Inebilizumab

Identification

Name
Inebilizumab
Accession Number
DB12530
Description

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

Pharmacology
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Indication

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

Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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 CD27high CD38high 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

TargetActionsOrganism
AB-lymphocyte antigen CD19
binder
Humans
Absorption

Inebilizumab is given intravenously and hence is immediately exposed to the systemic circulation. The mean reported Cmax 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 Cmax corresponding to 30, 100, and 600 mg of inebilizumab was 17.9, 43.1, and 248.0 μg/mL and the AUC0-∞ was 440, 1150, and 6950 μg*d/mL.7 In another trial for patients with systemic sclerosis, the mean Cmax varied between 2.7 and 227.0 μg/mL and the AUC0-∞ 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.

Affected organisms
  • Humans and other mammals
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.
DrugInteraction
AbataceptThe risk or severity of infection can be increased when Abatacept is combined with Inebilizumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Inebilizumab.
AdalimumabThe risk or severity of infection can be increased when Adalimumab is combined with Inebilizumab.
AlclometasoneThe risk or severity of infection can be increased when Alclometasone is combined with Inebilizumab.
AldesleukinThe risk or severity of infection can be increased when Aldesleukin is combined with Inebilizumab.
AlefaceptThe risk or severity of infection can be increased when Alefacept is combined with Inebilizumab.
AlemtuzumabThe risk or severity of infection can be increased when Alemtuzumab is combined with Inebilizumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Inebilizumab.
AltretamineThe risk or severity of infection can be increased when Altretamine is combined with Inebilizumab.
AmcinonideThe risk or severity of infection can be increased when Amcinonide is combined with Inebilizumab.
Interactions
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Food Interactions
No interactions found.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
UpliznaInjection10 mg/1mLIntravenousViela Bio, Inc.2020-06-11Not applicableUS flag

Categories

Drug Categories
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

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. [PubMed:20605905]
  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. [PubMed:28385199]
  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. [PubMed:30530071]
  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. [PubMed:27163209]
  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. [PubMed:26606525]
  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. [PubMed:31495497]
  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. [PubMed:29143550]
  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. [PubMed:27267753]
  9. FDA Approved Drug Products: Uplizna (inebilizumab-cdon) injection [Link]
PubChem Substance
347911342
RxNav
2373951
Wikipedia
Inebilizumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingPreventionIgG4 Related Disease1
3RecruitingTreatmentMyasthenia Gravis1
2Active Not RecruitingPreventionHighly Sensitized Patients on Waiting List for Kidney Transplantation1
2CompletedTreatmentChronic Lymphocytic Leukaemia (CLL)1
2CompletedTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
2Not Yet RecruitingTreatmentAutoimmune Encephalitis / Inflammation, Brain1
2TerminatedTreatmentMultiple Myeloma (MM)1
2, 3CompletedTreatmentNeuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders1
1CompletedTreatmentAdvanced B Cell Malignancies / Blood Cancers1
1CompletedTreatmentMultiple Sclerosis, Relapsing Forms1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous10 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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. [PubMed:20605905]
  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. [PubMed:27163209]
  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. [PubMed:26606525]
  4. FDA Approved Drug Products: Uplizna (inebilizumab-cdon) injection [Link]

Drug created on October 20, 2016 22:44 / Updated on February 21, 2021 18:53