Approval Recommended for Zinplava to Prevent Recurrence of C. Diff

In October, the U.S. Food and Drug Administration approved bezlotoxumab (Zinplava, Merck) to prevent the recurrence of Clostridium difficile (C. diff) infection (CDI) in patients aged 18 years and older. The recommendation was given despite the fact that Cheryl Dixon, PhD, a statistical reviewer at the FDA’s Center for Drug Evaluation and Research, disagreed with Merck’s analysis of the study end points. According to Dixon, there was “concern as to whether the efficacy of bezlotoxumab for the prevention of CDI recurrence has been adequately demonstrated.” Instead, in a 10-5 vote with one abstention, the FDA’s Antimicrobial Drugs Advisory Committee found that Merck “provided substantial evidence of safety and effectiveness” that a novel treatment — a human immunoglobulin G monoclonal antibody — prevented CDI recurrence.

The disagreement concerned the primary end points of the phase III MODIFY I and MODIFY II studies. FDA reviewers wrote that global cure rate would be a more relevant endpoint than infection recurrence rates, which were the primary endpoints of both MODIFY studies. The Centers for Disease Control and Prevention (CDC) has declared C. diff an urgent public health threat, causing an estimated 500,000 infections in the U.S. in 2011, 29,000 of whom died within 30 days of initial diagnosis. About 83,000 patients who develop CDI experience at least one recurrence. Antibiotic therapy is the standard of care for CDI, but it does not prevent recurrence of the disease. In fact, 40 percent of patients who have a recurrence experience another, and after two recurrences, the likelihood of an additional episode increases as high as 65 percent, said Donnette Staas, PhD, director of regulatory affairs at Merck. Bezlotoxumab, which is not an antibiotic, binds to the C. diff toxin B and would be given with standard-of-care antibiotics that are used to treat C. diff. It could be given as a single infusion any time during antibiotic therapy.

FDA is not bound by the committee’s recommendation but takes its guidance into consideration for its review.