ZINPLAVA (BEZLOTOXUMAB), Approved FDA

Bezlotoxumab (proprietary name Zinplava) is a human monoclonal antibody designed for the prevention of recurrence ofClostridium difficile infection.^[1]

Actoxumab and bezlotoxumab are fully human monoclonal antibodies which bind Clostridium difficile (C diff) toxins A and B, respectively.

This drug, along with actoxumab, was developed through Phase II efficacy trials by a partnership between Medarex Inc and MassBiologics of the University of Massachusetts Medical School.^[2] The project was then licensed to Merck Sharp & Dohme Corp for further development and commercialization.^[3]

A Phase III trial only showed a benefit from bezlotoxumab; the combination of actoxumab and bezlotoxumab worked no better to prevent recurrence of C.difficile associated diarrhea than bezlotoxumab alone.^[4]

Progress towards FDA approval

On June 9, 2016, the US FDA’s Antimicrobial Drugs Advisory Committee (formerly known as the Anti-Infective Drugs Advisory Committee)^[5] met to discuss bezlotoxumab and voted to recommend approval of Merck’s license application by a vote of 10 to 5, generally expressing a willingness to accept that the trials had proven that bezlotoxumab decreased recurrence of C.diff overall while tempering this acceptance with a robust discussion of whether or not the drug provide more marked benefit in some patient groups and concern over a potential safety signal in the group treated with bezlotoxumab. The data suggested that bezlotoxumab might have the most benefit in sicker, high-risk patients but did show a statistical benefit in all patient subgroups. Although the patient population as a whole contained many very sick individuals and thus there were many adverse events in both the subjects receiving placebo and those receiving bezlotoxumab, the panel focused on a small number of serious events in patients with pre-existing congestive heart failure. In this subset the patients receiving bezlotoxumab appeared to have a higher rate of negative outcomes than the placebo group, although there many have been imbalance in how sick the patients in those groups were.^[6][7]

The Prescription Drug User Fee Act (PDUFA) action date for the FDA’s review of bezlotoxumab is July 23, 2016.^[8]

Bezlotoxumab gained FDA approval in October 2016: “indicated to reduce the recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibiotics for CDI and are at high risk for recurrence.”^[9]

Mechanism of TcdB neutralization

By x-ray crystallized structure of N-terminal of Clostridium difficile toxin B (TcdB), the toxin was identified to consist of three domains: a GTD, a cysteine protease and a combined repetitive oligopeptides, CROP domain. The CROP domain consists of four different peptide units, B1, B2, B3 and B4. Bezlotoxumab specifically inhibits the CROP domain of TcdB. It recognizes a specific epitope on toxin TcdB and has high affinity for that region. The GTD domain does not interact with bezlotoxumab, but appears to interact with B1, which is representative of the entire CROP domain. Bezlotoxumab interacts with either B2 andB3 or the overlapping residues region between the two domains. The B4 fragment does not interact with the specific portion of the CROP domain. Characterization of peptide B1 as full CROP domain of TcdB suggests that the antibody specifically react with the B2 region of the CROP domain, leading to the conclusion that TcdB epitope lies within the N-terminus of the CROP domain.^[10]

References