Efficacy of Bezlotoxumab in Patients Infected with Strains of Clostridium difficile Associated with Poor Outcomes

Background:  MODIFY I and MODIFY II were global, randomized, double-blind, placebo-controlled trials of the efficacy and safety of the anti-C. difficile toxin B monoclonal antibody bezlotoxumab (bezlo) for the prevention of CDI recurrence in adults receiving standard of care antibiotic treatment (metronidazole, vancomycin, or fidaxomicin) for primary or recurrent CDI. A secondary objective was to assess the efficacy of bezlo against C. difficile strains associated with increased rates of morbidity and mortality (REA group BI, or ribotypes 027, 078 or 244).

Methods:  Subjects provided a stool sample within 72 hours of randomization and at the time of a new episode of diarrhea. Stool samples with a positive culture at the central laboratory were sent to reference laboratories for REA and PCR ribotyping. CDI recurrence was defined as a new episode of diarrhea (≥3 unformed stools in 24 hours) and positive stool test for toxigenic C. difficile after clinical cure of the baseline CDI episode. Data from MODIFY I and MODIFY II were combined for a pre-specified pooled efficacy analysis, providing increased precision for estimating treatment effects.

Results:  Across all treatment groups in MODIFY I+II, 1597 subjects (63% of the Full Analysis Set) had a positive baseline culture for C. difficile.  A BI strain was identified in 328 (20.5%) and ribotypes 027, 078, or 244 were identified in 337 baseline cultures (21.1%).  Overall, 84.8% of BI strains were ribotype 027. CDI recurrence rates by strain type for the bezlo and placebo groups are shown below (table).  CDI recurrence rates were lower in subjects who received bezlo compared with those who received placebo in the overall population, in subjects with a positive baseline culture, and in subjects infected with a strain associated with poor outcomes.  Although the study was not powered to demonstrate significant recurrence reduction according to strain type, the magnitude of the reduction for recurrent infections due to these strains was similar to the reduction in the overall population.

Conclusion:  Neutralization of C. difficile toxin B by the monoclonal antibody bezlotoxumab, in subjects receiving standard of care antibiotics for CDI, reduces CDI recurrence in subjects infected with strains associated with poor outcomes.