Bezlotoxumab

Source: Wikipedia, the free encyclopedia.

Bezlotoxumab
Clostridium difficile toxin B
Clinical data
Trade namesZinplava
AHFS/Drugs.comMonograph
MedlinePlusa617003
License data
Pregnancy
category
  • AU: B2
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

Bezlotoxumab, sold under the brand name Zinplava, is a human monoclonal antibody designed for the prevention of recurrence of Clostridioides difficile infections.[3]

Mechanism of TcdB neutralization

By x-ray crystallized structure of N-terminal of Clostridioides 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. This leads to the conclusion that the TcdB epitope lies within the N-terminus of the CROP domain.[4]

History

This drug, along with

University of Massachusetts Medical School.[5] The project was then licensed to Merck Sharp & Dohme Corp for further development and commercialization.[6]

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

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.[7]

In June 2016, the U.S. FDA's Antimicrobial Drugs Advisory Committee (formerly known as the Anti-Infective Drugs Advisory Committee)[8] 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 may have been an imbalance in how sick the patients in those groups were.[9][10]

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."[11][12][13]

References

  1. ^ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  2. ^ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  3. ^ "Statement On A Nonproprietary Name Adopted By The USAN Council - Bezlotoxumab" (PDF). American Medical Association. Archived from the original on 16 September 2012. Retrieved 25 October 2012.
  4. PMID 24821719
    .
  5. PMID 20089970
    .
  6. ^ "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. 21 April 2009.
  7. ^ "Pivotal Phase 3 Studies of Bezlotoxumab, Merck's Investigational Antitoxin to Prevent Clostridium Difficile Infection Recurrence, Met Primary Endpoint" (Press release). 20 September 2015.
  8. ^ "Antimicrobial Drugs Advisory Committee (Formerly known as the Anti-Infective Drugs Advisory Committee)". Food and Drug Administration. 18 February 2021.
  9. ^ "FDA Panel Favors New C. Diff. Biologic". 9 June 2016.
  10. ^ "Briefing Information for the June 9, 2016 Meeting of the Antimicrobial Drugs Advisory Committee (AMDAC)". FDA. 9 February 2019.
  11. ^ FDA Approves Zinplava for Recurrent C. difficile. Oct 25 2016
  12. ^ "Drug Trials Snapshots: Zinplava". U.S. Food and Drug Administration (FDA). 21 October 2016. Retrieved 26 March 2020.
  13. ^ "Drug Approval Package: Zinplava Injection (bezlotoxumab)". U.S. Food and Drug Administration (FDA). 21 October 2016. Retrieved 26 March 2020.
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