Anifrolumab

Identification

Summary

Anifrolumab is a monoclonal antibody that inhibits type 1 interferon receptors, indicated in the treatment of moderate to severe systemic lupus erythematosus.

Brand Names
Saphnelo
Generic Name
Anifrolumab
DrugBank Accession Number
DB11976
Background

Anifrolumab, or MEDI-546, is a type 1 interferon receptor (IFNAR) inhibiting IgG1κ monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus.7,11 The standard therapy for systemic lupus erythematosus consists of antimalarials like hydroxychloroquine, glucocorticoids like dexamethasone, and disease modifying antirheumatic drugs like methotrexate.8,11

Three monoclonal antibodies (anifrolumab, rontalizumab, and sifalimumab) that target the type 1 interferon pathway entered clinical trials as potential treatments for systemic lupus erythematosus, but so far only anifrolumab has been approved.3

The design of early clinical trials of anti-interferon treatments such as anifrolumab, rontalizumab, and sifalimumab have come under criticism.3 The design of the clinical trials use different definitions of autoantibody positivity, making comparison between trials difficult; all trials involve large portions of patients also using corticosteroids, which may alter patient responses in the experimental and placebo groups; and patient populations were largely homogenous, which may have increased the odds of success of the trial.3

Anifrolumab has also been investigated for the treatment of Scleroderma.1

Anifrolumab was granted FDA approval on 30 July 2021.11

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
148000.0 Da (Approximate)
Sequences
Not Available
Synonyms
  • Anifrolumab
  • anifrolumab-fnia
External IDs
  • MEDI 546
  • MEDI-546

Pharmacology

Indication

Anifrolumab is indicated in the treatment of adults with moderate to severe systemic lupus erythematosus.11

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Anifrolumab is a type 1 interferon receptor (IFNAR) inhibiting IgG1κ monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus.7,11 It has a long duration of action as it is given every 4 weeks.11 Patients should be counselled regarding the risks of serious infections, hypersensitivity reactions, and malignancies.11

Mechanism of action

Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple systems in the body.4 SLE may manifest as a rash on the skin, and can progress to life-threatening autoimmune reactions in the kidney or nervous system.6

Type 1 interferon pathway activation has been identified as a mediator of pathogenesis in SLE, and the level of type 1 interferon expression is correlated with severity of SLE.4,6,10 Activation of the type 1 interferon receptor (INFAR1) by interferons alpha, beta, epsilon, kappa, and omega lead to stimulation of gene transcription.4 Activation of INFAR1 and INFAR2 lead to phosphorylation of STAT1 and STAT2, which are translocated with interferon regulatory factor 9 (IRF9) to the cell nucleus to activate the interferon-stimulated response element (ISRE).6 Activation of ISRE leads to the expression of many proinflammatory and immunomodulatory proteins, as well as the activation of a positive feedback loop that produces more type 1 interferons.6

Interferon alpha stimulates monocytes to mature into myeloid dendritic cells that express self antigens.10 CD4+ and CD8+ T-cells, as well as B cells, that are autoreactive will respond to the self antigens and induce inflammmation and apoptosis in cells.10 This self-reactive immune response damages otherwise healthy tissue throughout the body.10

Anifrolumab is an immunoglobulin gamma 1 kappa (IgG1κ) monoclonal antibody that selectively binds to subunit 1 of INFAR1.2,11 The binding of anifrolumab to IFNAR1 inhibits the activity of the receptor, decreasing downstream signalling and gene transcription of inflammatory mediators.4,11

The Fc region of anifrolumab carries the triple mutaion L234F/L235E/P331S to prevent binding of the Fc region of the antibody to cell surface Fc receptors.6

In a phase IIb clinical trial, the primary endpoint was reached by 34.3% of patients in the 300 mg treatment group, 28.8% of patients in the 1000 mg treatment group, and 17.6% of patients in the placebo group.4 Patients with higher interferon-stimulated gene transcription at baseline showed a greater response to treatment.4

TargetActionsOrganism
AInterferon alpha/beta receptor 1
inhibitor
Humans
Absorption

A 300 mg intravenous dose reaches a mean Cmax of 82.4 µg/mL, with a Tmax of 0.03 days, and an AUC of 907 day*µg/mL.5

A 300 mg subcutaneous dose reaches a mean Cmax of 36.2 µg/mL, with a Tmax of 4.1 days, and an AUC of 785 day*µg/mL.5 A 600 mg subcutaneous dose reaches a mean Cmax of 63.9 µg/mL, with a Tmax of 7.0 days, and an AUC of 1828 day*µg/mL.5

Volume of distribution

The estimated volume of distribution of anifrolumab at steady state is 6.23 L for a 69.1 kg patient.11

Protein binding

Not Available

Metabolism

Monoclonal antibodies are mainly catabolized to smaller oligopeptides and individual amino acids.9,11

Route of elimination

Monoclonal IgG is predominantly eliminated by catabolism to individual amino acids that are either recycled in the body or metabolized for energy.9

Half-life

The serum elimination half life anifrolumab in a phase 1 trial in patients with scleroderma was 0.84 days for a 0.1 mg/kg single dose, 1.24 days for a 0.3 mg/kg single dose, 2.96 days for a 1.0 mg/kg single dose, 4.07 days for a 3.0 mg/kg single dose, and 7.70 days for a 10.0 mg/kg single dose.1

Clearance

The estimated systemic clearance of anifrolumab is 0.193 L/day.11

Adverse Effects
Adverseeffects
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Toxicity

Data regarding overdose is not readily available.11 In a phase 1 clinical trial, patients given a single dose of 20.0 mg/kg experienced upper respiratory tract infections, headache, diarrhea, and nausea.1 2 patients in the 3.0 mg/kg single dose group experienced osteomyelitis and skin ulcer.1 A single patient in the 1.0 mg/kg/week group developed chronic myelogenous leukemia.1 The frequency and severity of adverse effects does not appear to be closely related to dose.1 In the event of an overdose, treat patients with symptomatic and supportive measures.

