Ledaborbactam Etzadroxil

Ledaborbactam etzadroxil (LED-E), a novel oral prodrug that converts to the active β-lactamase inhibitor (BLI) ledaborbactam (LED), is being developed in combination with ceftibuten (CTB) to address a need for oral treatments against drug-resistant Enterobacterales infections. Two Phase 1 studies were conducted to (i) evaluate the safety and pharmacokinetics of single doses of LED-E 100 to 1000 mg and multiple doses of LED-E 75 to 500 mg every 8 h (q8h) for 10 days, (ii) assess potential drug interactions between CTB and LED, and (iii) evaluate safety and pharmacokinetics following multiple doses of LED-E 300 or 500 mg with CTB 400 mg or placebo q8h for 10 days. Treatment-emergent adverse events (TEAEs) were reported for 82% LED-E ± CTB (n = 109) and 78% placebo (n=27) participants, respectively. TEAEs of gastrointestinal disorders were reported for 28% of the LED-E ± CTB and 15% of placebo participants. Following single doses, LED-E AUC_inf was less than 2% of LED exposures, demonstrating extensive conversion to active BLI. LED AUC increased dose proportionally following single LED doses and less than proportionally following multiple LED-E doses. After 10 days of q8h dosing, the LED terminal half-life in plasma was approximately 11 to 12 h. Steady-state urinary excretion of LED-E-derived material (comprised almost entirely of unchanged LED) was 84%. No clinically relevant CTB and LED PK interactions occurred with the CTB + LED-E combination. These results support further development of the CTB + LED-E combination for the treatment of complicated urinary tract infections caused by drug-resistant Enterobacterales.CLINICAL TRIALSThese studies are registered with ClinicalTrials.gov as NCT04243863 and NCT04877379.

Ledaborbactam (formerly VNRX-5236), a bicyclic boronate β-lactamase inhibitor with activity against class A, C, and D β-lactamases, is under development as an orally bioavailable etzadroxil prodrug (VNRX-7145) in combination with ceftibuten for the treatment of urinary tract infections. At ceftibuten breakpoints of ≤1 mg/L (EUCAST) and ≤8 mg/L (CLSI), 92.5% and 99.0%, respectively, of 200 carbapenem-resistant Klebsiella pneumoniae isolates, predominantly K. pneumoniae carbapenemase producing, were susceptible to ceftibuten-ledaborbactam (ledaborbactam tested at a fixed concentration of 4 mg/L) compared to 4.5% and 30.5%, respectively, to ceftibuten alone.