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FDA Delays Approval Decision for Merck’s Bezlotoxumab
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The FDA has extended the Prescription Drug User Fee Act goal date for Merck’s investigational biologic for the prevention of recurrent Clostridium difficile infection, bezlotoxumab, by 3 months, according to a press release from the manufacturer.
The new PDUFA goal date is October 23. The company’s Biologics Licensing Application previously received priority review designation from the FDA, with an original PDUFA goal date of July 23.
Bezlotoxumab is a fully human IgG1 monoclonal antibody that neutralizes C. difficile toxin B, and would be the first treatment for preventing C. difficile infection recurrence — an alternative to antibiotic treatments — to be approved by the FDA.
The extension is due to the FDA’s request that Merck submit new data and analyses from the MODIFY I and II clinical trials previously submitted with the company’s Biologics Licensing Application.
The FDA’s Antimicrobial Drugs Advisory Committee supported the agent’s approval on June 9, with a 10-5 vote (with one abstention) that there was “substantial evidence of [its] efficacy and safety.” However, dissenting committee members expressed the need for additional data confirming both efficacy and safety.
“Merck looks forward to continuing to work with the FDA on the review of the bezlotoxumab BLA,” according to the press release.
Perspective
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Colleen R. Kelly, MD
Essentially, the FDA has concerns with the efficacy analyses in the MODIFY I and MODIFY II studies. The primary endpoint for both of the studies was C. difficile recurrence at 12 weeks, and if you look at the results it appears that treatment with bezlotoxumab resulted in about 10% fewer recurrences compared to the placebo-treated group. However, the way recurrence rates were calculated, patients who failed initial treatment of the C. difficile infection (CDI) were grouped together in the “success” category with those patients who were initially cured and did not recur. Also, if more patients failed initial treatment, there would be fewer who could potentially develop a recurrence. This is why the FDA suggested that Merck change the primary endpoint for MODIFY II to global cure, which defines “success” as cure of the initial CDI episode and absence of recurrence.
The company did not agree to do this, preferring to keep C. difficile recurrence as the primary endpoint and global cure as a secondary endpoint. Interestingly, global cure was only about 5% higher (not statistically significant) in the bezlotoxumab-treated patients compared to placebo in MODIFY I, but 15% higher (significant) in MODIFY II.
Additional sensitivity analyses took into account subjects with incomplete data or those that had received medications that could potentially be useful for treatment of CDI during the 12-week follow-up period. These analyses impacted the conclusions drawn for CDI recurrence endpoint in MODIFY II (bezlotoxumab vs. placebo no longer significant).
The FDA also raised concern that clinical cure rates in treatment arms that included bezlotoxumab (alone or in combination with antitoxin A) were actually lower that the placebo arm. There were also some safety concerns raised around treatment of patients with baseline congestive heart failure, who had numerically higher serious adverse events and deaths when treated with bezlotoxumab compared to placebo.
The FDA has asked for more data and analyses from these two phase 3 trials, and has extended the PDUFA goal date until October.
As a doctor who treats many patients with C. difficile, I look forward to having more effective therapies available, including narrow-spectrum antibiotics which will target C. diff while sparing other beneficial anaerobes, as well as microbiota-based therapeutics to restore gut diversity after C. difficile infection. Though fecal microbiota transplant (FMT) is very effective at preventing recurrence, physicians are still somewhat hesitant to use it early-on given lack of long-term safety data and logistical issues. It would be great if bezlotoxumab reduced the rates of C. diff recurrence, particularly for “high risk” populations like the elderly and those who are immunocompromised.
The FDA rightfully sets a very high bar for drug approval and I am hopeful that these questions around the efficacy and safety of bezlotoxumab will be answered prior to it being available for use in our patients. Also, it will be interesting to see analyses of the cost effectiveness of bezlotoxumab compared to FMT for prevention of C. difficile recurrence.
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