Sarilumab

Identification

Summary

Sarilumab is a monoclonal antibody used to treat moderate to severe rheumatoid arthritis who have responded poorly or are intolerant of other DMARDs.

Brand Names

Kevzara

Generic Name

Sarilumab

DrugBank Accession Number

DB11767

Background

Sarilumab is a fully human anti-IL-6R monoclonal IgG1 antibody that binds to both membrane bound and soluble interleukin 6 (IL-6) receptor forms, thus blocking the cis- and trans-inflammatory signalling cascades of IL-6 ¹. Sarilumab was developped by Sanofi and Regeneron Pharmaceuticals, Inc; it was US FDA-approved in May 2017 and followed by EU approval in June 2017 for the treatment of moderate to severe Rheumatoid Arthritis (RA) in combination with methotrexate ⁴. RA is a chronic inflammatory disease characterized by polyarthritis and its treatment has been challenged by the different response in every patient ³. Subcutaneous administration of Sarilumab has been shown to decrease acute-phase reactant levels and improve in clinical RA symptoms ².

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Structure

Protein Chemical Formula

C₆₃₈₈H₉₉₁₈N₁₇₁₈O₁₉₉₈S₄₄

Protein Average Weight

150000.0 Da (143900 Da in absence of N-glycosylation in heavy chains (Asn296))

Sequences

> Heavy chain
EVQLVESGGGLVQPGRSLRLSCAASRFTFDDYAMHWVRQAPGKGLEWVSGISWNSGRIGY
ADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYCAKGRDSFDIWGQGTMVTVSSASTK
GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF
LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK

>Light chain
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLESGVPS
RFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Download FASTA Format

Synonyms

• REGN88
• SAR153191
• Sarilumab

Pharmacology

Indication

Indicated for modere to severe reactive RA in adult patients who are irresponsive, respond inadequately or present intolerance to disease-modifying anti-rheumatic drugs (DMARDs) or tumor necrosis factor (TNF) antagonists. It is indicated to be used in combination with methotrexate (MTX) or as a monotherapy when there is intolerance to MTX or MTX administration is inappropriate.

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Associated Conditions

• Moderate, active Rheumatoid arthritis
• Severe, active Rheumatoid arthritis

Contraindications & Blackbox Warnings

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Pharmacodynamics

Single-dose subcutaneous administration of Sarilumab produced a rapid reduction of CRP levels, leading to normal levels after two weeks of treatment. Peak reduction in the absolute neutrophile count was observed after 3 to 4 days of treatment followed by a recovery to baseline levels. It is observed a decrease in fibrinogen and serum amyloid A as well as an increase in hemoglobin and serum albumin.

Mechanism of action

Sarilumab is a human recombinant IgG1 antibody that binds to both forms of interleukin 6 receptors (IL-6R), thus inhibiting the IL-6-mediated signaling. IL-6 is known to be a pleiotropic cytokine that activates immune cells (T and B cells), as well as hepatocytes for the release of acute phase proteins like CRP, serum amyloid A and fibrinogen which are biomarkers of RA activity. IL-6 is also found in synovial fluid and plays a major role in the pathological inflammation and joint destruction features of RA. Thus, it is used for the treatment of RA due to its ability to inhibit intra-articular and systemic IL-6 signaling ^5,6.

Target	Actions	Organism
AInterleukin-6 receptor subunit alpha	antagonist antibody	Humans
UHigh affinity immunoglobulin gamma Fc receptor I	unknown	Humans
ULow affinity immunoglobulin gamma Fc region receptor II-a	unknown	Humans
ULow affinity immunoglobulin gamma Fc region receptor II-b	unknown	Humans
ULow affinity immunoglobulin gamma Fc region receptor III-A	unknown	Humans
ULow affinity immunoglobulin gamma Fc region receptor III-B	unknown	Humans

Absorption

Sarilumab is shown to be well absorbed in RA patients after single SC administration with a maximum of serum concentration presented after 2 to 4 days. For the 150 mg every two weeks dose regimen, the AUC, Cmin and Cmax of sarilumab were 202 ± 120 mg.day/L, 6.35 ± 7.54 mg/L, and 20.0 ± 9.20 mg/L, respectively. For the 200 mg every two weeks dose regimen, the AUC, Cmin and Cmax of sarilumab were 395 ± 207 mg.day/L, 16.5 ± 14.1 mg/L, and 35.6 ± 15.2 mg/L, respectively ⁶.

