Zerbaxa Demonstrates Non-Inferiority to Meropenem in Pivotal Phase 3 Trial for Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia

Merck & Co. recently unveiled its novel combination drug for the first time at the 29th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) held in Amsterdam, the Netherlands.AntibioticsResults of the pivotal Phase III clinical study ASPECT-NP (NCT02070757) evaluating Zerbaxa (ceftolozane/tazobactam) for the treatment of nosocomial pneumonia [NP, also known as hospital-acquired pneumonia (HAP)].

This study is a prospective, randomized, double-blind, multicenter, non-inferiority trial involving 726 patients diagnosed with NP [including hospital-acquired bacterial pneumonia (HABP) and ventilator-associatedBacteria[ventilator-associated bacterial pneumonia (VABP)] and conducted in adult patients requiring intubation and mechanical ventilation, this study evaluated the efficacy and safety of Zerbaxa compared with meropenem. In the study, patients were randomized in a 1:1 ratio to receive either Zerbaxa (administered at an investigational dose of 3 g) or meropenem (administered at a dose of 1 g), both given as intravenous infusions every 8 hours for a treatment duration of 8–14 days. Meropenem is a broad-spectrum injectableAntibiotics, and is widely used in clinical practice for the treatment of severe infections. The primary endpoint and key secondary endpoints of the study were all-cause mortality on Day 28 in the intent-to-treat (ITT) population and clinical resolution at the test-of-cure (TOC) visit (defined as 7–14 days after the end of treatment).

The results demonstrated that Zerbaxa was non-inferior to meropenem with respect to the primary endpoint: the all-cause mortality rates on Day 28 in the ITT population were 24.0% (87/362) and 25.3% (92/364) for the two treatment groups, respectively, with a weighted difference in proportions of 1.1% (stratified 95% CI: -5.13%, 7.39%; non-inferiority margin: 10%). Furthermore, Zerbaxa was also non-inferior to meropenem regarding the key secondary endpoint: the clinical cure rates at the Test-of-Cure (TOC) visit in the ITT population were 54.4% (197/362) and 53.3% (194/364) for the two treatment groups, respectively, with a weighted difference in proportions of 1.1% (stratified 95% CI: -6.17%, 8.29%; non-inferiority margin: 12.5%).

Furthermore, an analysis of efficacy outcomes by causative pathogen demonstrated that Zerbaxa and meropenem had comparable clinical and microbiological response rates against Gram-negative respiratory pathogens, including Pseudomonas aeruginosa and Enterobacteriaceae. Among patients with baseline Gram-negative pathogens, in the microbiologically evaluable (ME) population, the clinical cure rates for Zerbaxa and meropenem were 75.2% (85/113) and 66.7% (78/117), respectively, and the microbiological response rates were 69.9% (79/113) and 62.4% (73/117), respectively. The results were consistent in the microbiological intent-to-treat (mITT) population, where the clinical cure rates for Zerbaxa and meropenem were 73% (189/259) and 67.9% (163/240), respectively.

Regarding safety, the incidence of treatment-emergent adverse events (TEAEs) was 85.9% (310/362) in the Zerbaxa group and 83.3% (299/364) in the meropenem group. The incidence of treatment-related adverse events (TRAEs) was 10.5% (38/362) in the Zerbaxa group and 7.5% (27/364) in the meropenem group. The most common adverse events associated with Zerbaxa were hepatic dysfunction, Clostridioides difficile colitis, and diarrhea. In critically ill patients (those with high APACHE scores), the incidence of adverse events was comparable between Zerbaxa and meropenem, with approximately 1% of patients discontinuing treatment due to treatment-related adverse events.

Dr. Marin Kollef, Professor of Medicine and Director of Medical Critical Care and Respiratory Care Services at Barnes-Jewish Hospital, Washington University School of Medicine, stated, “ASPECT-NP is unique among registry studies of hospital-acquired pneumonia because all patients in the study required intubation and mechanical ventilation, and nearly all were treated in the intensive care unit—a condition associated with high mortality. This study conducted by Merck Sharp & Dohme provides meaningful evidence that helps expand our understanding of the clinical management of this patient population.”

Dr. Joan Butterton, Vice President of Infectious Disease Clinical Research at MSD Research Laboratories, stated, “We are deeply grateful to all the patients and healthcare professionals who participated in this important trial. There remains an urgent need for additional treatment options for the patient population requiring intubation and mechanical ventilation in the ASPECT-NP study. We remain firmly committed to pursuing new therapeutic options for serious infectious diseases.”

Zerbaxa was originally developed byAntibioticsDeveloped by the industry giant Cubist, which was acquired by Merck & Co. (MSD) for $9.5 billion in late 2014, thisAntibioticsThis was the key factor in the acquisition. The drug is a combination antibiotic product administered via intravenous infusion, composed of ceftolozane, a novel cephalosporin antibiotic, and tazobactam, a β-lactamase inhibitor.

In the US market, Zerbaxa 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) was approved in late 2014. Its current indications are: 1) for the treatment of complicated urinary tract infections (cUTI, including pyelonephritis) caused by susceptible Gram-negative bacteria in adult patients; 2) in combination with metronidazole, for the treatment of complicated intra-abdominal infections (cIAI) caused by susceptible Gram-negative and Gram-positive bacteria in adult patients.

Currently, the supplemental new drug application (sNDA) for Zerbaxa for the treatment of HABP and VABP caused by susceptible Gram-negative bacteria is under review by the U.S.FDApriority review, with a target date of June 3, 2019, under the Prescription Drug User Fee Act (PDUFA). In addition, the supplemental application for Zerbaxa is also under review by the European Medicines Agency (EMA).BioValleyBioon.com）