MODIFY trials demonstrate efficacy of monoclonal antibody treatment for CDI

Issue: October 2015

SAN DIEGO — Bezlotoxumab, the monoclonal antibody that neutralizes Clostridium difficile toxin B, was an efficacious adjunctive therapy for the prevention of recurrent C. difficile infection, according to the results of two pivotal phase 3 studies presented at ICAAC 2015.

Although antibiotics have been approved for the treatment of C. difficile infection, none has been approved for the prevention of recurrent disease, which affects 15% to 35% of patients with the infection, according to Mark H. Wilcox, MD, FRCPath, professor of medical microbiology at Leeds Teaching Hospitals and the University of Leeds. In addition, the severity and frequency of C. difficile infection has risen sharply over the past decade, he said, which has led to an increase in hospitalizations, health care costs and mortality.

Mark H. Wilcox

Wilcox presented data from one of two large clinical trials that evaluated the safety and efficacy of adjunctive therapy with bezlotoxumab and another monoclonal antibody, actoxumab, which binds to C. difficile toxin A. The MODIFY I trial was conducted across 158 sites in 19 countries, and included 1,412 patients receiving antibiotic therapy — the standard of care — for C. difficile infection. In addition to their antibiotic regimen, patients were randomly assigned to a single infusion of 10 mg/kg each of actoxumab plus bezlotoxumab (n = 387), 10 mg/kg actoxumab alone (n = 235), 10 mg/kg bezlotoxumab alone (n = 390), or placebo (n = 400). Treatments were administered as soon as possible after the initiation of antibiotic therapy. According to Wilcox, 1,396 patients with C. difficile infection were included in the efficacy analyses, and 1,224 had completed the 12-week follow-up period. The primary endpoint was the prevention of C. difficile recurrence, and the researchers also measured sustained clinical response, or global cure, as a secondary endpoint.

Wilcox said rates of recurrent C. difficile were significantly lower for patients taking bezlotoxumab alone compared with placebo (17% vs. 28%; P = .0003). He noted that the efficacy of bezlotoxumab was demonstrated in patients who were at high risk for recurrent C. difficile infection, including those with a previous episode of C. difficile infection, patients with the BI/NAP1/027 strain, patients with severe infection, those aged older than 65 years and immunocompromised patients.

Although the researchers did observe an improvement in global cure among patients who received bezlotoxumab, the finding was not statistically significant.

Rates of the most common adverse events were similar between patients who received bezlotoxumab and the placebo, including those for abdominal pain (5.4% vs. 4.8%), diarrhea (6.7% vs. 5%) and nausea (7.4% vs. 6.5%).

“These are really landmark studies, because this treatment option would represent the first time that monoclonal antibodies could be used for the treatment of C. diff infection, indeed to prevent probably the most challenging aspect of C. diff infection, which is recurrence,” Wilcox said in an interview with Infectious Disease News.

In a separate presentation, Dale N. Gerding, MD, professor of medicine at Loyola University Stritch School of Medicine, presented findings from MODIFY II, which included 1,168 patients treated at 171 sites in 17 countries. Results were consistent with MODIFY I, demonstrating superior efficacy of bezlotoxumab in the prevention of recurrent C. difficile infection in adults receiving antibiotic therapy, compared with antibiotic use alone.

Dale N. Gerding

The difference in the proportion of patients with a recurrence of C. difficile infection who were treated with bezlotoxumab alone compared with placebo was maintained throughout the 12-week follow-up period (16% vs. 26%, respectively; P = .0003). The monoclonal antibody also was highly efficacious in high-risk patients. Further, those who received bezlotoxumab had a higher rate of global cure compared with the placebo arm (67% vs. 52%; P < .0001).

“Use of the monoclonal antibody provides passive immunity to patients at high risk for recurrence of C. diff and significantly reduces their chance of recurrence,” Gerding told Infectious Disease News.

Rates of common adverse events overall — diarrhea (5.3% vs. 6.6%), nausea (5.8% vs. 3.4%) and previous infection with C. difficile (4% vs. 6%) — were similar between the bezlotoxumab and placebo groups.

Results from both trials also suggested that the combination of bezlotoxumab and actoxumab did not provide added efficacy over bezlotoxumab alone, and that actoxumab offered no benefit in the prevention of recurrent C. difficile compared with placebo. Wilcox said some studies in animal models have shown that the neutralization of toxins A and B are necessary for successful treatment. However, it now appears from the MODIFY studies that the neutralization of toxin B is sufficient to prevent recurrent disease.

“It really is a remarkable finding,” Gerding said in an interview. “Everybody would have predicted that you needed both.”

Gerding said is unclear where monoclonal antibody therapy is going to fit into the treatment paradigm, especially given the current interest in another effective therapy — fecal transplant microbiota — which, like bezlotoxumab, has not yet been approved by the FDA.

“I think the two combined are going to provide a real advantage in terms of reducing recurrence,” he said. “I think they’re going to be very, very helpful. Recurrence is our second biggest problem. Our first big problem is preventing it in the first place.” – by John Schoen

Reference:

Gerding DN, et al. Phase 3 Double-Blind Study of Bezlotoxumab (BEZ) Alone & with Actoxumab (ACT) for Prevention of Recurrent C. difficile Infection (rCDI) in Patients on Standard of Care (SoC) Antibiotics (MODIFY II). Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Wilcox MH, et al. Phase 3 Double-blind Study of Actoxumab (ACT) & Bezlotoxumab (BEZ) for Prevention of Recurrent C. difficile Infection (rCDI) in Patients on Standard of Care (SoC) Antibiotics (MODIFY I). Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Disclosures: Gerding and Wilcox report financial relationships with several drug companies. The study was funded by Merck. Please see the full study for a list of all relevant financial disclosures.