MODIFY: Bezlotoxumab prevents recurrent C. difficile infection in high-risk patients

Issue: June 2016

SAN DIEGO — Bezlotoxumab was effective in reducing rates of recurrent Clostridium difficile infection in high-risk patients, according to data from the MODIFY trials presented at DDW 2016.

“The monoclonal antibody, bezlotoxumab ... is a fully human antibody directed against the putative ligand binding region of toxin B, and it’s a neutralizing antibody which neutralizes toxin B effects,” Ciaran P. Kelly, MD, from Beth Israel Deaconess Medical Center and Harvard Medical School, said during his presentation. “[Bezlotoxumab] has been evaluated together with its partner, [actoxumab], which is an anti-A monoclonal antibody given to patients with Clostridium difficile infection in an attempt to prevent recurrences. It’s given as ... a single IV infusion and has a long systemic half-life of almost 3 weeks.”

Ciaran P. Kelly

MODIFY I and II were global, randomized, double blind, placebo controlled trials of bezlotoxumab in patients with confirmed C. difficile infection who were treated with standard of care antibiotics. During standard of care therapy, patients were given a single IV infusion (n = 781) or placebo (n = 773) and were followed for 12 weeks. The primary efficacy endpoint was C. difficile infection recurrence, and the secondary efficacy endpoint was sustained clinical response.

Both trials showed that a single dose of bezlotoxumab was superior to placebo for preventing recurrent C. difficile infection (P = .0003), with a 10% reduction in recurrence rates and a 9.7% increase in global cure rates compared with placebo. Actoxumab was no different from placebo in the first study, and so was not studied in the MODIFY II trial.

“The adverse events profile was good. The agent was well tolerated and there were no substantial safety signals,” Kelly said. “There was a slight increase in drug-related adverse events and infusion reactions in the active treatment arm, but these were generally minor and short lived, and in terms of serious adverse events, in fact, these were slightly higher in the placebo group, mainly because of adverse events related to recurrence being more common in the placebo group.”

A secondary aim of the trials was to evaluate the efficacy of bezlotoxumab in subpopulations of patients who are at increased risk for C. difficile infection recurrence, including those aged older than 65 years, those with a recent C. difficile infection within 6 months, those with a history of prior recurrent C. difficile infection, those with compromised immunity, those with severe C. difficile infection or those infected with a hypervirulent, binary toxin positive strain. Most patients had at least one of these risk factors.

The absolute difference in recurrence rate reduction and global cure rates were higher among these high-risk subgroups, with the most significant differences in older patients (–16.0% and +16.2%, respectively), patients with a recent C. difficile infection (–16.1% and 12.2%, respectively), patients with a history of prior recurrent C. difficile infection (–13.1% and 12.3%, respectively) and immunocompromised patients (–12.9% and 15.3%, respectively).

“When administered intravenously [bezlotoxumab] was efficacious in reducing [C. difficile] recurrence through 12 weeks in adults who have been treated for [C. difficile] with antibiotics,” Kelly said. “Subjects with a priori identified risk factors showed higher recurrence rates than those lacking those risk factors, and in those key subpopulations who are at high risk for [C. difficile] recurrence, bezlotoxumab both reduced recurrence and increased rates of global cure.” – by Adam Leitenberger

Reference:

Kelly CP, et al. Abstract #599. Presented at: Digestive Disease Week; May 21-24, 2016; San Diego.

Disclosures: Kelly reports consulting and/or advisory roles with Alba, Merck, Sanofi Pasteur, Seres Therapeutics, and Summit. Please see the DDW disclosure list for all other researchers’ relevant financial disclosures.