# GSK positive results from the pivotal phase III trials for gepotidacin

- Link: https://www.directorstalkinterviews.com/gsk-positive-results-from-the-pivotal-phase-iii-trials-for-gepotidacin/4121114990
- Published: 2023-04-17T08:19:05+01:00
- Author: Amilia Stone

**[GSK plc](https://www.directorstalkinterviews.com/ftse-company/glaxosmithkline-plc/gsk.l)**(
LON/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.

·   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

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])

> **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 _N__eisseria 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.

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