Results of the phase 3 RESTORE-IMI 1 trial showed that relebactam was comparable to colistin when used in combination with imipenem/cilastatin in patients with drug-resistant infections, including those caused by carbapenem-resistant Enterobacteriaceae. Findings also showed that the drug was associated with lower treatment-emergent nephrotoxicity.
Based on these data, Merck said it plans to submit a new drug application to the FDA for the approval of imipenem/cilastatin plus relebactam (IMI/REL). The FDA has previously designated the regimen as a qualified infectious disease product with fast track status for the treatment of hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs).
“Infections caused by gram-negative bacteria continue to be a major problem for hospitalized patients,” Amanda Paschke, MD, MSCE, senior principal scientist of infectious disease clinical research at Merck, said in a press release. “The prevalence of carbapenem-resistant pathogens is increasing globally, highlighting the need for effective new antibacterial agents with gram-negative coverage.”
REL is an investigational beta-lactamase inhibitor that is designed to restore IMI activity against IMI-nonsusceptible gram-negative pathogens, according to Paschke and colleagues. The researchers compared the safety and efficacy of IMI/REL with colistin plus IMI (COL/IMI) in 47 patients with an HABP, VABP, cIAI or cUTI caused by at least one IMI-nonsusceptible pathogen. They randomly assigned participants in a 2:1 ratio to receive IMI/REL (n = 31) or colistin plus IMI (n = 16). Treatment duration ranged from 5 to 21 days for cUTIs and cIAIs, and 7 to 21 days for HABP/VABP. The primary endpoint was a favorable overall response in the microbiologically modified intent-to-treat (mMITT) population.
Keith S. Kaye
“It is important to note that in this trial of medically fragile patients, the colistin comparator dosing was optimized to ensure patients had the best chance of success and set up a ‘fair fight’ between the drugs,” study investigator and Infectious Disease News Editorial Board member Keith S. Kaye, MD, MPH, said in an interview. Kaye is also president of the Society of Healthcare Epidemiology of America and professor of internal medicine at the University of Michigan Medical School.
In the mMITT population, the favorable overall response was similar in the IMI/REL arm (n = 15; 71.4%) and the COL/IMI arm (n = 7; 70%). At day 28, IMI/REL was associated with higher favorable clinical response (71.4% vs. 40%) and lower all-cause mortality (9.5% vs. 30%) compared with COL/IMI.
In a safety analysis, fewer patients who received IMI/REL had a drug-related adverse event (16.1% vs. 31.3%), including treatment-emergent nephrotoxicity (10% vs. 56%).
IMI/REL is being further assessed in another phase 3 trial, RESTORE-IMI 2, according to the release. In this trial, IMI/REL is being compared with piperacillin/tazobactam in patients with HABP or VABP.
“We look forward to contributing to the knowledge of antibacterial therapy in this very challenging disease state,” Kaye said. – by Stephanie Viguers
Motsch J, et al. RESTORE-IMI 1: A multicenter, randomized, double-blind, comparator-controlled trial comparing the efficacy and safety of imipenem/relebactam versus colistin plus imipenem in patients with imipenem-non-susceptible bacterial infections. Presented at: European Congress of Clinical Microbiology and Infectious Diseases; April 21-24, 2017; Madrid.
Disclosure: Kaye reports being a consultant and receiving grant support from Merck. Paschke is an employee of Merck.