Volume of distribution

In patients with RA, the apparent volume of distribution at steady state was 7.3 L ⁶.

Protein binding

Sarilumab is a covalent heterotetramer composed by two disulfide linked heavy chains covelently linked to a kappa light chain. The heavy chain has a IgG1 constant region with a single N-linked glycosylation site in the Fc portion of the molecule. ⁶ The complimentarity-determining regions (CDRs) within variable domains of both light and heavy chains combine to form the binding site for IL-6R. As Sarilumab is an IgG1 molecule, it presents Fc-effector function and it is prompt to bind to FcγRI, FcγRIIa, FCγRIIb, FcγRIIIa and FcγRIIIB. However, it does not induce Antibody-Dependant Cell-mediated Cytotoxicity (ADCC) or Complement-Dependant Cytotoxicity (CDC) ⁵.

Metabolism

The metabolism of Sarilumab has not been characterized. As it is a monoclonal antibody, It is thought to be degraded into small peptides and amino acids [FDA file].

Route of elimination

At high concentrations, Sarilumab is thought to be eliminated predominantly through a non-saturated proteolytic pathway, while at lower concentrations, the elimination will be done by saturable target-mediated elimination ¹.

Half-life

The half life will depend on the administered concentration. At 200 mg every 2 weeks, half-life is up to 10 days in patients with RA at steady state. At 150 mg every 2 weeks, half-life is up to 8 days in patients with RA at steady state. After the last steady state dose of 150 mg and 200 mg, the time to reach nondetectable concentration is 28 and 43 days, respectively ⁵.

Clearance

Sarilumab is not eliminated via renal or hepatic pathways. RA patients have shown a trend toward higher clearance in presence of anti-sarilumab antibodies [FDA file].

Adverse Effects

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Toxicity

Repeat dose exposure has been shown to produce a partially reversible decrease in neutophil count and a reversible decrease in fibrinogen ⁵.

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 adverse effects can be increased when Abatacept is combined with Sarilumab.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Sarilumab.
Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Sarilumab.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Sarilumab.
Acenocoumarol	The serum concentration of Acenocoumarol can be increased when it is combined with Sarilumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Sarilumab.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Sarilumab.
Aducanumab	The risk or severity of adverse effects can be increased when Sarilumab is combined with Aducanumab.
Albendazole	The metabolism of Albendazole can be increased when combined with Sarilumab.
Aldesleukin	The risk or severity of adverse effects can be increased when Aldesleukin is combined with Sarilumab.

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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
Kevzara	Solution	150 mg / 1.14 mL	Subcutaneous	Sanofi Aventis	2017-03-29	Not applicable
Kevzara	Injection, solution	200 mg	Subcutaneous	Sanofi Aventis Groupe	2020-12-16	Not applicable
Kevzara	Injection, solution	150 mg/1.14mL	Subcutaneous	sanofi-aventis U.S. LLC	2017-05-22	Not applicable
Kevzara	Injection, solution	200 mg	Subcutaneous	Sanofi Aventis Groupe	2020-12-16	Not applicable
Kevzara	Injection, solution	200 mg	Subcutaneous	Sanofi Aventis Groupe	2020-12-16	Not applicable
Kevzara	Solution	150 mg / 1.14 mL	Subcutaneous	Sanofi Aventis	2018-06-21	Not applicable
Kevzara	Injection, solution	200 mg	Subcutaneous	Sanofi Aventis Groupe	2020-12-16	Not applicable
Kevzara	Injection, solution	150 mg	Subcutaneous	Sanofi Aventis Groupe	2020-12-16	Not applicable
Kevzara	Injection, solution	200 mg/1.14mL	Subcutaneous	sanofi-aventis U.S. LLC	2017-05-22	Not applicable
Kevzara	Injection, solution	150 mg	Subcutaneous	Sanofi Aventis Groupe	2020-12-16	Not applicable

