Bezlotoxumab

Bezlotoxumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetClostridium difficile toxin B
Names
Trade namesZinplava
Clinical data
Main usesClostridium difficile infections[1]
Side effectsNausea, diarrhea, fever, headache[1]
Pregnancy
category
  • AU: B2
  • US: N (Not classified yet)
    Routes of
    use    		Intravenous
    External links
    AHFS/Drugs.comMonograph
    US NLMBezlotoxumab
    MedlinePlusa617003
    Legal
    License data
    Legal status
    Chemical and physical data
    FormulaC6464H9974N1726O2014S46
    Molar mass145565.72 g·mol−1

    Bezlotoxumab, sold under the brand name Zinplava, is a medication used in Clostridium difficile infections to prevent recurrence.[1] It is used together with antibiotics.[1] It is given by injection into a vein.[1]

    Common side effects include nausea, diarrhea, fever, and headache.[1] Other side effects may include heart failure.[2] Safety in pregnancy is unclear.[3] It is a monoclonal antibody that binds to Clostridium difficile toxin B.[2]

    Bezlotoxumab was approved for medical use in the United States in 2016 and Europe in 2017.[2][1] In the United Kingdom a 1,000 mg vial costs the NHS about £2,500 as of 2021.[4] This amount in the United States costs about 4,000 USD.[5]

    Medical use

    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.[6]

    Dosage

    It is given as a single dose of 10 mg/kg.[1][4]

    Mechanism of action

    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.[7]

    History

    On June 9, 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 many have been imbalance in how sick the patients in those groups were.[9][10]

    The Prescription Drug User Fee Act (PDUFA) action date for the FDA's review of bezlotoxumab is July 23, 2016.[11]

    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."[12][13][14]

    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.[15] The project was then licensed to Merck Sharp & Dohme Corp for further development and commercialization.[16]

    References

    1. 1 2 3 4 5 6 7 8 "Zinplava". Archived from the original on 9 January 2021. Retrieved 10 January 2022.
    2. 1 2 3 "DailyMed - ZINPLAVA- bezlotoxumab injection, solution". dailymed.nlm.nih.gov. Archived from the original on 11 August 2021. Retrieved 10 January 2022.
    3. ↑ "Bezlotoxumab (Zinplava) Use During Pregnancy". Drugs.com. Archived from the original on 5 December 2020. Retrieved 10 January 2022.
    4. 1 2 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1338. ISBN 978-0857114105.
    5. ↑ "Zinplava Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 25 October 2021. Retrieved 10 January 2022.
    6. ↑ "Pivotal Phase 3 Studies of Bezlotoxumab, Merck's Investigational Antitoxin to Prevent Clostridium Difficile Infection Recurrence, Met Primary Endpoint". 20 September 2015. Archived from the original on 14 April 2021. Retrieved 6 October 2021.
    7. ↑ 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.
    8. ↑ "Antimicrobial Drugs Advisory Committee (Formerly known as the Anti-Infective Drugs Advisory Committee)". 18 February 2021. Archived from the original on 23 April 2019. Retrieved 6 October 2021.
    9. ↑ "FDA Panel Favors New C. Diff. Biologic". 9 June 2016. Archived from the original on 2021-04-14. Retrieved 2021-10-06.
    10. ↑ "Briefing Information for the June 9, 2016 Meeting of the Antimicrobial Drugs Advisory Committee (AMDAC)". FDA. 9 February 2019. Archived from the original on 24 April 2019. Retrieved 6 October 2021.
    11. ↑ "FDA Advisory Panel Gives Nod to Zinplava. June 2016". Archived from the original on 2021-11-04. Retrieved 2021-10-06.
    12. ↑ "FDA Approves Zinplava for Recurrent C. difficile. Oct 25 2016". Archived from the original on 2017-03-05. Retrieved 2021-10-06.
    13. ↑ "Drug Trials Snapshots: Zinplava". U.S. Food and Drug Administration (FDA). 21 October 2016. Archived from the original on 13 December 2019. Retrieved 26 March 2020.
    14. ↑ "Drug Approval Package: Zinplava Injection (bezlotoxumab)". U.S. Food and Drug Administration (FDA). 21 October 2016. Archived from the original on 27 March 2020. Retrieved 26 March 2020.
    15. ↑ 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.
    16. ↑ "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. Archived from the original on April 29, 2018. Retrieved October 6, 2021.
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