C. diff recurrence risk reduced with bezlotoxumab versus placebo, industry study finds

Compared to placebo, bezlotoxumab reduced recurrent infections in patients with Clostridium difficile, according to a new manufacturer-sponsored study.

The study included two double-blind, phase 3 trials, MODIFY I and MODIFY II, funded by Merck. A total of 2,655 adults receiving oral standard-of-care antibiotics for primary or current C. difficile were randomized to an infusion of bezlotoxumab (10 mg/kg), actoxumab plus bezlotoxumab (10 mg/kg each), or placebo. Bezlotoxumab and actoxumab are human monoclonal antibodies that bind to Clostridium difficile toxin B and toxin A, respectively. An actoxumab-alone arm was discontinued after interim analysis. Results were published in the Jan. 26 New England Journal of Medicine.

In 12 weeks of follow-up, patients in the bezlotoxumab group had significantly lower rates of recurrence than those on placebo (MODIFY I: 17% vs. 28%; adjusted difference, −10.1 percentage points [95% CI, −15.9 to −4.3; P<0.001]; MODIFY II: 16% vs. 26%; adjusted difference, −9.9 percentage points [95% CI, −15.5 to −4.3; P<0.001]). The actoxumab plus bezlotoxumab group showed similar recurrence rates to bezlotoxumab alone, leading researchers to conclude that the addition of actoxumab did not improve efficacy.

For all studied patients, the number needed to treat to prevent one C. difficile recurrence was 10, the authors calculated. Based on prespecified subgroup analyses, the number needed to treat was 6 in patients age 65 years and over and those with previous infections. Overall, adverse events were similar among the groups, but there were higher rates of death and serious adverse events in the actoxumab group, and the reasons for this are unclear, the authors said.

Rates of initial clinical cure were similar among the groups, consistent with the expectation that bezlotoxumab does not affect the efficacy of standard antibiotic treatment, the authors noted. The observed effectiveness of bezlotoxumab in preventing recurrence is consistent with toxin B being the main determinant of virulence in recurrent C. difficile, although it does not exclude toxin A as a contributing factor, they said.

The study had several limitations, including that the choice of standard-of-care antibiotic was at the discretion of the investigator, other therapies to prevent recurrence of C. difficile were not allowed, and that safety assessments were limited by the number of patients. An accompanying editorial noted other remaining questions about this recently FDA-approved drug, including relative risk stratification and cost. “The cost issue obviously looms large, given the realities of contemporary medical care and specifically the experience with fidaxomicin,” the editorialist wrote.