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
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Anifrolumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Anifrolumab.
AducanumabThe risk or severity of adverse effects can be increased when Anifrolumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Anifrolumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Anifrolumab.
AmivantamabThe risk or severity of adverse effects can be increased when Anifrolumab is combined with Amivantamab.
AnsuvimabThe risk or severity of adverse effects can be increased when Anifrolumab is combined with Ansuvimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Anifrolumab.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Anifrolumab.
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Anifrolumab.
Interactions
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Food Interactions
No interactions found.

Products

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International/Other Brands
Saphnelo (AstraZeneca)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SaphneloInjection, solution300 mg/2.0mLIntravenousAstraZeneca Pharmaceuticals LP2021-07-30Not 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
Affected organisms
  • Humans

Chemical Identifiers

UNII
38RL9AE51Q
CAS number
1326232-46-5

References

General References
  1. Goldberg A, Geppert T, Schiopu E, Frech T, Hsu V, Simms RW, Peng SL, Yao Y, Elgeioushi N, Chang L, Wang B, Yoo S: Dose-escalation of human anti-interferon-alpha receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study. Arthritis Res Ther. 2014 Feb 24;16(1):R57. doi: 10.1186/ar4492. [Article]
  2. Peng L, Oganesyan V, Wu H, Dall'Acqua WF, Damschroder MM: Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-alpha receptor 1 antibody. MAbs. 2015;7(2):428-39. doi: 10.1080/19420862.2015.1007810. [Article]
  3. Massarotti EM, Allore HG, Costenbader K: Editorial: Interferon-Targeted Therapy for Systemic Lupus Erythematosus: Are the Trials on Target? Arthritis Rheumatol. 2017 Feb;69(2):245-248. doi: 10.1002/art.39985. [Article]
  4. Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, Illei GG, Drappa J, Wang L, Yoo S: Anifrolumab, an Anti-Interferon-alpha Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376-386. doi: 10.1002/art.39962. [Article]
  5. Tummala R, Rouse T, Berglind A, Santiago L: Safety, tolerability and pharmacokinetics of subcutaneous and intravenous anifrolumab in healthy volunteers. Lupus Sci Med. 2018 Mar 23;5(1):e000252. doi: 10.1136/lupus-2017-000252. eCollection 2018. [Article]
  6. Riggs JM, Hanna RN, Rajan B, Zerrouki K, Karnell JL, Sagar D, Vainshtein I, Farmer E, Rosenthal K, Morehouse C, de Los Reyes M, Schifferli K, Liang M, Sanjuan MA, Sims GP, Kolbeck R: Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus. Lupus Sci Med. 2018 Apr 5;5(1):e000261. doi: 10.1136/lupus-2018-000261. eCollection 2018. [Article]
  7. Bui A, Sanghavi D: Anifrolumab . [Article]
  8. Trindade VC, Carneiro-Sampaio M, Bonfa E, Silva CA: An Update on the Management of Childhood-Onset Systemic Lupus Erythematosus. Paediatr Drugs. 2021 Jul;23(4):331-347. doi: 10.1007/s40272-021-00457-z. Epub 2021 Jul 10. [Article]
  9. 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]
  10. Koh JWH, Ng CH, Tay SH: Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials. Lupus. 2020 Dec;29(14):1845-1853. doi: 10.1177/0961203320959702. Epub 2020 Sep 22. [Article]
  11. FDA Approved Drug Products: Saphnelo (Anifrolumab-fnia) Intravenous Injection [Link]
PubChem Substance
347911264
RxNav
2565265
Wikipedia
Anifrolumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentActive Systemic Lupus Erythematosus1
3CompletedTreatmentActive Systemic Lupus Erythematosus2
3RecruitingTreatmentActive Systemic Lupus Erythematosus1
3RecruitingTreatmentSystemic Lupus Erythematosus (SLE)1
2CompletedTreatmentLupus Nephritis1
2CompletedTreatmentSystemic Lupus Erythematosus (SLE)4
2RecruitingTreatmentRheumatoid Arthritis1
1CompletedBasic ScienceHealthy Subjects (HS) / Pharmacokinetics / Safety1
1CompletedTreatmentScleroderma1
1RecruitingTreatmentSystemic Lupus Erythematosus (SLE)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous300 mg/2.0mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Type i interferon receptor activity
Specific Function
Associates with IFNAR2 to form the type I interferon receptor. Receptor for interferons alpha and beta. Binding to type I IFNs triggers tyrosine phosphorylation of a number of proteins including JA...
Gene Name
IFNAR1
Uniprot ID
P17181
Uniprot Name
Interferon alpha/beta receptor 1
Molecular Weight
63524.81 Da
References
  1. FDA Approved Drug Products: Saphnelo (Anifrolumab-fnia) Intravenous Injection [Link]

Drug created on October 20, 2016 21:07 / Updated on October 02, 2021 21:28