Bezlotoxumab

Last updated

Bezlotoxumab
Monoclonal antibody
Type Whole antibody
Source Human
Target Clostridium difficile toxin B
Clinical data
Trade names Zinplava
AHFS/Drugs.com Monograph
MedlinePlus a617003
License data
Pregnancy
category
  • AU:B2
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU:Rx-only
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6464H9974N1726O2014S46
Molar mass 145565.72 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. [2]

Contents

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. [3]

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. [4] The project was then licensed to Merck Sharp & Dohme Corp for further development and commercialization. [5]

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. [6]

In June 2016, the U.S. FDA's Antimicrobial Drugs Advisory Committee (formerly known as the Anti-Infective Drugs Advisory Committee) [7] 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. [8] [9]

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." [10] [11] [12]

Related Research Articles

<i>Clostridioides difficile</i> infection Disease caused by C. difficile bacteria

Clostridioides difficile infection , also known as Clostridium difficile infection, is a symptomatic infection due to the spore-forming bacterium Clostridioides difficile. Symptoms include watery diarrhea, fever, nausea, and abdominal pain. It makes up about 20% of cases of antibiotic-associated diarrhea. Antibiotics can contribute to detrimental changes in gut microbiota; specifically, they decrease short-chain fatty acid absorption which results in osmotic, or watery, diarrhea. Complications may include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis.

<span class="mw-page-title-main">Norfloxacin</span> Chemical compound, antibiotic

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<span class="mw-page-title-main">Fecal microbiota transplant</span> Process of transplantation of fecal bacteria from a healthy individual into a recipient

Fecal microbiota transplant (FMT), also known as a stool transplant, is the process of transferring fecal bacteria and other microbes from a healthy individual into another individual. FMT is an effective treatment for Clostridioides difficile infection (CDI). For recurrent CDI, FMT is more effective than vancomycin alone, and may improve the outcome after the first index infection.

<span class="mw-page-title-main">Rifaximin</span> Antibiotic medication

Rifaximin, is a non-absorbable, broad spectrum antibiotic mainly used to treat travelers' diarrhea. It is based on the rifamycin antibiotics family. Since its approval in Italy in 1987, it has been licensed in over more than 30 countries for the treatment of a variety of gastrointestinal diseases like irritable bowel syndrome, and hepatic encephalopathy. It acts by inhibiting RNA synthesis in susceptible bacteria by binding to the RNA polymerase enzyme. This binding blocks translocation, which stops transcription. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals.

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<span class="mw-page-title-main">Ofatumumab</span> Medication

Ofatumumab is a fully human monoclonal antibody to CD20, which appears to provide rapid B-cell depletion. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the European Union and other regions. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. It is sold by Novartis under license from Genmab.

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<span class="mw-page-title-main">DEFA5</span> Mammalian protein found in Homo sapiens

Defensin, alpha 5 (DEFA5) also known as human alpha defensin 5 (HD5) is a protein that in humans is encoded by the DEFA5 gene. DEFA5 is expressed in the Paneth cells of the ileum.

<i>Clostridioides difficile</i> toxin B Cytotoxin produced by Clostridioides difficile

Clostridioides difficile toxin B (TcdB) is a cytotoxin produced by the bacteria Clostridioides difficile. It is one of two major kinds of toxins produced by C. difficile, the other being a related enterotoxin. Both are very potent and lethal.

<i>Clostridioides difficile</i> toxin A Cytotoxin produced by Clostridioides difficile

Clostridioides difficile toxin A (TcdA) is a toxin produced by the bacteria Clostridioides difficile, formerly known as Clostridium difficile. It is similar to Clostridium difficile Toxin B. The toxins are the main virulence factors produced by the gram positive, anaerobic, Clostridioides difficile bacteria. The toxins function by damaging the intestinal mucosa and cause the symptoms of C. difficile infection, including pseudomembranous colitis.

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<i>Clostridioides difficile</i> Species of bacteria

Clostridioides difficile is a bacterium known for causing serious diarrheal infections, and may also cause colon cancer. It is known also as C. difficile, or C. diff, and is a Gram-positive species of spore-forming bacteria. Clostridioides spp. are anaerobic, motile bacteria, ubiquitous in nature and especially prevalent in soil. Its vegetative cells are rod-shaped, pleomorphic, and occur in pairs or short chains. Under the microscope, they appear as long, irregular cells with a bulge at their terminal ends. Under Gram staining, C. difficile cells are Gram-positive and show optimum growth on blood agar at human body temperatures in the absence of oxygen. C. difficile is catalase- and superoxide dismutase-negative, and produces up to three types of toxins: enterotoxin A, cytotoxin B and Clostridioides difficile transferase. Under stress conditions, the bacteria produce spores that are able to tolerate extreme conditions that the active bacteria cannot tolerate.

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References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  2. ↑ "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.
  3. ↑ 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 (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.
  4. ↑ 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.
  5. ↑ "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.
  6. ↑ "Pivotal Phase 3 Studies of Bezlotoxumab, Merck's Investigational Antitoxin to Prevent Clostridium Difficile Infection Recurrence, Met Primary Endpoint" (Press release). 20 September 2015.
  7. ↑ "Antimicrobial Drugs Advisory Committee (Formerly known as the Anti-Infective Drugs Advisory Committee)". Food and Drug Administration . 18 February 2021.
  8. ↑ "FDA Panel Favors New C. Diff. Biologic". 9 June 2016.
  9. ↑ "Briefing Information for the June 9, 2016 Meeting of the Antimicrobial Drugs Advisory Committee (AMDAC)". FDA. 9 February 2019.
  10. ↑ FDA Approves Zinplava for Recurrent C. difficile. Oct 25 2016
  11. ↑ "Drug Trials Snapshots: Zinplava". U.S. Food and Drug Administration (FDA). 21 October 2016. Retrieved 26 March 2020.
  12. ↑ "Drug Approval Package: Zinplava Injection (bezlotoxumab)". U.S. Food and Drug Administration (FDA). 21 October 2016. Retrieved 26 March 2020.
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