Cubist Pharmaceuticals, Inc. has reported positive top-line results from its pivotal phase III clinical trial of its antibiotic candidate ceftolozane/tazobactam in complicated intra-abdominal infections (cIAI). Ceftolozane/tazobactam, in combination with metronidazole, met the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) defined 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 Test of Cure visit). For the FDA, the primary analysis was conducted in the Microbiological Intent-to-Treat (MITT) population; the non-inferiority margin was 10 per cent; and the lower and upper bounds of the 95 per cent confidence interval were -8.9 per cent and 0.5 per cent, respectively. For the EMA, the primary analysis population was Clinically Evaluable (CE) patients; the non-inferiority margin was 12.5 per cent; and the lower and upper bounds of the 99 per cent confidence interval were -4.2 per cent and 4.3 per cent, respectively. Results of the secondary analysis were consistent with and supportive of the primary outcome.
The treatment emergent adverse event rate for ceftolozane/ tazobactam, in combination with metronidazole, was 44.0 per cent and for meropenem was 42.7 per cent. In this trial, the most commonly reported adverse events for ceftolozane/tazobactam in combination with metronidazole were nausea (7.9 per cent), diarrhoea (6.2 per cent), fever (5.2 per cent), insomnia (3.5 per cent), and vomiting (3.3 per cent). This adverse event profile is consistent with that seen with other cephalosporin antibiotics and comparable to meropenem in this trial.
In the cIAI trial, the spectrum of pathogens seen was typical with that seen in other pivotal trials in patients with these types of complicated infections. The most common Gram-negative pathogens observed in this trial included Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae) and Pseudomonas aeruginosa (P. aeruginosa).
The cIAI trial results follow the positive data reported last month from a phase III trial of ceftolozane/tazobactam compared to levofloxacin in patients with complicated urinary tract infections (cUTI).
“This is a significant and exciting milestone in our quest to provide new antibiotics to treat patients with serious and often life-threatening infections caused by drug-resistant bacteria,” said Steven Gilman, Ph.D., executive vice president of Research and Development and chief scientific officer of Cubist Pharmaceuticals. “With positive results from phase III clinical trials of ceftolozane/tazobactam in both cUTI and cIAI, we look forward to submitting these data to global regulatory authorities and presenting the full results at upcoming medical meetings.”
According to Philip S Barie, MD, MBA, Professor of Surgery and Public Health at Weill Cornell Medical College, attending surgeon at New York-Presbyterian Hospital/Weill Cornell Medical Centre, and executive director of the Surgical Infection Society Foundation for Research and Education, “These data are encouraging as we face alarmingly increasing rates of bacterial resistance. There is an urgent need for new antibiotics, especially in the hospital setting, in order to be able to manage effectively those conditions complicated by serious infections, including those caused by resistant Gram-negative bacteria.”
Based on the success of the cUTI and cIAI trials, Cubist expects to submit a New Drug Application (NDA) to the FDA in the first half of 2014 for approval in both of these indications. In the second half of 2014, the Company plans to submit a Marketing Authorization Application (MAA) to the EMA.
Additionally, ceftolozane/tazobactam is being developed for the potential treatment of Hospital-Acquired Bacterial Pneumonia (HABP)/Ventilator-Associated Bacterial Pneumonia (VABP). The Company expects to initiate a pivotal phase III trial to assess the safety and efficacy of ceftolozane/ tazobactam in this indication during the first half of 2014.
Results from the pivotal phase III cIAI clinical trial include data from two multi-center, global, double-blind, randomized studies. The trial compared the safety and efficacy of ceftolozane/tazobactam, administered intravenously (1.5 g q8h) plus metronidazole (0.5 g q8h), to meropenem, administered intravenously (1 g q8h), in adult patients (total n=993) with cIAI. The primary endpoint of the trial, as defined in collaboration with the U.S. Food and Drug Administration, was to establish non-inferiority of ceftolozane/tazobactam and metronidazole to the comparator meropenem with respect to the proportion of patients in the Microbiological Intent-to-Treat (MITT) population who achieve clinical cure at the Test of Cure (TOC) visit 26 - 30 days after the first dose of the study drug is administered. The primary endpoint of the trial for the EMA was to establish non-inferiority of ceftolozane/tazobactam and metronidazole to the comparator meropenem with respect to the proportion of patients in the Clinically Evaluable (CE) population.
Dr Barie is a consultant to Cubist, serving on the Advisory Board of the ceftolozane/ tazobactam programme.
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.