Preclinical and clinical properties of Bezlotoxumab (ZINPLAVA<sup>®</sup> 25 mg/mL concentrate for solution for infusion), novel therapeutic agent for <i>Clostridium difficile</i> infection

Abstract

Clostridium difficile (C. difficile), an enterobacteria, flourishes and produces potent toxins, toxin A (TcdA) and toxin B (TcdB), after the disruption of the normal colonic microbiota by antibiotic therapy. C. difficile infection (CDI) may induce life-threatening complications such as fulminant colitis through damage of the intestinal wall by the toxins, therefore the prevention of CDI recurrence is the most important in CDI treatment. Bezlotoxumab is a human monoclonal antibody that neutralizes the activity of TcdB directly. The antibody inhibited cytotoxicity by TcdB derived from various ribotypes of C. difficile at a concentration (EC50) of 1/150 or less of the serum concentration (Cmax: 169 μg/mL) in CDI patients at the clinical dose. Moreover the anti-cytotoxicity effects of the antibody were also observed against 81 clinically isolated C. difficile strains (incl. 018 [smz] and 369 [trf]: Japanese prevalent ribotypes; 027: hypervirulent ribotype) obtained in Japan and western countries. The antibody prolonged survival time of hamster and rat CDI models in a dose-dependent manner. In clinical phase III studies (MODIFY I and II), the recurrence rate of CDI up to 12 weeks after administration of the bezlotoxumab group was significantly lower (P<0.0001) than the placebo group. Bezlotoxumab is the world's first drug with an indication for reduce recurrence of CDI. In Japan, bezlotoxumab was approved for marketing in September, and launched in December in 2017. Bezlotoxumab is effective for broad ribotypes of C. difficile, therefore it expects to contribute to CDI treatment through the reduce recurrence of the CDI.