Key points

Key points

The content of this evidence summary was up-to-date in June 2017. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Regulatory status: Bezlotoxumab (Zinplava, Merck Sharp & Dohme Limited) is a human monoclonal antitoxin antibody that binds with high affinity to Clostridium difficile toxin B and neutralises its activity. It received a marketing authorisation in January 2017 and is expected to be launched in June 2017 (source: Merck Sharp & Dohme Limited, May 2017). Bezlotoxumab is indicated for preventing future episodes of diarrhoea in people who are taking antibiotics to treat their C difficile infection and who are at high risk of the infection coming back. It is administered as a single one-off intravenous infusion during a course of antibacterial therapy for C difficile infection (summary of product characteristics).

Overview

This evidence summary discusses 2 similar randomised controlled trials (RCTs; MODIFY I [n=1,396] and MODIFY II [n=1,163]) that compared the efficacy and safety of a single dose of bezlotoxumab 10 mg/kg with placebo for preventing the recurrence of C difficile infection in people taking usual standard-of-care antibiotics (usually metronidazole or vancomycin) (Wilcox MH et al. 2017).

In a pooled analysis of MODIFY I and MODIFY II, at the 12-week follow-up, 17% of participants given bezlotoxumab had recurrent C difficile infection compared with 27% of those given placebo (statistically significant difference). The European public assessment report highlights concerns over the population used to assess this primary endpoint and notes that the secondary endpoint of sustained clinical cure (initial clinical cure of the baseline infection and no recurrence for 12 weeks) is more relevant to clinical practice.

For sustained clinical cure, there was a statistically significant difference between bezlotoxumab and placebo in MODIFY II but not in MODIFY I. When data from these 2 trials were pooled, the difference was statistically significant (64% with bezlotoxumab compared with 54% with placebo).

Recurrence of C difficile infection and sustained clinical cure were each improved by about 10% in absolute terms with bezlotoxumab compared with placebo at 12 weeks (giving a number needed to treat of around 10). However, almost three quarters of participants given placebo did not have recurrent infection by week 12 (73% compared with 83% given bezlotoxumab), and around half had sustained cure (54% compared with 64% with bezlotoxumab). Nevertheless, recurrent C difficile infection is difficult to treat and is associated with more hospitalisations, severe outcomes, and higher costs than initial episodes (European public assessment report). The European public assessment report states that experts concluded that meaningful clinical relevant results were obtained in the pivotal trials, although the extent of actual benefit will only be established once the medicine has been used more widely. Only 4% of participants were taking fidaxomicin in the trials, so it is unclear what benefits bezlotoxumab has in people given this medicine to treat C difficile.

Bezlotoxumab is the first medicine that is indicated for preventing the recurrence of C difficile in adults who are at high risk of developing this infection again; however, its place in therapy is currently unclear. The benefits and risks of bezlotoxumab should be discussed with people considering treatment. Although bezlotoxumab was generally well-tolerated in the trials and had a similar adverse effect profile to placebo, given an explanation of the size of the potential benefits, some people may prefer not to have an intravenous infusion, particularly if they have very few risk factors for recurrent C difficile infection. The European public assessment report lists age over 65 years, history of previous C difficile infection, being immunocompromised, and having severe infection or infection with a hypervirulent strain as risk factors. However, the trials found no statistically significant difference in recurrence of infection between bezlotoxumab and placebo in participants with a hypervirulent strain of C difficile (027, 048 or 244 combined and 027 alone).

A summary to inform local decision-making is shown in table 1.

Table 1 Summary of the evidence on effectiveness, safety, patient factors and resource implications

Effectiveness

  • In the pooled dataset for MODIFY I and II (Wilcox MH et al. 2017), 16.5% of those given bezlotoxumab had recurrent C difficile infection compared with 26.6% of those given placebo (adjusted difference 10.0%, 95% confidence interval [CI] 6.0% to 14.0%, p<0.0001).

  • In the pooled dataset, in the subgroup of participants who had initial clinical cure (no diarrhoea for 2 consecutive days after completion of standard-of-care antibiotic therapy), recurrent infection was seen in 20.6% of people given bezlotoxumab compared with 33.2% given placebo (adjusted difference 12.2%, 95% CI 7.4% to 17.1%, p<0.0001).

  • In the pooled dataset, a statistically significant difference was also seen between the groups for sustained clinical cure (bezlotoxumab 63.5% compared with placebo 53.7%; adjusted difference 9.7%, 95% CI 4.8% to 14.5%, p=0.0001).

Safety

  • 60.5% of participants in the trials reported 1 or more adverse events, but the incidence was similar across the groups.

  • Infusion-specific reactions within 24 hours were reported by 10.3% of participants receiving bezlotoxumab.

  • Common adverse effects of bezlotoxumab (in more than 4 in 100 participants) included abdominal pain, diarrhoea, nausea, pyrexia, urinary tract infection and headache.

  • The European public assessment report states that a robust conclusion on safety is hampered by the small population and the underlying morbidity and co-morbidity of the participants. However, the safety profile is considered 'sufficiently reassuring'.

Patient factors

  • It is expected that bezlotoxumab will be used in people in hospital, under the guidance of a consultant in infectious disease. Bezlotoxumab is administered as a single, one-off intravenous infusion given over 60 minutes. It is administered alongside an antibiotic for treating the current episode of C difficile infection.

  • After initial treatment and resolution of diarrhoea, 15% to 35% of people with C difficile infection experience recurrence.

  • Recurrent infection is more difficult to treat and is associated with more hospitalisations, severe outcomes, and higher costs than initial episodes.

  • No medicines are currently licensed for preventing first episodes of C difficile infection. Only bezlotoxumab is licensed for preventing the recurrence of C difficile infection (in adults who are at high risk of developing this infection again).

Resource implications

  • The cost of 1 vial of bezlotoxumab 1,000 mg is £2,470.00 (source: Merck Sharp & Dohme Limited, May 2017).

  • The dose of bezlotoxumab is 10 mg/kg; therefore, more than 1 vial will be needed to treat people weighing more than 100 kg.

  • This cost is for the medicine only and does not include VAT, any local procurement discounts or other costs incurred, such as administration.