Cubist Presents Detailed Results from Positive Phase 3 Trials of Ceftolozane/Tazobactam at 2014 European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
Clinical trial data show antibiotic candidate’s activity against problematic resistant
Gram-negative bacteria in patients with complicated infections
Lexington, Mass., May 9, 2014 – Cubist Pharmaceuticals, Inc. (NASDAQ: CBST) today 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 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) being held in Barcelona May 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 U.S. Food and Drug Administration (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.
Growing antibiotic resistance poses a serious global health threat, as highlighted in the April 30, 2014 World Health Organization report. Collectively, the common Gram-negative pathogens E. coli, Klebsiella pneumoniae and Pseudomonas aeruginosa account for approximately one-third of all pathogens and 70% of all Gram-negative pathogens causing healthcare-associated infections (HAIs). These Gram-negative bacteria are common causes of urinary tract and intra-abdominal infections.
“We are delighted by the growing body of evidence indicating that ceftolozane/tazobactam may prove to be an important treatment option to address three of the most difficult to treat Gram-negative pathogens—specifically Pseudomonas aeruginosa and ESBL-producing E. coli and Klebsiella pneumoniae, —in cUTI and cIAI,” said Steven Gilman, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer of Cubist. “Cubist hopes to make this new tool available to physicians and patients worldwide to help fight antimicrobial resistance, and looks forward to next steps in our global regulatory submissions.”
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%
- 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.”
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.
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.
“Ceftolozane/tazobactam is a novel antibacterial candidate being developed for the potential treatment of common and problematic Gram-negative pathogens that cause infections in patients following a broad range of surgical procedures,” said presenting author Christian Eckmann, M.D., Chief of Surgery at the Department of Visceral and Thoracic Surgery Klinikum Peine, Academic Hospital of Medical University, Hannover. “These clinical trial data suggest that ceftolozane/tazobactam is a potential useful treatment for patients with complicated intra-abdominal infections.”
More information regarding presentations of ceftolozane/tazobactam Phase 3 data in cUTI and cIAI, as well as other Cubist presentations during ECCMID, is available on the Congress website here. Additionally, a list of selected presentations can be reviewed in A Guide to Sessions for Cubist Investors.
Ceftolozane/tazobactam, an antibiotic candidate being developed to treat certain Gram-negative infections, consists of ceftolozane, a novel cephalosporin that has demonstrated potent in vitro activity against Pseudomonas aeruginosa, with tazobactam, a well-established beta-lactamase inhibitor. The addition of tazobactam broadens coverage to include most extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. 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). Ceftolozane/tazobactam is also being developed for the potential treatment of hospital-acquired bacterial pneumonia (HABP)/ventilator-associated bacterial pneumonia (VABP).
About Gram-negative Bacteria
There has been a worldwide increase in the number of infections caused by Gram-negative bacteria. Highly adaptive pathogens that can develop resistance through several mechanisms, resistant Gram-negative bacteria are a serious global public health concern. Collectively, Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae) and Pseudomonas aeruginosa (P. aeruginosa) account for approximately one-third of all pathogens and 70% of all Gram-negative pathogens causing healthcare-associated infections (HAIs). Gram-negative bacteria are common causes of intra-abdominal infections (IAIs), urinary tract infections (UTIs), and nosocomial, or hospital-acquired, pneumonia, as well as bacteremia (bloodstream infections). E. coli is the most common cause of UTIs, and cases of UTI caused by extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae, as well as P. aeruginosa, including drug-resistant strains, are increasing. ESBL-producing E. coli and K. pneumoniae are also frequently isolated in patients with complicated IAIs (cIAIs). Additionally, P. aeruginosa is the most common Gram-negative organism causing ventilator associated pneumonia and the second most common cause of catheter-associated UTIs. For more information reference a video on Gram-negative bacteria mechanisms of resistance.
