Bezlotoxumab

Bezlotoxumab, sold under the brand name Zinplava, is a human monoclonal antibody designed for the prevention of recurrence of Clostridioides difficile infections.^[3][4] Bezlotoxumab binds to Clostridioides difficile toxin B.^[3]

Bezlotoxumab

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	Clostridioides difficile toxin B
Clinical data
Trade names	Zinplava
AHFS/Drugs.com	Monograph
MedlinePlus	a617003
License data	US DailyMed: Bezlotoxumab
Pregnancy category	AU: B2
Routes of administration	Intravenous
ATC code	J06BC03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1][2] UK: POM (Prescription only) US: ℞-only[3] EU: Rx-only
Identifiers
CAS Number	1246264-45-8
DrugBank	DB13140
ChemSpider	none
UNII	4H5YMK1H2E
KEGG	D10453
Chemical and physical data
Formula	C6464H9974N1726O2014S46
Molar mass	145565.72 g·mol−1

Medical uses

Bezlotoxumab is indicated to reduce recurrence of Clostridioides difficile infection in people who are receiving antibacterial drug treatment for Clostridioides difficile infection and are at a high risk for Clostridioides difficile infection recurrence.^[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 a 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.^[5]

History

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.^[6] The project was then licensed to Merck Sharp & Dohme Corp for further development and commercialization.^[7]

A phase III trial only showed a benefit from bezlotoxumab; the combination of actoxumab and bezlotoxumab worked no better to prevent a recurrence of C. difficile associated diarrhea than bezlotoxumab alone.^[8]

In June 2016, the Antimicrobial Drugs Advisory Committee of the US Food and Drug Administration^[9] voted to recommend approval of Merck's license application for bezlotoxumab 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.^[10] The committee tempered this acceptance with a robust discussion of whether or not the drug provides a 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 a 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.^[11][12][13]

Bezlotoxumab was approved for medical use in the United States in October 2016.^{[3][14][15][16]}

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. "Zinplava- bezlotoxumab injection, solution". DailyMed. 26 May 2023. Retrieved 20 October 2024.
4. "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.
5. Orth P, Hernandez LD, Reichert P, Sheth PR, Beaumont M, Yang XY, et al. (27 June 2014). "Mechanism of Action and Epitopes of Clostridium difficile Toxin B-neutralizing Antibody Bezlotoxumab Revealed by X-ray Crystallography". Journal of Biological Chemistry. 289 (26): 18008–18021. doi:10.1074/jbc.m114.560748. PMC 4140266. PMID 24821719.
6. Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, et al. (January 2010). "Treatment with monoclonal antibodies against Clostridium difficile toxins". N. Engl. J. Med. 362 (3): 197–205. doi:10.1056/NEJMoa0907635. PMID 20089970.
7. "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.
8. "Pivotal Phase 3 Studies of Bezlotoxumab, Merck's Investigational Antitoxin to Prevent Clostridium Difficile Infection Recurrence, Met Primary Endpoint" (Press release). 20 September 2015.
9. "June 9, 2016: Meeting of the Antimicrobial Drugs Advisory Committee Meeting Announcement". U.S. Food and Drug Administration. 9 June 2016. Retrieved 20 October 2024.
10. "Merck Statement on FDA Advisory Committee Meeting for Zinplava (bezlotoxumab), an Investigational Agent for Prevention of Clostridium difficile Infection Recurrence". Merck (Press release). 17 October 2024. Retrieved 20 October 2024.
11. "FDA Panel Favors New C. Diff. Biologic". 9 June 2016.
12. "Briefing Information for the June 9, 2016 Meeting of the Antimicrobial Drugs Advisory Committee (AMDAC)". U.S. Food and Drug Administration (FDA). 6 June 2016.
13. https://web.archive.org/web/20191215083218/https://www.fda.gov/advisory-committees/antimicrobial-drugs-advisory-committee-formerly-known-anti-infective-drugs-advisory-committee/2016-meeting-materials-antimicrobial-drugs-advisory-committee-formerly-known-anti-infective-drugs
14. "Drug Trials Snapshots: Zinplava". U.S. Food and Drug Administration (FDA). 21 October 2016. Retrieved 26 March 2020.
15. "Drug Approval Package: Zinplava Injection (bezlotoxumab)". U.S. Food and Drug Administration (FDA). 21 October 2016. Retrieved 26 March 2020.
16. "FDA Approves Merck's Zinplava (bezlotoxumab) to Reduce Recurrence of Clostridium difficile Infection (CDI) in Adult Patients Receiving Antibacterial Drug Treatment for CDI Who Are at High Risk of CDI Recurrence". Merck (Press release). 17 October 2024. Retrieved 20 October 2024.