11) , 12  (#_edn12) . Due to the equal and independent binding at both
enzymes, mutations in both enzymes are needed to significantly affect
gepotidacin susceptibility.

 

GSK in antibiotics

GSK has been developing and supplying antibiotics for more than 70 years.
Research and development continue to investigate new tools to prevent and
mitigate infectious disease - and get ahead of antimicrobial resistance. GSK
is already a leader on the Antimicrobial Resistance Benchmark of the Access to
Medicine Foundation. In September 2022, GSK entered into an exclusive licence
agreement with Spero Therapeutics to add a late-stage antibiotic, tebipenem
HBr for the potential treatment of complicated urinary tract infections
(cUTI), to our pipeline. The closing of the transaction is subject to the
expiration of the waiting period under the Hart-Scott-Rodino Antitrust
Improvements Act of 1976, as amended.

 

About GSK

GSK is a global biopharma company with a purpose to unite science, technology,
and talent to get ahead of disease together. Find out more at gsk.com/company
(https://www.gsk.com/en-gb/company/)

 

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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 in
the Company's Annual Report on Form 20-F for 2021, GSK's Q3 Results for 2022
and any impacts of the COVID-19 pandemic.

 

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 1  (#_ednref1) Hooton TM. Uncomplicated Urinary Tract Infection. N Engl J
Med. 2012;366:1028-37.

 2  (#_ednref2) Rich SN, Klann EM, Almond CR, Larkin EM, Nicolette G, Ball JD.
Associations between antibiotic prescriptions and recurrent urinary tract
infections in female college students. Epidemiology and Infection. 2019;147.

 3  (#_ednref3) Medina M, Castillo-Pino E. An introduction to the epidemiology
and burden of urinary tract infections. Therapeutic Advances in Urology.
2019;11:175628721983217.

 4  (#_ednref4) WHO. Global priority list of antibiotic-resistant bacteria to
guide research, discovery, and development of new antibiotics. 2017.

 5  (#_ednref5) CDC. Antibiotic resistance threats in the United States. 2019.
Available from:
https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
(https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf)
[Accessed October 2022]

 6  (#_ednref6) Kaye KS, et al. Clin Infect Dis. 2021;73(11):1992-1999

 7  (#_ednref7) 2020 Antibacterial agents in clinical and preclinical
development: an overview and analysis. Geneva: World Health Organization;
2021. Licence: CC BY-NC-SA 3.0 IGO.

 8  (#_ednref8) Gibson EG, et al. ACS Infect Dis 2019;5(4):570−581

 9  (#_ednref9) Bax BD, et al. Nature 2010;466(7309):935-940.

 10  (#_ednref10) Oviatt A, et al. Poster #L0178 presented at ECCMID, 23-26
Apr, 2022, Lisbon, Portugal.

 11  (#_ednref11) Biedenbach DJ, et al. Antimicrob Agents Chemother
2016;60(3):1918-1923

 12  (#_ednref12) Mushtaq S, et al. Poster #P1849 presented at ECCMID, 13-16
April, 2019, Amsterdam, The Netherlands.

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