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Gram-negative: CXA-201 (ceftolozane/tazobactam)

cUTI (complicated urinary tract infection)
Phase 3
cIAI (complicated intra abdominal infection)
Phase 3
NP (nosocomial pneumonia)
Phase 1
View Alan Hauser (Northwestern) Nature Reviews Microbiology poster on Pseudomonas aeruginosa via Nature.com
CXA-201 (ceftolozane/tazobactam)

Ceftolozane/Tazobactam Overview

CXA-201 (ceftolozane/tazobactam), which is being developed as a first-line intravenous therapy for the treatment of certain serious Gram-negative bacterial infections, including those caused by multi-drug resistant Pseudomonas aeruginosa, advanced into Phase 3 trials in July 2011. The initial Phase 3 studies will compare the safety and efficacy of CXA-201 relative to the comparator, levofloxacin, in patients with complicated Urinary Tract Infections (cUTI). A pivotal Phase 3 trial of CXA-201 in patients with complicated intra-abdominal infections (cIAI) was initiated in December 2011.

Additionally, it is expected that based on the overall clinical profile of CXA-201, Cubist will be begin Phase 3 studies in nosocomial pneumonia in the second half of 2012. Cubist estimates peak year sales for CXA-201, assuming approval in planned indications, of at least $1 billion for the U.S. and EU markets combined. CXA-201 is being developed for the treatment of infections caused by Gram-negative pathogens including multi-drug resistant Pseudomonas aeruginosa, E. coli, and Klebsiella pneumonia. CXA-201 is an intravenously administered combination consisting of CXA-101 (ceftolozane), a novel, rapidly-bactericidal cephalosporin with broad Gram-negative activity and particularly potent activity against Pseudomonas aeruginosa, along with tazobactam, a well-known beta-lactamase inhibitor that is a component of the long-established antibiotic, Zosyn®. Before human trials were initiated much was known about the potential of CXA-201:

  • The in vitro data demonstrated a well differentiated spectrum of potency against many of the key Gram-negative pathogens including unique activity against Pseudomonas aeruginosa and strains resistant to Zosyn, other cephalosporins, and carbapenems. This was very promising given the rising rates of resistance for Pseudomonas, and the lack of any other agents in development with this unique profile. In vitro research also provided Cubist with confidence that there should be a lower potential for the emergence of resistance to this new cephalosporin.
  • The efficacy data are very promising for the key indications when it comes to Gram-negative infections, including efficacy in pulmonary, urinary tract, and tissue infection models. Importantly, Cubist established that concentrations of CXA-101 remain above the MIC for approximately 40-50% of the time between dosage administrations, which is similar to the pharmacokinetic and pharmacodynamic or PK/PD driver for other cephalosporins. This PK/PD information made it more straightforward for Cubist to predict what dose and dose interval would provide human exposures that were likely to be efficacious. On the safety side, because ceftolozane is a member of the cephalosporin class in which several other members have already demonstrated acceptable human safety profiles, Cubist anticipated, and then established in animals, that large doses were well tolerated as assessed in Good Laboratory Practice (GLP) toxicology studies.

Assuming success in the clinic, Cubist plans to submit an initial New Drug Application (NDA) for the cUTI and cIAI indications in late 2013, with submission to the EMA shortly thereafter. Subsequent to that timeframe, we anticipate that we will be submitting for marketing approval the nosocomial pneumonia indication in both the U.S. and the EU.

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