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FDA advisory committee recommends bezlotoxumab for recurring C. difficile infection
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The FDA’s Antimicrobial Drugs Advisory Committee voted 10-5 today that bezlotoxumab is a safe and effective therapy for the prevention of Clostridium difficile infection recurrence and recommended its approval. There was one abstention.
Bezlotoxumab (Merck) is a fully human IgG1 monoclonal antibody that neutralizes C. difficile toxin B. It would be the first FDA-approved therapy for the prevention of recurring C. difficile infection (CDI) and an alternative to antibiotic treatments.
The recommendation was based on data from five phase 1 trials, two phase 2 trials and the phase 3 MODIFY I and MODIFY II trials. Previously presented at ICAAC 2015, the MODIFY trials evaluated the safety, efficacy and pharmacokinetics of IV bezlotoxumab alone and with actoxumab (Merck). At 12 weeks, bezlotoxumab was superior to placebo and the combination treatment in preventing CDI recurrence among patients who had achieved clearance with initial antibiotic treatment.
“The results of the pivotal phase 3 trials demonstrate that a single dose of bezlotoxumab is highly efficacious in preventing CDI recurrence, significantly decreasing the proportion of subjects with CDI recurrence by 10% compared to placebo, which translates to a 40% reduction in relative risk in CDI recurrence,” Donnette Staas, PhD, director of regulatory affairs at Merck, said during the meeting. “Bezlotoxumab is well-tolerated, with a safety profile similar to that of placebo [and] has been shown to have a positive benefit risk profile.”
Before the meeting, the FDA committee warned Merck that the primary endpoint of MODIFY I and MODIFY II — CDI recurrence — may not be an appropriate measure of the treatment’s efficacy, as it excludes diarrheic outcomes in patients whose initial clinical treatment failed. These concerns resurfaced as a major point of discussion during today’s deliberations.
“We are in general agreement with most of the results as presented by the applicant,” Cheryl Dixon, PhD, statistician at the FDA and the committee’s statistical reviewer, said. “However, we differ in the ability to interpret those results and the final conclusions drawn.”
The committee instead proposed the secondary endpoint of global cure — defined as successful initial treatment and no recurrence through 12 weeks — as a more appropriate measure of the monoclonal antibody’s efficacy, as this endpoint “captures the overall effect of the treatment,” Dixon said. She also noted concerns related to global cure’s significance within the MODIFY II trial and its implications for bezlotoxumab’s overall efficacy.
“Merck considered the CDI recurrence endpoint to be a more appropriate measure to assess efficacy of a therapy that does not treat the incident CDI episode, but only prevents CDI recurrence,” Staas said. “Thus, Merck retains CDI recurrence as the primary endpoint.”
After the panel’s 10-5-1 vote to recommend bezlotoxumab, some committee members noted concerns related to use of the term “recurrence” in relation to the observed patient outcomes and recommended a warning for patients with recorded heart issues. In addition, dissenting committee members expressed a desire for additional data confirming both efficacy and safety.
According to surveillance data published in 2015, there were an estimated 453,000 incident episodes of CDI in the United States in 2011. Further, there were 83,000 estimated first recurrences and 29,000 deaths associated with the infection.
Mark H. Wilcox
“I passionately believe patients should have better treatment options than are currently available for CDI,” Mark H. Wilcox, MD, FRCPath, professor of medical microbiology at the University of Leeds, and the lead investigator of the MODIFY I trial, said during the meeting. “Bezlotoxumab offers something different from a patient perspective: a novel approach, not based on antimicrobial therapy, to blocking the untoward events of toxin production.”
According to Merck, the Prescription Drug User Fee Act action date for the FDA’s review of bezlotoxumab is July 23. – by Dave Muoio
References:
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.
Lessa FC, et al. New Engl J Med. 2015;doi:10.1056/NEJMoa1408913.
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: Dixon reports no relevant financial outcomes, Staas is an employee of Merck, and Wilcox is a clinical consultant for Merck.