Inebilizumab

Identification

Summary

Inebilizumab is a humanized anti-CD19 cytolytic monoclonal antibody for B-cell depletion in autoimmune conditions. Currently approved only for neuromyelitis optica spectrum disorder (NMOSD).

Brand Names

Uplizna 3 Vial Kit

Generic Name

Inebilizumab

DrugBank Accession Number

DB12530

Background

Inappropriate growth of or self-directed antibody production by B-cells is the etiological underpinning of a variety of conditions, including the multiple sclerosis-like neurological condition neuromyelitis optica spectrum disorder (NMOSD).^2,3 Inebilizumab is a humanized afucosylated monoclonal IgG1 antibody directed against the broadly expressed B-cell surface antigen CD19. Inebilizumab is cytolytic, resulting in B-cell depletion and offering therapeutic benefit to patients suffering from NMOSD. Compared to the anti-CD20 antibody rituximab, which is also used to treat NMOSD, inebilizumab has broader specificity.^1,4,5,6,7,8

Inebilizumab was granted FDA approval on June 11, 2020, for the treatment of anti-aquaporin 4 positive NMOSD patients.⁹ Given its mechanism of action and good safety profile, it may prove useful in the treatment of other conditions linked to autoimmune antibody production or B-cell malignancies.^1,6

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Chemical Formula

Not Available

Protein Average Weight

149000.0 Da (approximate)

Sequences

Not Available

Synonyms

• Inebilizumab
• inebilizumab-cdon

External IDs

• MEDI 551
• MEDI-551
• MEDI551

Pharmacology

Indication

Inebilizumab is indicated for the treatment of aquaporin-4 (AQP4) immunoglobulin-positive (AQP4-IgG) neuromyelitis optica spectrum disorder (NMOSD) in adult patients.⁹

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Associated Conditions

• Neuromyelitis Optica Spectrum Disorders

Contraindications & Blackbox Warnings

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Pharmacodynamics

Inebilizumab is a CD19-directed monoclonal antibody that results in immunosuppression through B-cell depletion with sufficient efficacy to allow a six-month dosing schedule.^1,4,5,9 Due to this mechanism of action, patients undergoing inebilizumab treatment may be at higher risk of infections and should be monitored for active infections and immunoglobulin levels while undergoing treatment; vaccination is not recommended during inebilizumab treatment. Also, there is a risk of severe infusion reactions. Animal data suggests the possibility of fetal harm with inebilizumab and therefore, effective contraception during and for six months following inebilizumab treatment is recommended.⁹

Mechanism of action

Neuromyelitis optica spectrum disorder (NMOSD), formerly referred to as Devic's disease, is an antibody-mediated autoimmune condition resulting in astroglial cell death, demyelination, and central nervous system (CNS) inflammation.^2,3 The presence of anti-aquaporin 4 immunoglobulin (AQP4-IgG) is the most frequent biomarker, although AQP4-IgG negative, anti-myelin oligodendrocyte glycoprotein (anti-MOG) positive, variants with similar presentation also exist.^2,3 The theoretical origin of symptoms is through AQP4-IgG-mediated astrocyte cytotoxicity and subsequent infiltration of neutrophils, eosinophils, and macrophages, leading to inflammatory-mediated oligodendrocyte damage and myelin sheath loss.³ In general, this manifests as optic neuritis and transverse myelitis with occasional involvement of the diencephalic, brainstem, and cerebral hemisphere.⁶

CD19 is a B-cell surface antigen expressed on most B-cells,¹ including the expanded population of CD27^high CD38^high CD180^- CD19⁺ plasmablasts that are the origin of astrocytic AQP4-IgG in most NMOSD patients.^2,3 Inebilizumab binds to CD19 and, through one of several potential mechanisms, results in cell death.^1,4,5,9 Destruction of the specific AQP4-IgG-producing plasmablasts results in lower amounts of AQP4-IgG in the CNS and therefore slows neuronal damage and improves patient outcomes.⁶

Target	Actions	Organism
AB-lymphocyte antigen CD19	binder	Humans

Absorption

Inebilizumab is given intravenously and hence is immediately exposed to the systemic circulation. The mean reported C_max following second dose 300 mg administration was 108 μg/mL, and the cumulative AUC following 26 weeks of treatment with two IV administrations was 2980 μg*d/mL.⁹

In a clinical trial investigating the use of inebilizumab in relapsing multiple sclerosis, the mean C_max corresponding to 30, 100, and 600 mg of inebilizumab was 17.9, 43.1, and 248.0 μg/mL and the AUC_0-∞ was 440, 1150, and 6950 μg*d/mL.⁷ In another trial for patients with systemic sclerosis, the mean C_max varied between 2.7 and 227.0 μg/mL and the AUC_0-∞ varied between 16.1 and 2890.0 μg*d/mL for doses between 0.1 and 10.0 mg/kg.⁸

