Crizanlizumab

Identification

Summary

Crizanlizumab is a monoclonal antibody that targets selectin to reduce the frequency of vasooclusive crises in patients with sickle cell disease.

Brand Names

Adakveo

Generic Name

Crizanlizumab

DrugBank Accession Number

DB15271

Background

Crizanlizumab is a humanized IgG2 monoclonal antibody used to reduce the frequency of vaso-occlusive crises in patients with sickle cell disease.⁹ Sickle cell disease is a genetically inherited condition prevalent in the Middle East, Africa, and certain parts of India. The genetic mutation associated with this disease leads to the formation of abnormal, sickle shaped red blood cells that aggregate and block blood vessels throughout the body, causing vaso-occlusive crises. Sickle cell disease can lead to excruciating pain, stroke, infection, and various other complications arising from the blockage of blood vessels.⁸

Currently, patients are prescribed hydroxyurea to raise levels of fetal hemoglobin as a method of reducing morbidity and mortality.⁴ Though hydroxyurea has been shown to reduce the frequency of vaso-occlusive crises, adherence to this therapy is difficult due to adverse effects and the high variability of response to the drug between patients.⁵ Crizanlizumab, or SEG101, is given once every 4 weeks and may improve patient adherence. It was developed by Novartis and was granted FDA approval on November 15, 2019.⁹

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Chemical Formula

Not Available

Protein Average Weight

146000.0 Da (Theoretical)

Sequences

Not Available

Synonyms

Crizanlizumab
crizanlizumab-tmca

External IDs

SEG101

Pharmacology

Indication

Crizanlizumab is indicated to reduce the frequency of vaso-occlusive crisis in patients with sickle cell diseases who are ≥16 years old.⁹

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Associated Conditions

Vaso-occlusive Crisis

Contraindications & Blackbox Warnings

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Pharmacodynamics

Crizanlizumab is a P-selectin inhibitor that prevents interactions between endothelial cells, platelets, red blood cells, and leukocytes.⁹ It has a long duration of action as it is given every 4 weeks.⁹ Patients should be counselled regarding the risk of infusion reactions as well as crizanlizumab's interference with platelet counts using EDTA tubes.⁹

Mechanism of action

Crizanlizumab binds to P-selectin on endothelial cells and platelets, preventing their interaction with P-selectin glycoprotein ligand 1 on endothelial cells, platelets, red blood cells, and leukocytes.^6,9 By preventing this interaction, components of the blood are less likely to come together, causing a vaso-occlusive crisis in patients with sickle cell diseases.^6,9 The median per year incidence of vaso-occlusive crises was 1.04 in the high-dose crizanlizumab group, 2.00 in the low-dose crizanlizumab group, and 2.08 in the placebo group.³

Target	Actions	Organism
AP-selectin	inhibitor	Humans

Absorption

Crizanlizumab reaches a C_max of 0.16mg/mL with an AUC of 34.6mg*hr/mL.⁹

Volume of distribution

The volume of distribution of crizanlizumab is 4.26L.⁹

Protein binding

Monoclonal antibodies are generally not protein bound^1,2.

Metabolism

Crizanlizumab is expected to be metabolized into smaller peptides and amino acids.⁹

Route of elimination

Monoclonal antibodies are eventually phagocytosed and broken down to smaller peptides and amino acids which are eliminated in a similar fashion to other proteins.^1,2 Monoclonal antibodies are generally not eliminated in the urine, and only a small amount is excreted in bile.⁷

Half-life

Given a 5mg/kg dose of crizanlizumab, the mean terminal elimination half life of crizanlizumab is 10.6 days in healthy subjects and 7.6 days in patients with sickle cell disease.⁹

Clearance

Given a 5mg/kg dose of crizanlizumab, the clearance rate is 11.7ml/hr in healthy subjects.⁹

Adverse Effects

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Toxicity

Data regarding the toxicity of crizanlizumab is not readily available.⁹

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Adakveo	Injection, solution, concentrate	10 mg/ml	Intravenous	Novartis Europharm Limited	2020-12-16	Not applicable
Adakveo	Injection	10 mg/1mL	Intravenous	Novartis Pharmaceuticals Corporation	2019-11-15	Not applicable

Chemical Identifiers

UNII: L7451S9126
CAS number: 1690318-25-2

References

General References

Tabrizi MA, Tseng CM, Roskos LK: Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006 Jan;11(1-2):81-8. doi: 10.1016/S1359-6446(05)03638-X. [Article]
Lobo ED, Hansen RJ, Balthasar JP: Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004 Nov;93(11):2645-68. doi: 10.1002/jps.20178. [Article]
Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, Guthrie TH, Knight-Madden J, Alvarez OA, Gordeuk VR, Gualandro S, Colella MP, Smith WR, Rollins SA, Stocker JW, Rother RP: Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017 Feb 2;376(5):429-439. doi: 10.1056/NEJMoa1611770. Epub 2016 Dec 3. [Article]
Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M: Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003 Apr 2;289(13):1645-51. doi: 10.1001/jama.289.13.1645. [Article]
Riley TR, Riley TT: Profile of crizanlizumab and its potential in the prevention of pain crises in sickle cell disease: evidence to date. J Blood Med. 2019 Aug 30;10:307-311. doi: 10.2147/JBM.S191423. eCollection 2019. [Article]
Gardner RV: Sickle Cell Disease: Advances in Treatment. Ochsner J. 2018 Winter;18(4):377-389. doi: 10.31486/toj.18.0076. [Article]
Ryman JT, Meibohm B: Pharmacokinetics of Monoclonal Antibodies. CPT Pharmacometrics Syst Pharmacol. 2017 Sep;6(9):576-588. doi: 10.1002/psp4.12224. Epub 2017 Jul 29. [Article]
Ankit Mangla; Moavia Ehsan; Smita Maruvada (2019). Sickle Cell Anemia. Stat Pearls.
FDA Approved Drug Products: Adakveo Crizanlizumab-TMCA Intravenous Injection [Link]

External Links

RxNav: 2262421
Wikipedia: Crizanlizumab

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Recruiting	Treatment	Sickle Cell Disease (SCD)	2
3	Recruiting	Treatment	Sickle Cell Disease (SCD)	1
2	Active Not Recruiting	Treatment	Sickle Cell Disease (SCD)	1
2	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
2	Recruiting	Treatment	Priapism	1
2	Recruiting	Treatment	RVCL - Retinal Vasculopathy Cerebral Leukoencephalopathy	1
2	Recruiting	Treatment	Sickle Cell Disease (SCD)	2
1, 2	Recruiting	Treatment	Agnogenic Myeloid Metaplasia	1
Not Available	Available	Not Available	Sickle Cell Disease (SCD)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	10 mg/1mL
Injection, solution, concentrate	Intravenous	10 MG/ML

Prices

Not Available

Patents

Not Available

Properties

State: Solid
Experimental Properties: Not Available

Targets

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Details1. P-selectin

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Sialic acid binding
Specific Function: Ca(2+)-dependent receptor for myeloid cells that binds to carbohydrates on neutrophils and monocytes. Mediates the interaction of activated endothelial cells or platelets with leukocytes. The ligan...
Gene Name: SELP
Uniprot ID: P16109
Uniprot Name: P-selectin
Molecular Weight: 90833.105 Da

References

FDA Approved Drug Products: Adakveo Crizanlizumab-TMCA Intravenous Injection [Link]

Drug created on May 20, 2019 15:06 / Updated on February 21, 2021 18:55

Crizanlizumab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References