Categories

ATC Codes

L04AC14 — Sarilumab

• L04AC — Interleukin inhibitors
• L04A — IMMUNOSUPPRESSANTS
• L04 — IMMUNOSUPPRESSANTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amino Acids, Peptides, and Proteins
• Antibodies
• Antibodies, Monoclonal
• Antineoplastic and Immunomodulating Agents
• Antirheumatic Agents
• Biologics for Rheumatoid Arthritis Treatment
• Blood Proteins
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (weak)
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (weak)
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Disease-modifying Antirheumatic Agents
• Globulins
• Immunoglobulins
• Immunoproteins
• Immunosuppressive Agents
• Immunotherapy
• Interleukin Inhibitors
• Interleukin-6 Receptor Antagonist
• Proteins
• 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

NU90V55F8I

CAS number

1189541-98-7

References

General References

1. Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, Huang X, Yancopoulos GD, Stahl N, Genovese MC: Sarilumab, a fully human monoclonal antibody against IL-6Ralpha in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014 Sep;73(9):1626-34. doi: 10.1136/annrheumdis-2013-204405. Epub 2013 Dec 2. [Article]
2. Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, Martincova R, Fiore S, Rohane P, van Hoogstraten H, Garg A, Fan C, van Adelsberg J, Weinstein SP, Graham NM, Stahl N, Yancopoulos GD, Huizinga TW, van der Heijde D: Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. Arthritis Rheumatol. 2015 Jun;67(6):1424-37. doi: 10.1002/art.39093. [Article]
3. Cooper S: Sarilumab for the treatment of rheumatoid arthritis. Immunotherapy. 2016;8(3):249-50. doi: 10.2217/imt.15.127. Epub 2016 Feb 9. [Article]
4. Kaufman MB: Pharmaceutical Approval Update. P T. 2017 Sep;42(9):562-580. [Article]
5. ema.europa [Link]
6. Kevzara product monograph [Link]

External Links

PubChem Substance

347911238

RxNav

1923319

Wikipedia

Sarilumab

FDA label

Download (1.31 MB)

MSDS

Download (90.8 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Rheumatoid Arthritis	1
4	Not Yet Recruiting	Treatment	Atherosclerosis / Rheumatoid Arthritis	1
4	Recruiting	Treatment	Community-acquired Pneumonia, Influenza, COVID-19 / Coronavirus Disease 2019 (COVID‑19)	1
3	Active Not Recruiting	Treatment	Rheumatoid Arthritis	2
3	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19) / Infections, Coronavirus	1
3	Completed	Treatment	Rheumatoid Arthritis	8
3	Terminated	Treatment	Giant Cell Arteritis (GCA)	1
3	Terminated	Treatment	Polymyalgia Rheumatica (PMR)	1
3	Terminated	Treatment	Rheumatoid Arthritis	1
2	Active Not Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19) / COVID	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Parenteral; Subcutaneous	150 MG
Injection, solution	Parenteral; Subcutaneous	200 MG
Injection, solution	Subcutaneous	150 mg/1.14mL
Injection, solution	Subcutaneous	150 mg
Injection, solution	Subcutaneous	200 mg/1.14mL
Injection, solution	Subcutaneous	200 mg
Solution	Subcutaneous	150 mg / 1.14 mL
Solution	Subcutaneous	200 mg / 1.14 mL

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	69 °C (midpoint transition), 80 °C (whole IgG1)	Dashivets, et al. PLOS ONE. 10. e0143520. 10.1371/journal.pone.0143520. (2015).
isoelectric point	6.6 - 7.2	Jin, et al. Electrophoresis. Sep;23(19):3385-91. (2002).

Targets

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insights and accelerate drug research.

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Details1. Interleukin-6 receptor subunit alpha

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

Antibody

General Function

Protein homodimerization activity

Specific Function

Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with IL6ST. Activation may lead to the regulati...

