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FDA Accepts for Review a Biologics Licensing Application for Merck’s Investigational Anti-C.-difficile Toxin Monoclonal Antibody

January 29, 2016 On January 27, 2016, the U.S. Food and Drug Administration (FDA) accepted for review a Biologics Licensing Application (BLA) for bezlotoxumab (Merck), an investigational monoclonal antibody directed against the Clostridium difficile toxin B.1 The manufacturer also filed a Marketing Authorization Application with the European Medicines Agency.

C. difficile is the most common cause of health-care–associated infectious diarrhea2 and was responsible for almost half a million infections and approximately 29,000 deaths in 2011.3 Infection with C. difficile can occur following exposure to antibiotics such as clindamycin, fluoroquinolones, and cephalosporins.4  Two exotoxins produced by the bacteria, toxin A and toxin B, disrupt intestinal epithelial cells, increasing intestinal permeability and triggering the release of inflammatory mediators, resulting in intestinal injury and inflammation and C. difficile symptoms (i.e., abdominal pain, watery diarrhea).5,6 Bezlotoxumab is not an antibiotic, but a selective, fully human, monoclonal antibody designed to neutralize C. difficile toxin B and its pathologic effects.6

Merck submitted in support of the BLA the results of two unpublished Phase 3 trials known as MODIFY I and MODIFY II.7,8  The MODIFY trials tested bezlotoxumab, either alone or in combination with actoxumab (a fully human monoclonal antibody against C. difficile toxin A), compared to placebo for the prevention of recurrent C. difficile infection in patients on standard of care antibiotics for a primary or recurrent C. difficile infection.6 The studies were conducted in both hospital and outpatient settings, and the primary endpoint (i.e., the rate of C. difficile infection recurrence) for each study was evaluated through 12 weeks following study drug administration.  In both studies, the rate of C. difficile infection recurrence was lower in the bezlotoxumab arms compared to the placebo arms in patient subgroups known to be at high risk for C. difficile recurrence; treatment with bezlotoxumab plus actoxumab did not provide added efficacy over bezlotoxumab alone and actoxumab alone provided no benefit in the prevention of C. difficile recurrence compared with placebo.

The FDA granted the bezlotoxumab BLA “priority review” and the Agency is expected to render an approval decision by July 23, 2016; an FDA Advisory Committee meeting to discuss the application has not been scheduled.

References

  1. Press Release:  Merck Announces FDA Acceptance of Biologics License Application for Bezlotoxumab, an Investigational Antitoxin for Prevention of Clostridium Difficile Infection Recurrence. Kenilworth, N.J. : Merck. "http://www.mercknewsroom.com/news-release/corporate-news/merck-announces-fda-acceptance-biologics-license-application-bezlotoxuma". Accessed January 28, 2016.
  2. Barbut F, Corthier G, Charpak Y, et al. Prevalence and pathogenicity of Clostridium difficile in hospitalized patients. A French multicenter study. Arch Intern Med 1996;156(13):1449-54.
  3. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015;372(9):825-34.
  4. Deshpande A, Pasupuleti V, Thota P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother 2013;68(9):1951-61.
  5. Hirota SA, Iablokov V, Tulk SE, et al. Intrarectal instillation of Clostridium difficile toxin A triggers colonic inflammation and tissue damage: development of a novel and efficient mouse model of Clostridium difficile toxin exposure. Infect Immun 2012;80(12):4474-84.
  6. Press Release:  Pivotal Phase 3 Studies of Bezlotoxumab, Merck’s Investigational Antitoxin to Prevent Clostridium Difficile Infection Recurrence, Met Primary Endpoint. Kenilworth, N.J. : Merck. "http://www.mercknewsroom.com/news-release/research-and-development-news/pivotal-phase-3-studies-bezlotoxumab-mercks-investigation". Accessed January 28, 2016.
  7. A Study of MK-3415, MK-6072, and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MK-3415A-001) (MODIFY I). U.S. National Institutes of Health. "https://clinicaltrials.gov/ct2/show/NCT01241552". Accessed January 28, 2016.
  8. A Study of MK-6072 and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MK-3415A-002) (MODIFY II). U.S. National Institutes of Health. "https://clinicaltrials.gov/ct2/show/NCT01513239". Accessed January 28, 2016.

Prepared by: Center for Scientific Information, ADA Science Institute

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