Session : Late Breaking Abstracts

LB-3 - Oral Tebipenem Pivoxil Hydrobromide is Non-inferior to IV Ertapenem in Complicated Urinary Tract Infection (cUTI) and Acute Pyelonephritis (AP) – Results from the Pivotal ADAPT-PO Study

Saturday, October 24, 2020

10:10am – 10:20am EDT

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.

Conclusion: 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.

Presenter and Author(s)

Paul B. Eckburg, MD

Consultant
Spero Therapeutics
Mountain View, CA

Disclosure: AN2 Therapeutics (Consultant)Bugworks Research (Advisor or Review Panel member)Curza (Advisor or Review Panel member)Paratek Pharmaceuticals (Advisor or Review Panel member)SNIPR Biome (Consultant)

Slides

Co-Author(s)

LM

Lori A. Muir, n/a

Director
Spero Therapeutics
Cambridge, Massachusetts

Disclosure: Spero Therapeutics (Employee)Spero Therapeutics (Employee, Shareholder)
SW

Susannah M. Walpole, PhD

Vice President, Head of Clinical Operations
Spero Therapeutics, Inc.
Cambridge, Massachusetts

Disclosure: Spero Therapeutics, Inc. (Employee)
PW

Patricia A. Warfel, B.S.

Director
Spero Therapeutics
Boise, Idaho

Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
HK

Hanna Kwak, n/a

Senior Clinical Operation Manager
Spero Therapeutics
Arlington, Massachusetts

Disclosure: Spero Therapeutics (Employee)
AP

Anne-Marie Phelan, n/a

Director, Clinical Compliance
Spero Therapeutics
Cambridge, Massachusetts

Disclosure: Spero Therapeutics (Employee)Spero Therapeutics (Employee, Shareholder)
GM

Gary E. Moore, BS/MS

Statistical Programming Consultant
Moore Computing Services, Inc.
Little Rock, Arkansas

Disclosure: Spero Therapeutics (Consultant)
AJ

Akash Jain, PhD

Dr
Spero Therapeutics
Cambridge, Massachusetts

Disclosure: Spero Therapeutics (Employee)
TK

Tim Keutzer, BA

Chief Development Officer
Spero Therapeutics, inc
Cambridge, Massachusetts

Disclosure: Spero Therapeutics, Inc (Employee)
AD

Aaron Dane, MSc

Director
DaneStat Consulting
Macclesfield, Cheshire, England, United Kingdom

Disclosure: Da Volterra (Consultant)Spero theraputics (Consultant)
DM

David Melnick, MD

Chief Medical Officer
Spero Therapeutics
Cambridge, MA

Disclosure: Spero Therapeutics (Employee)Spero Therapeutics (Employee)
Angela K. Talley, MD

Vice President, Clinical Development
Spero Therapeutics
Cambridge, Massachusetts

Disclosure: Spero Therapeutics (Employee, Shareholder)