In two phase III trials, Bezlotoxumab appeared to cut recurrence rates by almost half relative to placebo. In the FDA's technical review, however, agency staff expressed reservations about the trial design and results. From MedPage Today.
by Shannon Firth
A drug that has shown promise for preventing recurrent Clostridium difficile infection comes before an FDA advisory committee Thursday, but the agency's technical staff have raised questions about the quality of the sponsor's data.
Bezlotoxumab, a product of Merck Sharpe & Dohme, is a fully human monoclonal antibody that binds to one of two toxins produced by C. difficile toxin B, preventing its pathogenic effects. The FDA's Antimicrobial Drugs Advisory Committee will be asked to vote on the safety and efficacy of bezlotoxumab and offer suggestions regarding any labeling or future studies for the injectable biologic. At present there are no FDA-approved drugs for preventing C. diff recurrence.
In two phase III trials, the drug appeared to cut recurrence rates by almost half relative to placebo.
In the FDA's technical review prepared for the meeting, however, agency staff expressed reservations about the trial design and results.
In both trials, Merck tested bezlotoxumab alongside a second biologic, actoxumab, which targets the C. diff A toxin. That agent appeared to be much less effective, showing no difference from placebo when used alone. MODIFY I tested each drug individually and in combination, along with a placebo control arm. MODIFY II omitted the actoxumab-alone arm, testing bezlotoxumab alone, the two-drug combination, and placebo.
In both studies, the recurrence rate with placebo was 26%-28%; it was 15%-17% in the bezlotoxumab arms, both alone and in combination with the other drug.
In 2012-2013, the FDA urged the sponsor to change the primary endpoint in MODIFY II from CDI recurrence rate to rate of global cure, but the firm declined. Instead it left global cure as a secondary endpoint. Merck also suggested it would measure this secondary marker using pooled data from both phase III trials. The agency warned that pooling data for the secondary endpoint was a bad idea and that it would need "confirmatory evidence from separate trials."
As the agency briefing documents noted, the FDA also voiced concern about "inappropriate" elements of the sponsor's study design. Specifically, for the primary endpoint, participants who failed treatment of their initial CDI episode were viewed as "successes" and inappropriately lumped with the "sustained response" participants.
"[S]ubjects who were clinical failures of the initial CDI episode cannot be evaluated for recurrence, since one has to be cured first in order to develop recurrence," staff noted, adding that such factors make the primary endpoint "difficult to interpret."
Lastly, technical staff raised concerns over the "discordant results" seen with bezlotoxumab across the two pivotal trials.
In MODIFY I, neither clinical nor global cure rates for bezlotoxumab monotherapy were better than in the placebo group, and there was actually a trend toward lower clinical cure rates for the drug. In MODIFY II, bezlotoxumab alone did show a significantly higher rate of global cure than placebo, but clinical cure rates did not differ.
"Overall these results suggest that bezlotoxumab may negatively affect cure rate of the initial CDI episode," agency staff argued.
The review also noted that bezlotoxumab had "an overall favorable safety profile" with the exception of a potential signal from "numerically higher numbers of [serious adverse events] and deaths in bezlotoxumab-treated subjects with baseline congestive heart failure as compared to placebo."
In 2011, the CDC reported roughly 500,000 C. difficile infections in the U.S. and 29,000 deaths. It noted that the individuals most vulnerable to infection are older adults receiving antibiotics and frequent medical care.
Final FDA decisions usually reflect advisory committee recommendations but not always.