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FDA Panel Recommends Approval of C. difficile Drug Bezlotoxumab

Approval decision set for July 23

The FDA’s Antimicrobial Drugs Advisory Committee has backed the approval of bezlotoxumab (Zinplava, Merck), an experimental drug for the treatment of the most common cause of hospital-associated infectious diarrhea. The panel voted 10 to five, with one abstention, that the drug was effective in preventing a recurrence of Clostridium difficile infection (CDI), which causes inflammation of the colon and potentially fatal diarrhea.

The FDA is not obliged to follow the advice of its advisory panels but typically does.

The committee’s vote follows an internal review by FDA staff, which found an apparent reduction in the recurrence of CDI, but expressed concern as to whether the drug could hurt the cure rate of the initial C. difficile episode.

Bezlotoxumab is a fully human monoclonal immunoglobulin 1/kappa antibody that binds to C. difficile toxin B. It is hypothesized that bezlotoxumab prevents the binding of toxin B to colonic cells, thus averting colonic cell inflammation. Treatment with bezlotoxumab neutralizes C. difficile toxin B, thereby suppressing symptoms long enough for the body’s natural flora to replenish, eliminating the need for additional cycles of antibiotics. The treatment is administered as a single intravenous infusion.

The proposed indication for bezlotoxumab is the prevention of CDI recurrence in adults (18 years of age or older) receiving antibacterial therapy for the infection. No drugs are currently approved for the prevention of CDI recurrence.

Two phase 3 trials (P001 and P002) were conducted to support the proposed indication. Study P001 was designed to evaluate the efficacy, safety, and pharmacokinetics of actoxumab (antitoxin A antibody), bezlotoxumab (antitoxin B antibody), or actoxumab plus bezlotoxumab compared with placebo (0.9% sodium chloride) in the prevention of CDI recurrence in 1,452 patients who were receiving antibacterial treatment for CDI. Study P002 included 1,203 patients. This trial was essentially identical to Study P001, except that the actoxumab monotherapy arm was not included.

In Study P001, a significantly lower proportion of patients had CDI recurrence in the actoxumab-plus-bezlotoxumab group (15.9%) and in the bezlotoxumab group (17.4%) compared with the placebo group (27.6%) (P < 0.0001 and P = 0.0006, respectively). The adjusted differences in CDI recurrence were –11.6% between actoxumab plus bezlotoxumab and placebo, and –10.1% between bezlotoxumab and placebo.

In Study P002, a significantly lower proportion of patients had CDI recurrence in the actoxumab-plus-bezlotoxumab group (14.9%) and in the bezlotoxumab group (15.7%) compared with placebo (25.7%) (P = 0.0002 and P = 0.0006, respectively). The adjusted differences in CDI recurrence were –10.7% between actoxumab plus bezlotoxumab and placebo, and –9.9% between bezlotoxumab and placebo.

Spores from C. difficile bacteria cling to surfaces and can spread easily in hospitals and nursing homes. The germ infected nearly 500,000 people in 2011 and killed 15,000, according to the Centers for Disease Control and Prevention.

Sources: Reuters; June 9, 2016; and FDA briefing document; June 7, 2016.

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