REG - GSK PLC - Gepotidacin positive phase III data

GSKAnnouncement

17/04/2023 07:00

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RNS Number : 3395W  GSK PLC  17 April 2023

Issued: 15 April 2023, London UK

 

Gepotidacin's positive phase III data shows potential to be the first in a new
class of oral antibiotics for uncomplicated urinary tract infections in over
20 years

 

·   Gepotidacin is a late-stage antibiotic in development in GSK's growing
infectious diseases portfolio

·   EAGLE-2 and EAGLE-3 phase III trials met primary endpoint of
non-inferiority to nitrofurantoin; EAGLE-3 demonstrated statistical
superiority

·   US FDA submission is planned for Q2 2023

 

GSK plc (LSE/NYSE: GSK) presented positive results from the pivotal EAGLE-2
and EAGLE-3 phase III trials for gepotidacin, an investigational,
first-in-class oral antibiotic with a novel mechanism of action for
uncomplicated urinary tract infections (uUTI) in female adults and
adolescents. The data were disclosed today in an oral presentation at the
European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in
Copenhagen, Denmark.

 

These positive data highlight GSK's world-leading infectious diseases
portfolio, which represents about two-thirds of the Company's pipeline. In
addition, they reinforce GSK's commitment to developing new antibiotics in
high unmet medical need areas, such as uUTI. Today's presentation follows the
decision to stop the EAGLE-2 and EAGLE-3 pivotal trials early for efficacy
following a recommendation made by the Independent Data Monitoring Committee
in November 2022. The full results will be submitted for publication in a
peer-reviewed scientific journal later this year.

 

Over half of all women are affected by uUTIs in their lifetime 1 , with more
than a quarter suffering from recurrent disease 2 (, 3 , 4 ) , which can cause
significant patient burden, including discomfort and restriction of daily
activities. The number of uUTIs caused by resistant bacteria is increasing,
which can result in higher treatment failure rates. 5 

 

Chris Corsico, SVP Development, GSK, said: "Despite uncomplicated urinary
tract infections being one of the most common infections in women and mounting
concern over rising resistance rates to existing treatments, there has been no
new class of antibiotics for over 20 years. We believe that gepotidacin, if
approved, will offer a much-needed additional oral treatment option for
patients at risk of treatment failure associated with resistance or recurrence
of uUTI. We are committed to working with global regulators to bring this new
antibiotic to patients as quickly as possible."

 

In the EAGLE-2 and EAGLE-3 phase III trials, gepotidacin demonstrated
non-inferiority to nitrofurantoin, an existing first-line treatment for uUTI,
in patients with a confirmed uUTI and a uropathogen susceptible to
nitrofurantoin. Additionally, in the EAGLE-3 phase III trial, gepotidacin
demonstrated statistically significant superiority versus nitrofurantoin.
These results are based on a primary efficacy endpoint of therapeutic success,
an endpoint comprised of combined clinical resolution and microbiological
eradication of bacteria at the Test-of-Cure (ToC) visit 10-13 days after
initiation of treatment.

 

In the EAGLE-2 phase III trial, gepotidacin demonstrated therapeutic success
in 50.6% of patients compared to 47% for nitrofurantoin. In the EAGLE-3 phase
III trial, gepotidacin demonstrated therapeutic success in 58.5% of patients
compared to 43.6% for nitrofurantoin. Across both trials, it was noted that
94% of patients treated with gepotidacin did not receive an additional
antibiotic for uUTI during trial participation through the follow-up visit on
day 28. The safety and tolerability profile of gepotidacin in the EAGLE-2 and
EAGLE-3 phase III trials was consistent with previous trials of gepotidacin.

 

Gepotidacin also demonstrated consistent efficacy (therapeutic success)
compared to nitrofurantoin in key subgroups, including patients with
Escherichia coli pathogens resistant to other antibiotics, those with a
history of recurrence and those over 50 years old. These subgroups are at
higher risk of treatment failure. 6 (, 7 )

The table below summarises the key efficacy data for phase III trials at the
ToC visit:

 

                              EAGLE-2                                                                                              EAGLE-3
                              Gepotidacin 1,500mg BID (n=320)  Nitrofurantoin 100mg BID (n=287)  Treatment Difference(i) (95% CI)  Gepotidacin 1,500mg BID (n=277)  Nitrofurantoin 100mg BID (n=264)  Treatment Difference(i)

                                                                                                                                                                                                      (95% CI)
 Therapeutic success(ii)      162 (50.6%)                      135 (47.0%)                       4.3%                              162 (58.5%)                      115 (43.6%)                       14.6%

                                                                                                 (-3.6%, 12.1%)                                                                                       (6.4%, 22.8%)
 Clinical success(iii)        210 (65.6%)                      187 (65.2%)                       1.2%                              188 (67.9%)                      167 (63.3%)                       4.4%

                                                                                                 (-6.3%, 8.7%)                                                                                        (-3.5%, 12.3%)
 Microbiological success(iv)  232 (72.5%)                      194 (67.6%)                       5.2%                              200 (72.2%)                      151 (57.2%)                       15.0%

                                                                                                 (-2.1%, 12.5%)                                                                                       (7.2%, 22.9%)

Both trials were stopped for non-inferiority based on pre-defined
non-inferiority success boundaries. In addition, the EAGLE-3 phase III trial
met the pre-defined boundary for superiority.