Gene Name

IL6R

Uniprot ID

P08887

Uniprot Name

Interleukin-6 receptor subunit alpha

Molecular Weight

51547.015 Da

References

1. Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, Huang X, Yancopoulos GD, Stahl N, Genovese MC: Sarilumab, a fully human monoclonal antibody against IL-6Ralpha in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014 Sep;73(9):1626-34. doi: 10.1136/annrheumdis-2013-204405. Epub 2013 Dec 2. [Article]
2. June RR, Olsen NJ: Room for more IL-6 blockade? Sarilumab for the treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2016 Oct;16(10):1303-9. doi: 10.1080/14712598.2016.1217988. Epub 2016 Aug 8. [Article]
3. Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, Nam J, Ramiro S, Voshaar M, van Vollenhoven R, Aletaha D, Aringer M, Boers M, Buckley CD, Buttgereit F, Bykerk V, Cardiel M, Combe B, Cutolo M, van Eijk-Hustings Y, Emery P, Finckh A, Gabay C, Gomez-Reino J, Gossec L, Gottenberg JE, Hazes JMW, Huizinga T, Jani M, Karateev D, Kouloumas M, Kvien T, Li Z, Mariette X, McInnes I, Mysler E, Nash P, Pavelka K, Poor G, Richez C, van Riel P, Rubbert-Roth A, Saag K, da Silva J, Stamm T, Takeuchi T, Westhovens R, de Wit M, van der Heijde D: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017 Jun;76(6):960-977. doi: 10.1136/annrheumdis-2016-210715. Epub 2017 Mar 6. [Article]
4. Kampan NC, Xiang SD, McNally OM, Stephens AN, Quinn MA, Plebanski M: Immunotherapeutic Interleukin-6 or Interleukin-6 receptor blockade in cancer: challenges and opportunities. Curr Med Chem. 2017 Jul 12. doi: 10.2174/0929867324666170712160621. [Article]
5. Lin P: Targeting interleukin-6 for noninfectious uveitis. Clin Ophthalmol. 2015 Sep 11;9:1697-702. doi: 10.2147/OPTH.S68595. eCollection 2015. [Article]

Details2. High affinity immunoglobulin gamma Fc receptor I

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Unknown

General Function

Receptor signaling protein activity

Specific Function

High affinity receptor for the Fc region of immunoglobulins gamma. Functions in both innate and adaptive immune responses.

Gene Name

FCGR1A

Uniprot ID

P12314

Uniprot Name

High affinity immunoglobulin gamma Fc receptor I

Molecular Weight

42631.525 Da

References

1. ema.europa [Link]

Details3. Low affinity immunoglobulin gamma Fc region receptor II-a

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Unknown

General Function

Not Available

Specific Function

Binds to the Fc region of immunoglobulins gamma. Low affinity receptor. By binding to IgG it initiates cellular responses against pathogens and soluble antigens. Promotes phagocytosis of opsonized ...

Gene Name

FCGR2A

Uniprot ID

P12318

Uniprot Name

Low affinity immunoglobulin gamma Fc region receptor II-a

Molecular Weight

35000.42 Da

References

1. ema.europa [Link]

Details4. Low affinity immunoglobulin gamma Fc region receptor II-b

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Unknown

General Function

Not Available

Specific Function

Receptor for the Fc region of complexed or aggregated immunoglobulins gamma. Low affinity receptor. Involved in a variety of effector and regulatory functions such as phagocytosis of immune complex...

Gene Name

FCGR2B

Uniprot ID

P31994

Uniprot Name

Low affinity immunoglobulin gamma Fc region receptor II-b

Molecular Weight

34043.355 Da

References

1. ema.europa [Link]

Details5. Low affinity immunoglobulin gamma Fc region receptor III-A

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Unknown

General Function

Not Available

Specific Function

Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as...

Gene Name

FCGR3A

Uniprot ID

P08637

Uniprot Name

Low affinity immunoglobulin gamma Fc region receptor III-A

Molecular Weight

29088.895 Da

References

1. ema.europa [Link]

Details6. Low affinity immunoglobulin gamma Fc region receptor III-B

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Unknown

General Function

Not Available

Specific Function

Receptor for the Fc region of immunoglobulins gamma. Low affinity receptor. Binds complexed or aggregated IgG and also monomeric IgG. Contrary to III-A, is not capable to mediate antibody-dependent...

Gene Name

FCGR3B

Uniprot ID

O75015

Uniprot Name

Low affinity immunoglobulin gamma Fc region receptor III-B

Molecular Weight

26215.64 Da

References

1. ema.europa [Link]

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Drug created on October 20, 2016 20:46 / Updated on September 28, 2021 07:54