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

>SUBUNIT_1
EVQLVQSGAEVKKPGESLKISCKGSGYIFTNYWIAWVRQMPGKGLESMGIIYPGDSDIRY
SPSFQGQVTISADKSITTAYLQWSSLKASDTAMYYCARHDIEGFDYWGRGTLVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK

>SUBUNIT_2
EVQLVQSGAEVKKPGESLKISCKGSGYIFTNYWIAWVRQMPGKGLESMGIIYPGDSDIRY
SPSFQGQVTISADKSITTAYLQWSSLKASDTAMYYCARHDIEGFDYWGRGTLVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK

>SUBUNIT_3
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFFAWYQQKPGQAPRLLIYGASSRATGIP
DRLSGSGSGTDFTLTITRLEPEDFAVYYCQQYDSSAITFGQGTRLEIKRTVAAPSVFIFP
PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

>SUBUNIT_4
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFFAWYQQKPGQAPRLLIYGASSRATGIP
DRLSGSGSGTDFTLTITRLEPEDFAVYYCQQYDSSAITFGQGTRLEIKRTVAAPSVFIFP
PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

NIH Inxight: Anifrolumab [Link]

Download FASTA Format

Synonyms

Anifrolumab
anifrolumab-fnia

External IDs

MEDI 546
MEDI-546

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Pharmacology

Indication

Anifrolumab is indicated in the treatment of adults with moderate to severe systemic lupus erythematosus who are receiving standard therapy.¹¹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Moderate systemic lupus erythematosus (sle)		••••••••••••	•••••	•••••••• •••••••	•••••••••
Treatment of	Severe systemic lupus erythematosus (sle)		••••••••••••	•••••	•••••••• •••••••	•••••••••

Contraindications & Blackbox Warnings

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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 counseled regarding the risks of serious infections, hypersensitivity reactions, and malignancies.¹¹

In patients with SLE, following the administration of anifrolumab- at 300 mg dose, via intravenous infusion every 4 weeks for 52 weeks, neutralization (≥80%) of a type I IFN gene signature was observed from Week 4 to Week 52 in blood samples of patients with elevated levels of type I IFN inducible genes and returned to baseline levels within 8 to 12 weeks following withdrawal of anifrolumab at the end of the 52-week treatment period. However, the clinical relevance of the type I IFN gene signature neutralization is unclear.¹²

In SLE patients with positive anti-dsDNA antibodies at baseline (Trials 2 and 3), treatment with anifrolumab 300 mg led to numerical reductions in anti-dsDNA antibodies over time through Week 52.¹²

In patients with low complement levels (C3 and C4), increases in complement levels were observed in patients receiving anifrolumab through Week 52.¹²

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 This binding inhibits type I IFN signaling, thereby blocking the biological activity of type I IFNs. Anifrolumab also induces the internalization of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor-mediated type I IFN signaling inhibits IFN-responsive gene expression as well as downstream inflammatory and immunological processes. Inhibition of type I IFN blocks plasma cell differentiation and normalizes peripheral T-cell subsets.^4,12

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

Target	Actions	Organism
AInterferon alpha/beta receptor 1	inhibitor	Humans

Absorption

The PK of anifrolumab was studied in adult patients with SLE following intravenous doses ranging from 100 to 1000 mg once every 4 weeks, and healthy volunteers following a single intravenous dose at 300 mg. Anifrolumab exhibits non-linear PK in the dose range of 100 mg to 1000 mg with more than dose-proportional increases in the exposure as measured by AUC. Following the 300 mg every 4 weeks intravenous administrations of anifrolumab, a steady state was reached by Day 85. The accumulation ratio was approximately 1.36 for C_max and 2.49 for C_trough.¹²

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

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

Volume of distribution

Based on population PK analysis, the estimated volume of distribution at steady state for a typical patient with SLE (69.1 kg) is 6.23 L.¹²

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

Following the administration of anifrolumab at a dose of 300 mg via intravenous infusion every 4 weeks, the estimated systemic clearance (CL) for anifrolumab was 0.193 L/day.¹²

Adverse Effects

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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.

Drug	Interaction
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Abatacept	The risk or severity of adverse effects can be increased when Abatacept is combined with Anifrolumab.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Anifrolumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Anifrolumab.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Anifrolumab.
Aducanumab	The risk or severity of adverse effects can be increased when Anifrolumab is combined with Aducanumab.

Food Interactions

No interactions found.

Products

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International/Other Brands

Saphnelo (AstraZeneca)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Saphnelo	Injection, solution	300 mg/2.0mL	Intravenous	AstraZeneca Pharmaceuticals LP	2021-07-30	Not applicable
Saphnelo	Injection, solution, concentrate	300 mg	Intravenous	Astra Zeneca Ab	2022-05-04	Not applicable
Saphnelo	Solution	150 mg / mL	Intravenous	Astra Zeneca	2022-03-01	Not applicable

Chemical Identifiers

UNII: 38RL9AE51Q
CAS number: 1326232-46-5

References

General References

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]
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]
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]
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]
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]
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]
Bui A, Sanghavi D: Anifrolumab . [Article]
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]
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]
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]
FDA Approved Drug Products: Saphnelo (Anifrolumab-fnia) Intravenous Injection [Link]
FDA Approved Drug Products: SAPHNELO (anifrolumab-fnia) injection, for intravenous use (Dec 2023) [Link]

External Links

PubChem Substance: 347911264
RxNav: 2565265
Wikipedia: Anifrolumab

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Active Systemic Lupus Erythematosus	1
3	Completed	Treatment	Active Systemic Lupus Erythematosus	3
3	Not Yet Recruiting	Treatment	Cutaneous Lupus Erythematosus (CLE)	1
3	Not Yet Recruiting	Treatment	Systemic Lupus Erythematosus	1
3	Recruiting	Treatment	Lupus Nephritis	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Intravenous	300 mg/2.0mL
Injection, solution, concentrate	Intravenous	300 mg
Solution	Intravenous	150 mg / mL
Solution	Intravenous	300.00 mg

Prices

Not Available

Patents

Not Available

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. Interferon alpha/beta receptor 1

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

FDA Approved Drug Products: Saphnelo (Anifrolumab-fnia) Intravenous Injection [Link]

Drug created at October 20, 2016 21:07 / Updated at December 22, 2023 19:51

Anifrolumab

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References