FDA Accepts for Review New Drug Application (NDA) for Merck’s Investigational Combination of Imipenem/Cilastatin and Relebactam, and Supplemental NDA (sNDA) for ZERBAXA® (Ceftolozane and Tazobactam)

KENILWORTH, NJ, USA I February 5, 2019 I Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has accepted for review regulatory filings for two antibacterial agents. These filings are: (1) a NDA accepted for Priority Review for the combination of relebactam, the company’s investigational beta-lactamase inhibitor, with imipenem/cilastatin (MK-7655A, IMI/REL), for the treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) caused by certain susceptible Gram-negative bacteria, in adults with limited or no alternative therapies available; and (2) a sNDA accepted for Priority Review for ZERBAXA® (ceftolozane and tazobactam) to treat adult patients with nosocomial pneumonia, including ventilator-associated pneumonia caused by certain susceptible Gram-negative microorganisms. The Prescription Drug User Fee Act (PDUFA) target action date for IMI/REL is July 16, 2019, while the PDUFA target action date for ZERBAXA is June 3, 2019.

In the U.S., ZERBAXA is currently indicated for the treatment of adult patients with cUTI, including pyelonephritis, caused by certain susceptible Gram-negative microorganisms, and is also indicated, in combination with metronidazole, for the treatment of adult patients with cIAI caused by certain susceptible Gram-negative and Gram-positive microorganisms.

Corresponding applications for both medicines have been filed with the European Medicines Agency (EMA) and are currently under review.

“There is a major unmet need for new treatment options to address the growing danger of serious and potentially life-threatening infections caused by Gram-negative bacteria,” said Dr. Nicholas Kartsonis, senior vice president, head of clinical research for infectious diseases and vaccines, Merck Research Laboratories. “In a space where there are currently very few treatment options, these filings underscore Merck’s ongoing commitment to delivering new antibacterial agents to healthcare practitioners and patients.”

The IMI/REL (MK-7655A) NDA is based on the results of the pivotal Phase 3 RESTORE-IMI 1 trial, which were presented at the 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) meeting in Madrid, Spain, in April 2018. The ZERBAXA sNDA is based on the pivotal Phase 3 ASPECT-NP trial in adults with ventilated hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia. Merck plans to present results from the ASPECT-NP study at a future scientific conference.

About imipenem, cilastatin and relebactam

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 Gram-negative bacterial infections. The FDA has designated the combination of relebactam with imipenem/cilastatin for intravenous use as a Qualified Infectious Disease Product (QIDP) with Fast Track status for the treatment of complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI) and hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP).

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 coliKlebsiella pneumoniaeProteus 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 cloacaeEscherichia coliKlebsiella oxytocaKlebsiella pneumoniaeProteus mirabilisPseudomonas aeruginosaBacteroides fragilis, Streptococcus anginosusStreptococcus 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 (ceftolozane and tazobactam) 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.

Merck’s 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 Merck’s infectious diseases pipeline, visit www.merck.com.

About Merck

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 world’s 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, Alzheimer’s 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.

SOURCE: Merck

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