EAGLE trials herald new era for uncomplicated UTI treatment

Oral gepotidacin, an investigational, first-in-class oral antibiotic with a novel mechanism of action, showed favourable signals for the treatment of uncomplicated urinary tract infections (uUTIs), according to the results of two phase III trials.

“Gepotidacin was noninferior to nitrofurantoin – a guideline-recommended first-line antibiotic for the treatment of uUTIs – in both the EAGLE*-2 and EAGLE-3 studies,” said Professor Dr Florian Wagenlehner from the Justus-Liebig-University, Giessen, Germany, and EAGLE-2 principal investigator. “However, the superiority of gepotidacin over nitrofurantoin was also declared in EAGLE-3.”

At test-of-cure (ToC), therapeutic success rates with gepotidacin were 51 percent and 58 percent in EAGLE-2 and EAGLE-3, respectively. The corresponding rates with nitrofurantoin were 47 percent and 44 percent. [ECCMID 2023, abstract O0326]

Noninferiority was declared if the observed Z statistic exceeds the noninferiority boundary. These were met in both EAGLE-2 (3.55 [Z statistic for noninferiority] vs 2.06 [boundary]) and EAGLE-3 (5.88 vs 2.09).

Superiority was declared if the one-sided p-value was below the superiority boundary. This was the case in EAGLE-3 (0.0003 vs 0.018). “The lower microbiological success rate for nitrofurantoin is driving the larger treatment difference at ToC in EAGLE-3,” noted Wagenlehner. The rate was 57 percent, as opposed to 72 percent with gepotidacin, yielding a treatment difference of 15 percent.

“Therapeutic success was a novel stringent FDA and EMA regulatory efficacy endpoint,” Wagenlehner stressed. In the current study, therapeutic success was a combination of clinical success** and microbiological success***. In historical cohorts, it was either of the two components.

Use of other non-study antibiotic for uUTI was low across all study arms (between 1 percent and 6 percent).

 

Subgroup analysis, safety

The differences in success rates between gepotidacin and nitrofurantoin were broadly similar for the key subgroups and uropathogens, including older patients (>50 years), those with a history of recurrence, and drug-resistant Escherichia coli (E. coli), noted Wagenlehner. These subgroups of patients are at higher risk of treatment failure. [Open Forum Infect Dis 2022;9:ofac623]

In EAGLE-2, therapeutic success rates for the above-noted three subgroups were 52, 49, and 51 percent with gepotidacin, and 45, 40, and 46 percent with nitrofurantoin. The corresponding rates in EAGLE-3 were 62, 51, and 60 percent (gepotidacin) and 43, 38, and 44 percent (nitrofurantoin).

“Our safety findings were in line with phase I and II data. [The rates of] adverse events (AEs) were somewhat higher in the gepotidacin arms, but these were mostly mild to moderate in severity. Study drug discontinuation or withdrawal from study due to AEs were low, as were serious AEs,” said Wagenlehner.

Key AEs were mostly gastrointestinal which, according to Wagenlehner, could be due to acetylcholinesterase inhibition. “These were mainly mild and self-limiting,” he said. Clostridium difficile incidence was low in both arms, as were cardiovascular events.

 

An unmet need for new oral antibiotics

Most women with uUTI deal with recurrence, causing a significant patient burden. [N Engl J Med 2012;366:1028-1037; Epidemiol Infect 2019;147:e119; Ther Adv Urol 2019;11:1756287219832172] Moreover, uUTIs caused by resistant bacteria is on the rise, resulting in higher incidences of treatment failure. [Clin Infect Dis 2021;73:1992-1999]

With uUTI treatments limited by antimicrobial resistance, antibiotic allergies, or intolerance, there is an unmet need for new oral antibiotics that are active against resistant uropathogens, said Wagenlehner.

Gepotidacin is a novel bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and binding site and provides well-balanced inhibition of two type II topoisomerase enzymes. [ACS Infec Dis 2019;51:570-581; Nature 2010;466:935-940]

EAGLE-2 (n=607) and EAGLE-3 (n=541) are near-identical, large, pivotal, global phase III trials comparing the efficacy and safety of gepotidacin against nitrofurantoin. Female adolescents and adults with suspected uUTIs were randomized 1:1 to receive gepotidacin 1,500 mg BID or nitrofurantoin 100 mg BID and matching placebo for 5 days. The ToC visit was 10–13 days after treatment initiation. Overall, 41 percent had a history of recurrence. The primary baseline pathogen was E. coli (91 percent).

 

A much-needed addition to treatment pipeline

“Despite uUTIs 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 >20 years,” noted GSK SVP Development Chris Corsico, in a press release. [www.gsk.com/en-gb/media/press-releases/gepotidacin-s-positive-phase-iii-data-shows-potential-to-be-the-first-in-a-new-class-of-oral-antibiotics-for-uncomplicated-urinary-tract-infections, accessed April 22, 2023]

“[Our findings] 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 uUTIs,” noted Wagenlehner.

“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,” Corsico added.

Submission for US FDA approval is planned for the second quarter of this year.