Merck issued the following announcement on April 22.
Merck known as MSD outside the United States and Canada, announced that a pivotal Phase 3 study of relebactam, the company’s investigational beta-lactamase inhibitor, in combination with imipenem/cilastatin, demonstrated a favorable overall response in the treatment of certain imipenem–non-susceptible bacterial infections, the primary endpoint, with lower treatment-emergent nephrotoxicity (kidney toxicity), a secondary endpoint, compared to a Colistin (colistimethate sodium) plus imipenem regimen.
Based on these results, the company plans to submit a New Drug Application to the U.S. Food and Drug Administration seeking regulatory approval of a fixed-dose combination of imipenem/cilastatin and relebactam.
“Infections caused by Gram-negative bacteria continue to be a major problem for hospitalized patients. The prevalence of carbapenem-resistant pathogens is increasing globally, highlighting the need for effective new antibacterial agents with Gram-negative coverage,” said Dr. Amanda Paschke, senior principal scientist, infectious disease clinical research, Merck Research Laboratories. “We look forward to advancing relebactam in combination with imipenem/cilastatin, and continuing to build on Merck's longstanding commitment in the fight against infectious disease.”
Results of the RESTORE-IMI 1 study were presented at the 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2018 meeting in Madrid, Spain, April 21-24. The study was a multicenter, randomized, double-blind, comparator-controlled trial comparing the efficacy and safety of imipenem/cilastatin/relebactam (IMI/REL) versus Colistin plus imipenem/cilastatin (COL+IMI) in patients with imipenem-non-susceptible bacterial infections. Patients with hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI), or complicated urinary tract infection (cUTI) caused by one or more imipenem-non-susceptible (but Colistin- and IMI/REL-susceptible) pathogens, were randomized 2:1 to receive IMI/REL or COL+IMI in a double-blind fashion. Colistin dosing was based on medical literature, and was consistent with recent regulatory guidance. Study therapy duration was to be 5-21 days for cUTI and cIAI, and 7-21 days for HABP/VABP.
The primary endpoint of the study was favorable overall response (defined by relevant endpoints for each different infection type) in the microbiological modified intent-to-treat (mMITT) population (defined as patients having a qualifying baseline pathogen and having received at least one dose of study treatment). Secondary endpoints included favorable clinical response at Day 28, 28-day all-cause mortality, incidence of treatment-emergent nephrotoxicity, and incidence of adverse events.
In the study, 31 of 47 randomized and treated patients met mMITT criteria. Favorable overall response was comparable for the IMI/REL (71.4%; n=15) and COL+IMI (70.0%; n=7) treatment arms. Favorable clinical response at Day 28 was higher in the IMI/REL arm (71.4%; n=15) compared to the COL+IMI (40.0%; n=4) arm, and 28-day all-cause mortality was lower in the IMI/REL arm (9.5%; n=2) vs. COL + IMI (30.0%; n=3), respectively.
Among all treated patients, drug-related adverse events occurred in 16.1% of patients (n=31) in the IMI/REL arm compared to 31.3% of patients (n=16) in the COL+IMI arm. Treatment-emergent nephrotoxicity was lower with IMI-REL (10%; 3/29 patients) compared to COL+IMI (56%; 9/16 patients) (p=0.002).
Second Pivotal IMI/REL Phase 3 study, RESTORE-IMI 2, ongoing
Merck is conducting a second pivotal Phase 3 clinical study, RESTORE-IMI 2, comparing treatment with imipenem/cilastatin/relebactam, as a fixed-dose combination, versus piperacillin/tazobactam in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia. The primary hypothesis of this study is that imipenem/cilastatin/relebactam is non-inferior to piperacillin/tazobactam in the incidence rate of all-cause mortality (www.ClinicalTrials.gov Identifier: NCT02493764).
Original source can be found here.
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