Basilea announces UK launch of broad-spectrum Cephalosporin Zevtera for first-line treatment of pneumonia

Jun 25 2015

Basilea Pharmaceutica AG today announces the UK launch of its broad-spectrum Cephalosporin Zevtera^® (Ceftobiprole medocaril) for the first-line treatment of serious bacterial pneumonia. Zevtera^® is the only antibiotic approved as a monotherapy in the UK for the treatment of community-acquired (CAP) and hospital-acquired (nosocomial) pneumonia (HAP) (excluding ventilator-associated pneumonia (VAP)), that is effective against Methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative pathogens such as strains of Pseudomonas aeruginosa and Enterobacteriaceae.

The emergence of resistant strains of bacteria has been described by the World Health Organisation (WHO) as the single greatest challenge in infectious diseases today. According to a UK review on antimicrobial resistance (AMR), by 2050 the global cost of AMR will be up to $100 trillion and will account for 10 million extra deaths a year. The UK and the international community have made a commitment to tackle AMR with key areas of focus including rapid diagnostics and new drug development in order to sustain the supply of effective treatments available in the future. Zevtera^® is a new therapy option for clinicians in the UK, with its fast-acting bactericidal activity against a large variety of gram-positive and gram-negative pathogens. In particular it is effective against resistant pathogens such as MRSA or Penicillin- and Ceftriaxone-resistant pneumococci. Zevtera^® is indicated for the treatment of CAP and HAP, which are common and lead to a high mortality rate in the UK.

Simple administration as monotherapy

Zevtera^® contains Ceftobiprole, the active ingredient of the water soluble prodrug Ceftobiprole medocaril. The active ingredient belongs to the latest generation of Cephalosporin* antibiotics.

Zevtera^® is administered intravenously as a monotherapy, can be used as empiric therapy, and is based on a dose of 500 mg once every 8 hours. It demonstrates predictable and linear pharmacokinetic properties. It is excreted largely unchanged via the kidneys and therefore no dose adjustments are required for patients with impaired liver function. Also the risk of clinically relevant interaction with other simultaneously administered medication is low.

Efficacy demonstrated in two Phase 3 trials

The efficacy and tolerability of Zevtera^® has been demonstrated in two Phase 3 trials relevant to its licensing for use in patients with CAP and HAP. In an international, double-blind, randomised trial with 781 patients with HAP the non-inferiority of Zevtera^® compared to Ceftazidime plus Linezolid was demonstrated. The clinical cure at the test-of-cure visit 7 to 14 days after the end of the therapy (primary endpoint) was achieved by 69.3% with Zevtera^® and 71.3% with the combination. Non-inferiority of Zevtera^® versus the comparator therapy could not be demonstrated for VAP.

In a further multi-centre, double-blind, randomised study Zevtera^® had non-inferior efficacy in 638 hospitalised patients with CAP compared to Ceftriaxone with or without Linezolid. The primary endpoint, clinical cure at the test-of-cure visit 7 to 14 days after the end of the therapy, was achieved by 86.6% receiving Zevtera^® therapy and by 87.4% of patients in the group receiving Ceftriaxone with or without Linezolid. The non-inferiority of Zevtera^® was also demonstrated with the intent-to-treat (ITT) analysis.

Post-hoc-analyses of the Phase 3 trial data show an early clinical response for Zevtera^® particularly for HAP (with the exception of VAP) when compared to a standard combination of antibiotics. Zevtera^® led as early as day 4 to a clinical cure or an improvement of the symptoms in 87% of patients (versus 78% for the comparator combination). The early improvement was particularly noticeable in patients with confirmed MRSA at baseline. 95% (versus 53% on the combination) of the MRSA-patients showed a clinical cure or improvement by day 4.

Ceftobiprole was well tolerated in clinical trials. The most frequent side effects in ≥ 3 % of patients treated with Zevtera^® were nausea, vomiting, diarrhoea, reaction at the infusion site, hypersensitivity (including urticaria, itchy skin rash and drug allergy) and taste impairment.

Extension of the infusion time with increased clearance

Renal function is frequently altered in patients in intensive care.

Increased renal clearance above the normal range may necessitate a change in infusion time. Data from a randomised parallel-group trial using Zevtera^® was presented recently at the 25^th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Copenhagen, Denmark. The trial of 33 intensive care patients, showed that a dose of 1,000 mg/every 8 or 12 hours administered as an infusion over 4 hours was tolerated well by the patients. By doubling the infusion time in patients with a creatinine clearance > 150 ml/min the plasma levels could be maintained at above 4 mg/ml. The authors of the research therefore recommend that patients with increased renal clearance receive an extended duration of infusion of Zevtera^®. This same recommendation is also included in the summary of product characteristics for Zevtera at the approved 500mg dose.

A further post-hoc analysis of the Phase 3 data by Awad et al., presented at ECCMID 2015, showed that the bacterial profile of the patients with early or late onset HAP was similar and that the time to onset of HAP was not a strong predictor of the pathogen distribution. Zevtera^® was similarly effective to Ceftazidime plus Linezolid both in early and in late onset HAP.