(i ) Difference: gepotidacin - nitrofurantoin. Micro-ITT NTF-S (IA set), the
microbiological intent-to-treat nitrofurantoin-susceptible interim analysis
set population

(ii) Composite endpoint of clinical and microbiological success
(iii) Clinical success at Test-Of-Cure (TOC) = symptom resolution
(iv) Eradication of qualifying uropathogen to <10(3) CFU/mL

Prof. Dr Florian Martin Erich Wagenlehner, Principal Investigator for the
EAGLE-2 phase III trial, said: "These results are a significant step forward
in an area that has seen very little innovation for decades. Gepotidacin is
the first antibiotic to meet contemporary regulatory criteria, which set a
high threshold for the efficacy of treatments in uncomplicated urinary tract
infections. Gepotidacin has the potential to offer healthcare professionals
another oral option to treat this common community infection."

The most commonly reported adverse events (AEs) in gepotidacin subjects were
gastrointestinal (GI). Diarrhoea was the most common (16% of subjects),
followed by nausea (9%). Of the subjects who reported GI AEs in the
gepotidacin arm, the maximum severity of most subjects were mild (69% Grade 1)
and moderate (28% Grade 2). Grade 3 GI events were 3% of the total GI events
and occurred in <1% of subjects. There was one drug-related serious adverse
event in each treatment arm (gepotidacin and nitrofurantoin) across the two
trials.

 

The development of gepotidacin has been funded in whole or in part with U.S.
federal funds from the U.S. Department of Health and Human Services,
Administration for Strategic Preparedness and Response, Biomedical Advanced
Research and Development Authority, under Other Transaction Agreement number
HHSO100201300011C and with federal funds awarded by the Defense Threat
Reduction Agency under agreement number HDTRA1-07-9-0002.

 

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:

 

The EAGLE-2 and EAGLE-3 phase III trials were near-identical global,
randomised, parallel-group, double-blind, non-inferiority (10% margin) trials
comparing the efficacy and safety of oral gepotidacin to nitrofurantoin for
the treatment of uUTI. A total of 3,136 patients were enrolled across both
trials.

 

EAGLE-2 (non-inferiority uUTI trial) compared the efficacy and safety of
gepotidacin (1,500mg administered orally twice daily for five days) to
nitrofurantoin (100mg administered orally twice daily for five days). The
trial duration for participants was approximately 28 days. The primary
endpoint was the combined clinical and microbiological response at the ToC
visit (days 10-13) in patients with qualifying uropathogens susceptible to
nitrofurantoin.

 

EAGLE-3 (non-inferiority uUTI trial) compared the efficacy and safety of
gepotidacin (1,500mg administered orally twice daily for five days) to
nitrofurantoin (100mg administered orally twice daily for five days). The
trial duration for participants was approximately 28 days. The primary
endpoint was the combined clinical and microbiological response at the ToC
visit (days 10-13) in patients with qualifying uropathogens susceptible to
nitrofurantoin.

 

EAGLE-1 (non-inferiority urogenital gonorrhoea trial) compares the efficacy
and safety of gepotidacin to ceftriaxone plus azithromycin in approximately
600 patients with uncomplicated urogenital gonorrhoea caused by Neisseria
gonorrhoeae. The EAGLE-1 trial is investigating gepotidacin for the treatment
of uncomplicated urogenital gonorrhoea and is ongoing, with a data read out
anticipated in the second half of 2023.

 

About gepotidacin

Gepotidacin, discovered by GSK scientists, is an investigational bactericidal,
first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA
replication by a novel mechanism of action and binding site and provides
well-balanced inhibition of two different Type II topoisomerase enzymes. This
provides activity against most strains of target uropathogens, such as E. coli
and Staphylococcus saprophyticus, including isolates resistant to current
antibiotics. Furthermore, due to the well-balanced inhibition of two enzymes,
mutations in both enzymes are needed to significantly affect susceptibility to
gepotidacin.

 

GSK in antimicrobials
The Company is committed to investing in solutions to help get ahead of
antimicrobial resistance. GSK is already a leader on the Antimicrobial
Resistance Benchmark of the Access to Medicine Foundation. As well as a legacy
in antibiotics, GSK has a growing late-stage pipeline of antimicrobials
alongside gepotidacin for the potential treatment of UTI. In September 2022,
GSK entered into an exclusive licence agreement with Spero Therapeutics to add
a late-stage antibiotic, tebipenem HBr, to potentially treat complicated
urinary tract infections (cUTI) to GSK's pipeline. In addition, in March 2023,
GSK entered into an exclusive licence agreement with SCYNEXIS, Inc to add a US
FDA-approved, first-in-class antifungal Brexafemme (ibrexafungerp) for the
treatment of vulvovaginal candidiasis in adult and post-menarchal pediatric
females to GSK's growing portfolio of antimicrobials. 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
https://www.gsk.com/en-gb/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 under
Item 3.D 'Risk factors" in the company's Annual Report on Form 20-F for 2022,
GSK's Q4 Results for 2022 and any impacts of the COVID-19 pandemic.

 

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 1  Historic self-reported data from a survey sample of 2000 women in the US.
1. Foxman, 2000, 2. Foxman, 2003

 2  Hooton TM. Uncomplicated Urinary Tract Infection. N Engl J Med.
2012;366:1028-37.

 3  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.

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

 5  Kaye KS, et al. Antimicrobial resistance trends in urine Escherichia coli
isolates from adult and adolescent females in the United States from 2011 to
2019: rising ESBL strains and impact on patient management. Clin Infect Dis
2021;73:1992-1999. doi: 10.1093/cid/ciab560

 6  Trautner et al. Risk Factors Associated With Antimicrobial Resistance and
Adverse Short-Term Health Outcomes Among Adult and Adolescent Female
Outpatients With Uncomplicated Urinary Tract Infection

 7  Data on file

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