About Cubist’s Commitment to Antibiotic R&D
Cubist has a growing commitment to global public health through its leadership in the discovery, development and commercialization of novel antibiotics to treat serious and life-threatening infections caused by a broad range of increasingly drug-resistant bacteria. The Company hopes to deliver at least four new antibiotics in support of the Infectious Diseases Society of America (IDSA) goal of 10 new antibiotics by 2020. Cubist expects to invest approximately $400M USD in 2014 on antibacterial R&D and approximately 75% of its employee base is focused on the research, development, commercialization and support of antibiotics.
Cubist Pharmaceuticals, Inc. is a global biopharmaceutical company focused on the research, development, and commercialization of pharmaceutical products that address significant unmet medical needs in the acute care environment. Cubist is headquartered in Lexington, Massachusetts, with a central international office located in Zurich, Switzerland. Additional information can be found at Cubist’s web site at www.cubist.com. Also, connect with Cubist on Twitter @cubistbiopharma and @cubistcareers, LinkedIn, or YouTube.
Forward Looking Statements
This press release contains forward-looking statements. Any statements contained herein which do not describe historical facts, including but not limited to, statements regarding: the therapeutic potential of ceftolozane/tazobactam; positive results from our Phase 3 clinical trials of ceftolozane/tazobactam, including that the cUTI Phase 3 clinical trial data indicated that ceftolozane/tazobactam was statistically superior to levofloxacin; next steps in our global regulatory submissions for ceftolozane/tazobactam; our aspirations to achieve a portion of the IDSA goal of 10 new antibiotics by 2020; and the level of our financial and personnel commitments towards antibiotic research, development and commercialization, are forward-looking statements which involve risks and uncertainties that could cause actual results to differ materially from those discussed in such forward-looking statements. Such risks and uncertainties include, among others: regulatory developments, including the risk that the FDA, and foreign regulatory authorities, may not respectively accept for filing, or approve on a timely basis or at all, our New Drug Application for ceftolozane/tazobactam, or any future marketing approval applications that we may submit for ceftolozane/tazobactam outside the U.S., may not agree with our interpretation of the results from the clinical studies of ceftolozane/tazobactam, or may require additional data, analysis, information or further studies that may not be clinically feasible or financially practicable; any marketing approval for ceftolozane/tazobactam may impose significant limitations on its use and additional post-marketing requirements; our ability to obtain adequate pricing and reimbursement levels for ceftolozane/tazobactam; our ability to successfully commercialize ceftolozane/tazobactam, including as a result of regulatory authorities’ decisions regarding labeling and other matters, including adverse side effects, that could affect its availability or commercial potential; our ability to maintain and enforce intellectual property protection for ceftolozane/tazobactam; competitive risks from current and future therapeutic alternatives to ceftolozane/tazobactam; additional clinical trials of ceftolozane/tazobactam may not be successful or initiated or conducted in a timely manner; technical difficulties or excessive costs relating to the manufacture or supply of ceftolozane/tazobactam, including our ability to work with our third party contract manufacturers that manufacture and supply ceftolozane/tazobactam on our behalf; our ability to work with, and the performance of our third party contract research organizations that help us conduct our clinical trials; we may encounter other unanticipated or unexpected risks with respect to the development or manufacture of ceftolozane/tazobactam; our ability to achieve our strategic goals, including as a result of our ability to continue to grow revenues from the sale of CUBICIN® (daptomycin for injection), DIFICID® (fidaxomicin) and ENTEREG® (alvimopan), generic and other competition, manufacturing issues, our ability to successfully develop, gain marketing approval for and commercially launch our product candidates for their planned indications and on their expected timelines, and our ability to discover, in-license or acquire new products and product candidates and those additional factors discussed in our most recent annual report on Form 10-K and subsequent quarterly reports on Form 10-Q filed with the Securities and Exchange Commission. We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. These forward-looking statements speak only as of the date of this press release, and we undertake no obligation to update or revise any of these statements.
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