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FDA says oral UTI treatment application is insufficient for approval


The FDA has sent a complete response letter to Spero Therapeutics saying its New Drug Application (NDA) lacked sufficient data to support the approval of tebipenem pivoxil hydrobromide (tebipenem HBr), the company’s oral agent for the treatment of adult patients with complicated urinary tract infection (cUTI), including pyelonephritis.1

The NDA was supported by data from the phase 3 ADAPT-PO trial showing that tebipenem HBr has noninferior efficacy and safety compared to intravenous ertapenem in this setting.2

“We are disappointed with the FDA’s decision, but we look forward to our continued dialogue, addressing the agency’s concerns and outlining a clear path forward for tebipenem HBr,” Ankit Mahadevia, MD, Chief Executive Officer of Spero Therapeutics, stated in a news release “With this development, we continue to believe that tebipenem HBr offers patients and their providers an important new treatment option, that if approved, has the potential to address the critical unmet need for a new oral antibiotic for patients with cUTI.”

Findings from the phase 3 ADAPT-PO trial were published earlier this year in the New England Journal of Medicine (NEJM).2 Explaining the background of the international, double-blind, double-dummy phase 3 trial, Angela Talley, MD, senior vice president, Clinical Development at Spero, and senior author of the study, and her coauthors wrote in the 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 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.”

“Our commitment to the development of effective new agents to address unmet medical needs remains strong, as we seek to identify the optimal path forward for tebipenem’s regulatory approval, commercialization, and value creation, potentially through external partnerships,” Mahadevia stated in the news release.


1. Spero Therapeutics Receives Complete Response Letter from U.S. Food and Drug Administration for Tebipenem HBr New Drug Application. Published online June 27, 2022. Accessed June 28 2022. https://bit.ly/3a1GBwL

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.

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