Bezlotoxumab

Bezlotoxumab, sold under the brand name Zinplava, is a human monoclonal antibody designed for the prevention of recurrence of Clostridium difficile infections.[1]

Bezlotoxumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetClostridium difficile toxin B
Clinical data
Trade namesZinplava
AHFS/Drugs.comMonograph
MedlinePlusa617003
License data
Pregnancy
category
  • AU: B2
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6464H9974N1726O2014S46
Molar mass145565.72 g·mol−1

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]

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

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 U.S. FDA's Antimicrobial Drugs Advisory Committee (formerly known as the Anti-Infective Drugs Advisory Committee)[5] met to discuss bezlotoxumab. The committee 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. difficile overall. The committee tempered this acceptance with a robust discussion of whether or not the drug provide more marked benefit in some patient groups and expressed 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][10][11]

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 and B3 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 reacts with the B2 region of the CROP domain. The leads to the conclusion that TcdB epitope lies within the N-terminus of the CROP domain.[12]

References
  1. "Statement On A Nonproprietary Name Adopted By The USAN Council - Bezlotoxumab" (PDF). American Medical Association. Archived from the original on 2012-09-16. Retrieved 2012-10-25.
  2. Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, Nichol G, Thomas WD, Leney M, Sloan S, Hay CA, Ambrosino DM (January 2010). "Treatment with monoclonal antibodies against Clostridium difficile toxins". N. Engl. J. Med. 362 (3): 197–205. doi:10.1056/NEJMoa0907635. PMID 20089970.
  3. "Merck & Co., Inc., Medarex, Inc. and Massachusetts Biologic Laboratories Sign Exclusive Licensing Agreement for Investigational Monoclonal Antibody Combination for Clostridium Difficile Infection". Press Release. Merck Sharp & Dohme Corp. April 21, 2009.
  4. http://www.businesswire.com/news/home/20150920005053/en/Pivotal-Phase-3-Studies-Bezlotoxumab-Merck%E2%80%99s-Investigational
  5. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/default.htm
  6. http://www.medpagetoday.com/Washington-Watch/FDAGeneral/58433?xid=nl_mpt_DHE_2016-06-10&eun=g411987d0r
  7. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm505289.htm
  8. FDA Advisory Panel Gives Nod to Zinplava. June 2016
  9. FDA Approves Zinplava for Recurrent C. difficile. Oct 25 2016
  10. "Drug Trials Snapshots: Zinplava". U.S. Food and Drug Administration (FDA). 21 October 2016. Retrieved 26 March 2020.
  11. "Drug Approval Package: Zinplava Injection (bezlotoxumab)". U.S. Food and Drug Administration (FDA). 21 October 2016. Retrieved 26 March 2020.
  12. Orth P, Hernandez LD, Reichert P, Sheth PR, Beaumont M, Yang XY, Murgolo N, Ermakov G, DiNunzio E, Racine F, Karczewskl J, Secore S, Ingram RN, Mayhood T, Strickland C, Therien AG (June 27, 2014). "Mechanism of Action and Epitopes of Clostridium difficile Toxin B-neutralizing Antibody Bezlotoxumab Revealed by X-ray Crystallography". Biological Chemistry. 289 (26): 18008–18021. doi:10.1074/jbc.m114.560748. PMC 4140266. PMID 24821719.
  • "Bezlotoxumab". Drug Information Portal. U.S. National Library of Medicine.
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