FDA Advisory Committee Supports Merck's Bezlotoxumab for Clostridium difficile Infection Recurrence Prevention

• The FDA Antimicrobial Drugs Advisory Committee voted 10-5, with one abstention, that Merck's bezlotoxumab demonstrates safety and effectiveness in preventing Clostridium difficile infection recurrence.
• Bezlotoxumab, a human monoclonal antibody, neutralizes the effects of C. difficile toxin B and is administered alongside standard-of-care antibiotics.
• The FDA approved bezlotoxumab (ZINPLAVA) in 2016 to reduce the recurrence of CDI in adult patients at high risk, used in conjunction with antibacterial drug treatment.
• Clinical trials indicated a higher incidence of heart failure in bezlotoxumab-treated patients with a history of congestive heart failure, necessitating careful benefit-risk assessment.

Merck's bezlotoxumab, later branded as ZINPLAVA, received a positive recommendation from the FDA's Antimicrobial Drugs Advisory Committee for the prevention of Clostridium difficile infection (CDI) recurrence. The committee voted 10 to 5, with one abstention, in favor of the drug's safety and efficacy in adult patients aged 18 years and older. This decision was a crucial step toward potential FDA approval, which was granted in 2016.

Mechanism of Action

ZINPLAVA (bezlotoxumab) is a human monoclonal antibody that targets and neutralizes C. difficile toxin B. Clostridium difficile infection is caused by bacteria that produce toxins, including toxin B, leading to symptoms such as diarrhea, abdominal pain, and fever. By neutralizing toxin B, bezlotoxumab helps to prevent the recurrence of CDI in high-risk patients.

Clinical Efficacy and Safety

Bezlotoxumab is administered via infusion in conjunction with standard-of-care antibiotics used to treat CDI. It is not an antibiotic itself. Clinical trial data demonstrated that bezlotoxumab significantly reduced the recurrence of CDI in patients at high risk. However, the FDA approval came with a warning regarding heart failure. In clinical trials, heart failure was more commonly reported in bezlotoxumab-treated patients compared to those receiving a placebo, particularly in patients with a history of congestive heart failure (CHF). Specifically, 12.7% of bezlotoxumab-treated patients with a history of CHF experienced heart failure as a serious adverse reaction, compared to 4.8% in the placebo group. Additionally, there were more deaths in the bezlotoxumab group (19.5%) compared to the placebo group (12.5%) among patients with a history of CHF. The causes of death varied and included cardiac failure, infections, and respiratory failure.

Implications for Clinical Practice

Given the observed safety concerns, particularly in patients with a history of CHF, the use of bezlotoxumab should be carefully considered, weighing the benefits against the risks. The most common adverse reactions reported within four weeks of infusion included nausea (7% vs 5% in placebo), pyrexia (5% vs 3%), and headache (4% vs 3%).