Pivotal data published for oral UTI treatment as FDA weighs approval

As the FDA weighs approval of tebipenem pivoxil hydrobromide (tebipenem HBr) for the treatment of patients with complicated urinary tract infection (UTI), including acute pyelonephritis, the New England Journal of Medicine (NEJM) has published findings from the pivotal phase 3 ADAPT-PO trial showing that the oral agent has noninferior efficacy and safety compared to intravenous ertapenem in this setting.1,2

Spero Therapeutics, the developer of tebipenem HBr, previously reported that its new drug application (NDA) for tebipenem HBr, which was based on data from the ADAPT-PO trial, had received a priority review designation from the FDA, with the agency scheduled to decide on the NDA on or before June 27, 2022.

“ADAPT-PO was a landmark trial that is the first phase 3 head-to-head comparison of an all-oral versus all-IV treatment regimen in complicated UTI or acute pyelonephritis,” Angela Talley, MD, senior vice president, Clinical Development at Spero, and senior author of the NEJM paper, stated in a news release.

Explaining the background of the international, double-blind, double-dummy phase 3 ADAPT-PO trial, Talley and coauthors wrote in their NEJM manuscript, “There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase–producing and fluoroquinolone-resistant strains.”

The microbiologic intention-to-treat population for the ADAPT-PO trial trial included 868 patients, comprising 50.8% with complicated UTIs and 49.2% with pyelonephritis. Patients were randomized in a 1:1 ratio to oral tebipenem HBr (449 patients; 600 mg every 8 hours) or intravenous ertapenem (419 patients; 1 g every 24 hours). The treatments were administered for 7 to 10 days, or up to 14 days in patients with bacteremia).

The primary end point of the trial was overall response on day 19 (±2 days)in the microbiologic intention-to-treat population, measured as a composite of clinical cure and favorable microbiologic response. The margin to achieve noninferiority was 12.5%.

The overall response rate was 58.8% (264/449) among patients receiving tebipenem HBr compared with 61.6% (258/419) in patients treated with ertapenem (weighted difference, −3.3 percentage points; 95% CI, −9.7 to 3.2). Further, clinical cure at the test-of-cure visit was reported in 93.1% versus 93.6% of the groups, respectively (weighted difference, −0.6 percentage point; 95% CI, −4.0 to 2.8).

“The majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria,” wrote Talley et al.

Safety was also comparable between the treatment arms, with 25.7% versus 25.6% of the tebipenem HBr and ertapenem groups, respectively, experiencing adverse events (AEs). Across the study, mild diarrhea and headache were the most common AEs.

“In this trial, tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem for the treatment of patients with complicated urinary tract infection or acute pyelonephritis,” Talley et al wrote in their concluding remarks. “Results were consistent across trial populations and subpopulations, infection types, and causative uropathogens. Clinical cure was observed in 90% or more of the patients in both treatment groups at the end-of-treatment and test-of-cure visits and was sustained in follow-up.”

For more insight on oral tebipenem pivoxil hydrobromide and the ADAPT-PO trial, watch our video interviews with Dr. Talley:

Investigational oral agent noninferior to intravenous ertapenem for complicated UTIs

Dr. Talley on “landmark study” of investigational oral treatment for complicated UTIs

References

1. Spero Therapeutics Tebipenem Pivoxil Hydrobromide Phase 3 Data Published in The New England Journal of Medicine Published online April 6, 2022. Accessed April 18, 2022. https://bit.ly/3xEV5Mf

2. Eckburg PB, Muir L, Critchley IA, et al. Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection. N Engl J Med. 2022;386(14):1327-1338. doi: 10.1056/NEJMoa2105462.