Recombinant Antibodies for Infectious Diseases by Theam Soon Lim

Author:Theam Soon Lim
Language: eng
Format: epub, pdf
Publisher: Springer International Publishing, Cham

7.4.4.3 Bezlotoxumab (ZINPLAVATM)

C. difficile infection (CDI) is the most prevalent cause of antibiotic-associated gastrointestinal infections in healthcare facilities in the developed world. The Centers for Disease Control and Prevention estimated that CDI caused almost 500,000 illnesses and 29,000 deaths within 1 month of the initial diagnosis in 2011. The standard therapy for CDI involves administration of the antibiotics vancomycin or metronidazole but relapse occurs in 10–20% of patients on cessation of treatment [101]. Disease symptoms are mainly caused by two exotoxins TcdA and TcdB.

A combination of two human mAbs, actoxumab (MK-3415, aka CDA1, MDX-066) and bezlotoxumab (MK-6072 aka CDB1, MDX-1388), against TcdA and TcdB, respectively, were developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol Myers Squibb), using Medarex’s human antibody transgenic mice technology. The antibodies were shown to be protective in multiple animal models of CDI, including systemic and local (gut) toxin challenge models, as well as in primary and recurrent models of infection in mice, hamsters and piglets [7, 125]. A systemically administered combination of actoxumab and bezlotoxumab prevented both damage to the gut wall and the inflammatory response. Mutant antibodies, with a N297Q mutation that diminished binding to Fcγ receptors, gave a similar level of protection to wild-type antibodies, demonstrating that the mechanism of protection is through direct neutralization of the toxins and does not involve host effector functions [149].

Actoxumab and bezlotoxumab were licensed to Merck & Co in 2009. Two global, Phase 3 double-blind studies – MODIFY I and MODIFY II (Monoclonal antibodies for C. difficile therapy) were conducted to evaluate bezlotoxumab, either alone or in combination with actoxumab 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 [143]. The MODIFY I study enrolled 1452 patients in 19 countries and the MODIFY II study enrolled 1203 patients in 17 countries. The primary endpoint for each study was evaluated through 12 weeks following study drug administration. Treatment with the combination of bezlotoxumab and actoxumab did not provide added efficacy over bezlotoxumab alone. Furthermore, actoxumab alone provided no benefit in the prevention of C. difficile recurrence compared with placebo. Based on these results, only bezlotoxumab (ZINPLAVA™) was selected for the marketing authorization application. ZINPLAVA™ was approved by the FDA in October, 2016 to reduce recurrence of C. difficile infection in adult patients receiving anti-bacterial drug treatment.

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