Pooled EAGLE subgroup analyses boost gepotidacin potential for uUTI in females

In a pooled analyses of data from the EAGLE*-2 and EAGLE-3 studies, the investigational, first-in-class, oral, triazaacenaphthylene bactericidal antibiotic gepotidacin showed consistent therapeutic efficacy across key patient subgroups and had an acceptable safety profile in female adults and adolescents with uncomplicated urinary tract infections (uUTI) compared with nitrofurantoin.

Across the five subgroups (age, geographic region, uUTI recurrence history, diabetes history, renal function) evaluated in the microbiological-intent-to-treat (micro-ITT**) population, differences in therapeutic success at test-of-cure visit generally favoured gepotidacin over nitrofurantoin. [IDWeek 2023, abstract 2831]

Success rate differences were higher for patients aged >50 vs 18–50 years (14.6 percent vs 8.8 percent) and for those with mild renal impairment compared with those who had normal renal function (22.5 percent vs 9.6 percent). In patient categories within other subsets (with adequate patient numbers), treatment differences were consistent.

“Results were similar in the subpopulation of patients in the micro-ITT population who had uropathogen(s) susceptible to nitrofurantoin,” said presenting author Dr Thomas Hooton from the University of Miami, Coral Gables, Florida, US, at IDWeek 2023.

In the pooled safety cohort (n=3,128), adverse event (AE) rate was higher in the gepotidacin than the nitrofurantoin arm (35.1 percent vs 23.4 percent), but these were mostly mild to moderate (33.6 percent vs 22.5 percent) and gastrointestinal (27.1 percent vs 10.9 percent) in nature.

The rates of serious AEs were low in both gepotidacin and nitrofurantoin arms (<1 percent for both), as were the rates of AEs leading to drug discontinuation or study withdrawal (5.0 and 1.9 percent) and drug-related AEs leading to treatment discontinuation (4.5 percent vs 1.3 percent). Gepotidacin had an overall acceptable safety profile with no new safety concerns identified.

A new oral treatment alternative?

Data were pooled from two near-identical phase III, double-blind, double-dummy, active-controlled noninferiority trials comparing oral gepotidacin 1,500 mg against nitrofurantoin 100 mg. Females aged ≥12 years with ≥2 uUTI symptoms (dysuria, frequency, urgency, lower abdominal pain) were eligible.

The pooled micro-ITT population comprised 1,201 patients (mean age 51.5 years, 54 percent aged >50 years). They were randomized 1:1 to receive either treatment twice daily for 5 days. Strict measure of success required full symptom resolution plus microbiological eradication*** (from ≥10⁵ to <10³ CFU/mL), without using any additional non-study systemic antibiotic.

The current findings reinforce the initial results of both trials, which have been previously reported. EAGLE-2 and EAGLE-3 both met the primary endpoint of noninferiority of gepotidacin to nitrofurantoin. In addition, EAGLE-3 has demonstrated statistical superiority of the experimental drug over the comparator. [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 October 24, 2023]

In this post hoc analyses, gepotidacin generally showed consistent therapeutic efficacy vs nitrofurantoin across clinically important patient subgroups, including those at higher risk of treatment failure with other antibiotics such as older patients and those with a history of recurrent uUTI. [Open Forum Infect Dis 2022;9:ofac623]

“Gepotidacin has the potential to be a novel oral treatment for uUTI, offering benefit for key patient subgroups,” Hooton concluded.