Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the first presentation of results from ASPECT-NP, a randomized, double-blind, multi-center Phase 3 clinical trial evaluating the efficacy and safety of ZERBAXA (ceftolozane and tazobactam) for the treatment of adult patients with ventilated nosocomial (hospital acquired) pneumonia. The results demonstrated non-inferiority of an investigational dose of ZERBAXA to meropenem, the active comparator, in the primary and key secondary endpoints. Based on these results, Merck has submitted supplemental new drug applications to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) seeking regulatory approval for ZERBAXA for this potential new indication. The FDA Prescription Drug User Fee Act (PDUFA) date is June 3, 2019. Detailed findings of the ASPECT-NP Phase 3 trial are scheduled to be presented at the 29th European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), on Monday, April 15 at 1:30 pm local time in Amsterdam, Netherlands (Poster P1917).
ASPECT-NP is unique among registration trials for nosocomial pneumonia, as all patients were intubated and mechanically ventilated and nearly all were treated in the intensive care unit, said Dr. Marin Kollef, director of Medical Critical Care and Respiratory Care Services of Barnes-Jewish Hospital and the Golman Professor of Medicine at Washington University School of Medicine, St. Louis, MO. This is a disease state with a high mortality rate, and Mercks commitment to this trial provides meaningful evidence that helps expand our understanding of the management of this patient population.
In the U.S., ZERBAXA is currently indicated for the treatment of adult patients with complicated urinary tract infections, including pyelonephritis, caused by certain susceptible Gram-negative microorganisms, and is indicated, in combination with metronidazole, for the treatment of adult patients with complicated intra-abdominal infections caused by certain susceptible Gram-negative and Gram-positive microorganisms. To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.
ASPECT-NP is a prospective, randomized, double-blind, multicenter, non-inferiority, Phase 3 clinical trial to evaluate the safety and efficacy of ZERBAXA compared to meropenem in ventilated patients diagnosed with nosocomial pneumonia, including hospital-acquired and ventilator-associated bacterial pneumonia. In the study, 726 patients were randomized 1:1 to receive an investigational 3g dose (2g ceftolozane/1g tazobactam) of ZERBAXA or meropenem 1g dose, administered intravenously every eight hours for eight to 14 days. Meropenem is an approved broad-spectrum injectable antibiotic widely used to treat serious infections. The primary and key secondary endpoints are Day 28 all-cause mortality and Clinical Response at test-of-cure (TOC) in the intent-to-treat (ITT) population.
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We are very grateful to the patients and healthcare professionals who made this important trial possible, said Dr. Joan Butterton, associate vice president, infectious disease clinical research, Merck Research Laboratories. There remains an urgent need for additional treatment options for the intubated and mechanically ventilated patient population that was studied in ASPECT-NP. Merck is firmly committed to pursuing new treatment options for serious infectious diseases.
ZERBAXA was non-inferior to meropenem for the primary endpoint of 28-day all-cause mortality in the ITT population (all randomized patients), 24.0% (87/362) and 25.3% (92/364) respectively, for a weighted proportion difference of 1.1% (stratified 95% CI: -5.13%, 7.39%; non-inferiority margin of 10%). In addition, ZERBAXA was non-inferior to meropenem in the key secondary endpoint, clinical cure at Test-of-Cure (7-14 days after the end of therapy) in the ITT population, 54.4% (197/362) and 53.3% (194/364) respectively, for a weighted proportion difference of 1.1% (stratified 95% CI: -6.17%, 8.29%; non-inferiority margin of 12.5%).
Additionally, an analysis of efficacy outcomes by causative pathogens showed that clinical and microbiologic response rates for ZERBAXA were comparable to meropenem for Gram-negative respiratory tract pathogens, including Pseudomonas aeruginosa and Enterobacteriaceae. In the microbiologically evaluable (ME) population in patients with a Gram-negative pathogen at baseline clinical cure rates were 75.2% (85/113) and 66.7% (78/117) and microbiologic response rates were 69.9% (79/113) and 62.4% (73/117) for ZERBAXA and meropenem respectively. Results were consistent in the microbiologic intention-to-treat (mITT) population with clinical cure rates of 73% (189/259) and 67.9% (163/240) for ZERBAXA and meropenem respectively (Related mini oral ePoster O0302).
Treatment-emergent adverse events (AE) were reported in 85.9% (310/362) of ZERBAXA versus 83.3% (299/364) of meropenem treated patients. The incidence of treatment-related AEs was 10.5% (38/362) in the ZERBAXA group and 7.5% (27/364) in the meropenem group. The most commonly reported AEs with ZERBAXA were abnormal liver function tests, Clostridium difficile colitis and diarrhea. Comparable rates of AEs were reported for ZERBAXA and meropenem in critically ill patients (those with high APACHE scores), and approximately 1% of patients had treatment-related AEs leading to discontinuation of therapy.
About ZERBAXA (ceftolozane and tazobactam)
ZERBAXA is an antibacterial combination product for intravenous infusion consisting of the cephalosporin antibacterial drug ceftolozane sulfate and the beta-lactamase inhibitor tazobactam sodium.
ZERBAXA 1.5g (ceftolozane 1g and tazobactam 0.5g) is approved in the United States and is indicated in adult patients for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa. ZERBAXA used in combination with metronidazole is indicated in adult patients for the treatment of complicated intra-abdominal infections (cIAI) caused by the following Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Important Safety Information about ZERBAXA (ceftolozane and tazobactam)
Patients with renal impairment: Decreased efficacy of ZERBAXA has been observed in patients with baseline creatinine clearance (CrCl) of 30 to ‰¤50 mL/min. In a clinical trial, patients with cIAIs with CrCl >50 mL/min had a clinical cure rate of 85.2% when treated with ZERBAXA (ceftolozane and tazobactam) plus metronidazole vs. 87.9% when treated with meropenem. In the same trial, patients with CrCl 30 to ‰¤50 mL/min had a clinical cure rate of 47.8% when treated with ZERBAXA plus metronidazole vs. 69.2% when treated with meropenem. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly.
Hypersensitivity: ZERBAXA is contraindicated in patients with known serious hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or other members of the beta-lactam class. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactams. If an anaphylactic reaction to ZERBAXA occurs, discontinue use and institute appropriate therapy.
Clostridium difficile-associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents. If CDAD is confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.
Development of drug-resistant bacteria: Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Adverse reactions: The most common adverse reactions occurring in ‰¥5% of patients were headache (5.8%) in the cUTI trial, and nausea (7.9%), diarrhea (6.2%) and pyrexia (5.6%) in the cIAI trial.
Mercks commitment to infectious diseases
For more than 100 years, Merck has contributed to the discovery and development of novel medicines and vaccines to combat infectious diseases. In addition to a combined portfolio of vaccines and antibacterial, antiviral and antifungal medicines, Merck has multiple programs that span discovery through late-stage development. To learn more about Mercks infectious diseases pipeline, visit www.merck.com.
For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the worlds most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimers disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
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Please see Prescribing Information for ZERBAXA (ceftolozane and tazobactam) at http://www.merck.com/product/usa/pi_circulars/z/zerbaxa/zerbaxa_pi.pdf