Volume of distribution

Inebilizumab has an estimated central volume of distribution of 2.95L and a peripheral volume of distribution of 2.57L.⁹ The steady-state volume of distribution in patients administered with a range of doses between 0.1 and 10.0 mg/kg ranged from 53.7 to 71.7 mL/kg.⁸

Protein binding

Not Available

Metabolism

Inebilizumab is a monoclonal antibody and is hence likely degraded through proteolysis.⁹

Route of elimination

Not Available

Half-life

Inebilizumab exhibits biphasic pharmacokinetics with a mean terminal half-life of 18 days.⁹ The terminal half-life reported in phase I studies varied by dose but was typically close to 18 days, with a range of 6.8 to 18.7 days.^7,8

Clearance

Inebilizumab has an estimated systemic clearance of 0.19 L/day.⁹ In phase I studies, the reported clearance varied between 139-180 mL/day in one study,⁷ and 3.5-6.2 mL/kg/day in another,⁸ depending on the dose.

Adverse Effects

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Toxicity

Toxicity information regarding inebilizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as severe infusion reactions, infections, and arthralgia. Symptomatic and supportive measures are recommended.

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abatacept	The risk or severity of infection can be increased when Abatacept is combined with Inebilizumab.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Inebilizumab.
Adalimumab	The risk or severity of infection can be increased when Adalimumab is combined with Inebilizumab.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Inebilizumab.
Aducanumab	The risk or severity of adverse effects can be increased when Aducanumab is combined with Inebilizumab.
Alclometasone	The risk or severity of infection can be increased when Alclometasone is combined with Inebilizumab.
Aldesleukin	The risk or severity of infection can be increased when Aldesleukin is combined with Inebilizumab.
Alefacept	The risk or severity of infection can be increased when Alefacept is combined with Inebilizumab.
Alemtuzumab	The risk or severity of infection can be increased when Alemtuzumab is combined with Inebilizumab.
Alirocumab	The risk or severity of adverse effects can be increased when Alirocumab is combined with Inebilizumab.

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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
Uplizna	Injection	10 mg/1mL	Intravenous	Horizon Therapeutics USA, Inc.	2020-06-11	Not applicable
Uplizna	Injection	10 mg/1mL	Intravenous	Viela Bio, Inc.	2020-06-11	Not applicable
Uplizna	Injection, solution, concentrate	100 mg	Intravenous	Horizon Therapeutics Ireland Dac	2022-05-24	Not applicable

Categories

ATC Codes

L04AA47 — Inebilizumab

• L04AA — Selective immunosuppressants
• L04A — IMMUNOSUPPRESSANTS
• L04 — IMMUNOSUPPRESSANTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amino Acids, Peptides, and Proteins
• Antibodies
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic and Immunomodulating Agents
• Blood Proteins
• CD19 Directed Cytolytic Antibodies
• CD19-directed Cytolytic Antibody
• Globulins
• Immunoglobulins
• Immunoproteins
• Immunosuppressive Agents
• Proteins
• Selective Immunosuppressants
• Serum Globulins

Chemical TaxonomyProvided by Classyfire

Description

Not Available

Kingdom

Organic Compounds

Super Class

Organic Acids

Class

Carboxylic Acids and Derivatives

Sub Class

Amino Acids, Peptides, and Analogues

Direct Parent

Peptides

Alternative Parents

Not Available

Substituents

Not Available

Molecular Framework

Not Available

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

74T7185BMM

CAS number

1299440-37-1

References

Synthesis Reference

Herbst R, Wang Y, Gallagher S, Mittereder N, Kuta E, Damschroder M, Woods R, Rowe DC, Cheng L, Cook K, Evans K, Sims GP, Pfarr DS, Bowen MA, Dall'Acqua W, Shlomchik M, Tedder TF, Kiener P, Jallal B, Wu H, Coyle AJ: B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther. 2010 Oct;335(1):213-22. doi: 10.1124/jpet.110.168062. Epub 2010 Jul 6.

