Date: 2014-05-09
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the ECCMID conference
Company: Cubist Pharmaceuticals (USA - MA)
Product: ceftolozane/tazobactam
Action
mechanism: Ceftolozane/tazobactam consists of ceftolozane, a novel cephalosporin that has demonstrated potent in vitro activity against Pseudomonas aeruginosa, with tazobactam, a well-established β-lactamase inhibitor. The addition of tazobactam broadens coverage to include most Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli, Klebsiella pneumoniae, and other Enterobacteriaceae.
Ceftolozane/tazobactam is being developed for the potential treatment of Complicated Urinary Tract Infections (cUTI) and Complicated Intra-Abdominal Infections (cIAI). In pivotal Phase 3 clinical trials of ceftolozane/tazobactam in cUTI when studied against levofloxacin and of ceftolozane/tazobactam, in combination with metronidazole, in cIAI when studied against meropenen, ceftolozane/tazobactam met its primary endpoints of statistical non-inferiority. Ceftolozane/tazobactam is also being developed for the potential treatment of Hospital-Acquired Bacterial Pneumonia (HABP)/Ventilator-Associated Bacterial Pneumonia (VABP) at a dose of 3 g every 8 hours. Ceftolozane/tazobactam has been granted Fast Track status, pursuant to the GAIN Act, by the FDA for its respective Qualified Infectious Disease Product (QIDP) indications. The QIDP designation for ceftolozane/tazobactam allows for certain incentives related to the development of new antibiotics, including eligibility for Fast Track status and Priority Review.
Disease: complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI)
Therapeutic area: Infectious diseases
Country:
Trial details:
Latest
news: * On May 9, 2014, Cubist Pharmaceuticals announced the first detailed results from positive pivotal Phase 3 clinical trials of its antibiotic candidate ceftolozane/tazobactam in development to treat serious infections including complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). Results will be presented at the 24thEuropean Congress of Clinical Microbiology and Infectious Diseases (ECCMID) being held in BarcelonaMay 10 - 13. These new data include additional details on ceftolozane/tazobactam’s clinical cure and/or microbiological eradication rates, which met or exceeded pre-specified FDA and European Medicines Agency (EMA) non-inferiority margins, as well as details on the overall safety profile. Additionally, for the first time Cubist is presenting data on microbiological eradication of key problematic Gram-negative pathogens, including Pseudomonas aeruginosa and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) and Klebsiella pneumoniae. Microbiological eradication rates for ceftolozane/tazobactam were 84% - 100% in these pathogens across the cUTI and cIAI clinical trials, as detailed more fully below. Phase 3 clinical trial in cUTI: Ceftolozane/tazobactam met its primary endpoint of statistical non-inferiority compared to levofloxacin (10% non-inferiority margin). The primary endpoint was a composite of microbiological eradication and clinical cure rate (composite cure rate) at 5 - 9 days after end of therapy—the Test of Cure (TOC) visit. The composite cure rates at TOC in the Microbiological Modified Intent-to-Treat (mMITT) and Per Protocol (PP) populations were 76.9% versus (vs.) 68.4% and 83.3% vs. 75.4%, respectively. Although this trial was not prospectively designed to demonstrate superiority, the finding that the lower bound of the confidence interval around the positive treatment differences in favor of ceftolozane/tazobactam was greater than zero, indicated statistical superiority over levofloxacin in this trial. Results of the secondary analyses were consistent with and supportive of the primary outcome. Microbiological eradication rates for ceftolozane/tazobactam vs. levofloxacin were 80.4% vs. 72.1% in the mMITT population and 86.2% vs. 77.6% in the PP population. Clinical trial data showed the following per-pathogen microbiological eradication rates in the Microbiologically Evaluable (ME) populationfor ceftolozane/tazobactam vs. levofloxacin: E. coli (n=546): 91% vs. 80% Phase 3 clinical trial in cIAI: Ceftolozane/tazobactam, in combination with metronidazole, met both the FDA and EMA primary endpoints of statistical non-inferiority compared to meropenem. The primary endpoint was a clinical cure rate 26 - 30 days after the initiation of therapy—the TOC visit. For the FDA, the primary analysis was conducted in the Modified Intent-to-Treat (MITT) population where the overall clinical cure rate was 83.0% for ceftolozane/tazobactam in combination with metronidazole vs. 87.3% for meropenem. For the FDA, statistical non-inferiority was defined at a pre-specified 10% non-inferiority margin. For the EMA, the primary analysis was conducted in the Clinically Evaluable (CE) population where the overall clinical cure rate was 94.1% for ceftolozane/tazobactam in combination with metronidazole vs. 94.0% for meropenem. For the EMA, statistical non-inferiority was defined at a pre-specified 12.5% non-inferiority margin.
Klebsiella pneumoniae (n=48): 84% vs. 61%
Pseudomonas aeruginosa (n=19):86% vs. 58%
In the mMITT population, ceftolozane/tazobactam demonstrated a composite cure rate of 60.0% vs. 39.3% against levofloxacin-resistant pathogens, and 62.3% vs. 35.1% against ESBL-producing pathogens.
Drug-related adverse events occurred in 10.3% and 12.0% of the ceftolozane/tazobactam and levofloxacin groups, respectively. The most commonly reported adverse event for ceftolozane/tazobactam was headache (5.8%). Additionally, in this trial, adverse events for ceftolozane/tazobactam included constipation (3.9%), hypertension (3%), nausea (2.8%), and diarrhea (1.9%). This adverse event profile is consistent with that seen with ceftolozane/tazobactam in the prior Phase 2 trial in cUTI and comparable to levofloxacin in this trial.
“Pseudomonas aeruginosa and ESBL-producing Enterobacteriaceae are resistant pathogens we see in patients with complicated urinary tract infections,” said presenting author Florian Wagenlehner, M.D., Ph.D., Clinic for Urology, Pediatric Urology and Andrology, Justus-Liebig University, Giessen University. “The data presented during ECCMID demonstrate the activity of ceftolozane/tazobactam against these problematic pathogens.”
Results of the secondary analyses were consistent with and supportive of the primary outcome. Per-pathogen microbiological eradication rates for ceftolozane/tazobactam vs. meropenem were comparable between groups. Clinical cure in patients infected with ESBL-producing Enterobacteriaceae was achieved in 86.2% and 82.8% of patients in the ceftolozane/tazobactam in combination with metronidazole and meropenem treatment groups, respectively.
Clinical trial data showed the following per-pathogen microbiological eradication rates in Gram-negative aerobes in the ME population for ceftolozane/tazobactam in combination with metronidazole vs. meropenem:
E. coli (n=426): 96% vs. 95%
Klebsiella pneumoniae (n=53): 100% vs. 88%
Pseudomonas aeruginosa (n=53): 100% vs. 100%
The most commonly reported adverse events for ceftolozane/tazobactam in combination with metronidazole were nausea (7.9%), diarrhea (6.2%), and fever (5.2%). In this trial, other adverse events for ceftolozane/tazobactam included insomnia (3.5%) and vomiting (3.3%). This adverse event profile is consistent with that seen with other cephalosporin antibiotics and comparable to meropenem in this trial.
