Background: Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an orally bioavailable prodrug that is rapidly converted in plasma to the carbapenem, tebipenem. Tebipenem has in vitro activity against select multidrug-resistant Gram-negative pathogens, including fluoroquinolone-resistant and extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales. TBP-PI-HBr is being developed in the United States as the first oral carbapenem for treatment of cUTI and AP.
Methods: ADAPT-PO was a global, double-blind, Phase 3 study to evaluate the efficacy and safety of oral TBP-PI-HBr vs. IV ertapenem in hospitalized adult patients with cUTI or AP. The primary endpoint was overall response (composite clinical cure and microbiologic eradication) at the test-of-cure (TOC) visit (Day 19 ± 2) in the micro-ITT population. Patients (N=1372) were randomized 1:1 to receive TBP-PI-HBr 600 mg PO q8h plus placebo IV q24h or ertapenem 1 g IV q24h plus oral placebo q8h for 7-10 days (or up to 14 days in patients with bacteremia).
Results: Oral TBP-PI-HBr met the primary objective of non-inferiority compared with IV ertapenem with an overall response rate of 58.8% (264/449) vs. 61.6% (258/419), respectively (treatment difference -3.3%; 95% CI: -9.7, 3.2; -12.5% NI margin). Clinical cure rates at TOC were > 93% in both treatment groups. Microbiological response rates for target uropathogens were comparable across treatment groups.TBP-PI-HBr was well tolerated. Treatment-emergent adverse events (TEAEs) were observed in 25.7% TBP-PI-HBr and 25.6% ertapenem patients. Most TEAEs were mild; premature discontinuation of study drug was uncommon (< 1%). The most frequent TEAEs were diarrhea (5.0%) and headache (3.8%). No C. difficile-associated TEAEs were observed in the TBP-PI-HBr group; 3 cases occurred in the ertapenem group. Serious adverse events were infrequent (1.3% vs. 1.7%), with no deaths.
Conclusions: Results from this pivotal Phase 3 study provide the first head-to-head demonstration of non-inferiority of an oral (TBP-PI-HBr) antibacterial agent to an IV (ertapenem) agent in patients with cUTI and AP, with a comparable tolerability profile. If approved in the U.S., TBP-PI-HBr would provide a new oral therapeutic option — and the first oral carbapenem — for patients with serious Gram-negative infections.