General References

1. Herbst R, Wang Y, Gallagher S, Mittereder N, Kuta E, Damschroder M, Woods R, Rowe DC, Cheng L, Cook K, Evans K, Sims GP, Pfarr DS, Bowen MA, Dall'Acqua W, Shlomchik M, Tedder TF, Kiener P, Jallal B, Wu H, Coyle AJ: B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther. 2010 Oct;335(1):213-22. doi: 10.1124/jpet.110.168062. Epub 2010 Jul 6. [Article]
2. Weinshenker BG, Wingerchuk DM: Neuromyelitis Spectrum Disorders. Mayo Clin Proc. 2017 Apr;92(4):663-679. doi: 10.1016/j.mayocp.2016.12.014. [Article]
3. Wu Y, Zhong L, Geng J: Neuromyelitis optica spectrum disorder: Pathogenesis, treatment, and experimental models. Mult Scler Relat Disord. 2019 Jan;27:412-418. doi: 10.1016/j.msard.2018.12.002. Epub 2018 Dec 3. [Article]
4. Gallagher S, Turman S, Yusuf I, Akhgar A, Wu Y, Roskos LK, Herbst R, Wang Y: Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice. Int Immunopharmacol. 2016 Jul;36:205-212. doi: 10.1016/j.intimp.2016.04.035. Epub 2016 May 7. [Article]
5. Gallagher S, Yusuf I, McCaughtry TM, Turman S, Sun H, Kolbeck R, Herbst R, Wang Y: MEDI-551 Treatment Effectively Depletes B Cells and Reduces Serum Titers of Autoantibodies in Mice Transgenic for Sle1 and Human CD19. Arthritis Rheumatol. 2016 Apr;68(4):965-76. doi: 10.1002/art.39503. [Article]
6. Cree BAC, Bennett JL, Kim HJ, Weinshenker BG, Pittock SJ, Wingerchuk DM, Fujihara K, Paul F, Cutter GR, Marignier R, Green AJ, Aktas O, Hartung HP, Lublin FD, Drappa J, Barron G, Madani S, Ratchford JN, She D, Cimbora D, Katz E: Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019 Oct 12;394(10206):1352-1363. doi: 10.1016/S0140-6736(19)31817-3. Epub 2019 Sep 5. [Article]
7. Agius MA, Klodowska-Duda G, Maciejowski M, Potemkowski A, Li J, Patra K, Wesley J, Madani S, Barron G, Katz E, Flor A: Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study. Mult Scler. 2019 Feb;25(2):235-245. doi: 10.1177/1352458517740641. Epub 2017 Nov 16. [Article]
8. Schiopu E, Chatterjee S, Hsu V, Flor A, Cimbora D, Patra K, Yao W, Li J, Streicher K, McKeever K, White B, Katz E, Drappa J, Sweeny S, Herbst R: Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study. Arthritis Res Ther. 2016 Jun 7;18(1):131. doi: 10.1186/s13075-016-1021-2. [Article]
9. FDA Approved Drug Products: Uplizna (inebilizumab-cdon) injection [Link]

External Links

PubChem Substance

347911342

RxNav

2373951

Wikipedia

Inebilizumab

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Immunoglobulin G4 Related Sclerosing Disease	1
3	Recruiting	Treatment	Myasthenia Gravis	1
3	Recruiting	Treatment	Systemic Sclerosis (SSc)	1
2	Completed	Treatment	Chronic Lymphocytic Leukemia	1
2	Completed	Treatment	Diffuse Large B-Cell Lymphoma (DLBCL)	1
2	Recruiting	Treatment	Auto-immune Encephalitis / Encephalitis	1
2	Recruiting	Treatment	Neuromyelitis Optica Spectrum Disorders	1
2	Terminated	Treatment	Multiple Myeloma (MM)	1
2	Withdrawn	Prevention	Highly Sensitized Patients on Waiting List for Kidney Transplantation	1
2, 3	Completed	Treatment	Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders (NMO/NMOSD)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	10 mg/1mL
Injection, solution, concentrate	Intravenous	100 mg

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Not Available

Targets

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Details1. B-lymphocyte antigen CD19

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Binder

Curator comments

Inebilizumab is an anti-CD19 antibody. Binding to CD19 results in B-cell cytotoxicity and depletion, which alleviates the autoimmune symptoms of NMOSD.

General Function

Receptor signaling protein activity

Specific Function

Assembles with the antigen receptor of B-lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation.

Gene Name

CD19

Uniprot ID

P15391

Uniprot Name

B-lymphocyte antigen CD19

Molecular Weight

61127.985 Da

References

1. Herbst R, Wang Y, Gallagher S, Mittereder N, Kuta E, Damschroder M, Woods R, Rowe DC, Cheng L, Cook K, Evans K, Sims GP, Pfarr DS, Bowen MA, Dall'Acqua W, Shlomchik M, Tedder TF, Kiener P, Jallal B, Wu H, Coyle AJ: B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther. 2010 Oct;335(1):213-22. doi: 10.1124/jpet.110.168062. Epub 2010 Jul 6. [Article]
2. Gallagher S, Turman S, Yusuf I, Akhgar A, Wu Y, Roskos LK, Herbst R, Wang Y: Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice. Int Immunopharmacol. 2016 Jul;36:205-212. doi: 10.1016/j.intimp.2016.04.035. Epub 2016 May 7. [Article]
3. Gallagher S, Yusuf I, McCaughtry TM, Turman S, Sun H, Kolbeck R, Herbst R, Wang Y: MEDI-551 Treatment Effectively Depletes B Cells and Reduces Serum Titers of Autoantibodies in Mice Transgenic for Sle1 and Human CD19. Arthritis Rheumatol. 2016 Apr;68(4):965-76. doi: 10.1002/art.39503. [Article]
4. FDA Approved Drug Products: Uplizna (inebilizumab-cdon) injection [Link]

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Drug created at October 20, 2016 22:44 / Updated at August 05, 2021 01:52