Amid Trial Concerns, FDA Delays Approval Decision for Merck & Co.'s C. Diff Drug, New PDUFA Date Set

Published: Jul 22, 2016

Amid Trial Concerns, FDA Delays Approval Decision for Merck & Co.'s C. Diff Drug, New PDUFA Date Set July 22, 2016
By Mark Terry, Breaking News Staff

The U.S. Food and Drug Administration (FDA), which was to make a decision on Merck ’s pending Biologics Licensing Application (BLA) for bezlotoxumab tomorrow, has delayed a decision until Oct. 23, 2016.

As reported on June 8, a FDA review panel had questions as to whether the drug works. On June 9, the Antimicrobial Drugs Advisory Committee voted 10 to 5, with one abstention, in support of the drug showing evidence of efficacy and safety. Advisory committee votes are recommendations to the FDA, but are not binding.

Bezlotoxumab is a fully human monoclonal IgGa/kappa antibody. It binds to one of the Clostridium difficile (C. diff) toxins, which prevents it from binding to cells in the colon. C. diff is a bacteria that inflames the colon, resulting in severe diarrhea that can be life threatening. It is a common cause of infectious diarrhea in hospitals and nursing homes.

About 25 percent of patients with a C. diff infection have a recurrence. More than 40 percent of those with a recurrence have additional recurrence.

The strategy behind the use of bezlotoxumab is that it would be given in conjunction with standard of care antibiotics. That way it would minimize the likelihood of recurrence.

Clinical trials have demonstrated a decrease in C.difficile recurrence in patients treated with bezlotoxumab, but the FDA expressed concern whether the drug’s efficacy had actually been demonstrated. As summed up by a June article in Reuters, “The review said results suggest the drug may ‘negatively affect’ the cure rate of an initial C. difficile episode.”

The FDA briefing stated, “While there appears to be a decrease in CDI recurrence with the use of bezlotoxumab, there is concern as to whether the efficacy of bezlotoxumab for the prevention of CDI recurrence has been adequately demonstrated. It was anticipated that the monoclonal antibody would have no impact on clinical cure of the initial CDI episode. However there were numerical differences observed in clinical cure between bezlotoxumab and placebo in both trials. In Study P001, the difference was in favor of placebo whereas the difference was in favor of bezlotoxumab in Study P002.”

In the Phase III trials, the rate of recurrence through week 12 were significantly lower in patients receiving bezlotoxumab, 17.4 percent and 15.7 percent, or bezlotoxumab and actoxumab (15.9 percent and 14.9 percent) compared to patients taking a placebo. The two placebo groups had recurrence rates of 27.6 percent and 25.7 percent.

The drug was developed by Medarex, which was acquired by Bristol-Myers Squibb , and then licensed to Merck in 2009.

Despite the overall favorable vote by the advisory committee, the FDA has requested new data and analyses from both the MODIFY I and II clinical trials.

The FDA’s advisory panel had problems with the small size of the trials compared to the extremely large size of the patient population. In addition, there were some concerns about the data itself.

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