Company Initiates Pivotal Phase 3 Studies Evaluating Relebactam in Combination with Imipenem/Cilastatin for Treatment of Serious Bacterial Infections known as MSD outside the United States and Canada, today announced that a Phase 2 study of relebactam, the company’s investigational beta-lactamase inhibitor for the treatment, in combination with imipenem/cilastatin (an approved carbapenem antibiotic), of complicated intra-abdominal infections, met its primary endpoint, and that Merck is now initiating pivotal Phase 3 studies. In the Phase 2 study, relebactam in combination with imipenem/cilastatin demonstrated noninferiority in the percentage of microbiologically evaluable patients with favorable clinical response at the end of intravenous therapy compared to imipenem/cilastatin alone. The addition of relebactam is designed to restore activity of imipenem against certain imipenem-resistant strains of Gram-negative bacteria, including Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae.
The results were presented at the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and International Congress of Chemotherapy and Infection (ICC) joint meeting in San Diego, Sept. 17-21.
“New medicines are urgently needed to address the growing threat of antibiotic-resistant bacteria,” said Dr. Nicholas Kartsonis, associate vice president, infectious disease clinical research, Merck Research Laboratories. “We look forward to advancing our Phase 3 clinical program evaluating relebactam, in combination with imipenem/cilastatin, for use in the treatment of several complicated Gram-negative bacterial infections, and to continue to build on Merck’s commitment to infectious diseases.”
In this multicenter, double-blind Phase 2 study, 351 adult patients with complicated intra-abdominal infections, most commonly complicated appendicitis (53%) and complicated cholecystitis (17%), were randomized to receive either relebactam 250mg, relebactam 125mg or placebo, each given intravenously in combination with imipenem/cilastatin 500mg every six hours for 4 to 14 days. The percentage of microbiologically evaluable patients with favorable clinical response at the end of intravenous therapy, the primary efficacy endpoint, was similar across treatment groups: relebactam 250mg (96.3%) (n=83),
relebactam 125mg (98.8%) (n=87) and placebo (95.2%) (n=85).
Safety analysis focused on adverse events occurring while on intravenous study therapy or during the 14 days following the end of therapy. The most common adverse events (nausea, diarrhea and vomiting) occurred at similar rates across treatment groups: relebactam 250mg (6.8%, 6.0%, 6.0%), relebactam 125mg (7.8%, 6.0%, 7.8%) and placebo (7.0%, 4.4%, 2.6%), respectively.
Phase 3 Clinical Program of Imipenem/Cilastatin/Relebactam Initiated
Based in part on the results of this Phase 2 study, Merck is planning to initiate two pivotal Phase 3 clinical studies of relebactam with imipenem/cilastatin given as a fixed-dose combination. A study comparing imipenem/cilastatin/relebactam to colistimethate sodium in combination with imipenem/cilastatin for the treatment of imipenem-resistant bacterial infections, including those caused by P.
aeruginosa and KPC-producing organisms, is currently recruiting patients. Infections evaluated in this study are hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, complicated intra-abdominal infections and complicated urinary tract infections. (www.ClinicalTrials.gov Identifier: NCT02452047)
A second Phase 3 study, which will initiate later this year, will compare treatment with the fixed-dose combination of imipenem/cilastatin/relebactam to piperacillin/tazobactam in patients with hospital- acquired and ventilator-associated bacterial pneumonia. (www.ClinicalTrials.gov Identifier: NCT02493764)
Relebactam is an investigational intravenous, class A and C, beta-lactamase inhibitor currently being evaluated in combination with imipenem/cilastatin for the treatment of certain complicated Gram- negative bacterial infections. In preclinical studies, relebactam administered in combination with imipenem demonstrated antibacterial activity against a broad range of Gram-negative and beta-lactam- resistant pathogens. The U.S. Food and Drug Administration (FDA) has designated this combination as a Qualified Infectious Disease Product (QIDP) with designated Fast Track status for the treatment of hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, complicated intra-abdominal infections and complicated urinary tract infections.