Identification

Name
Sarilumab
Accession Number
DB11767
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

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].

Protein structure
Db11767
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
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
KevzaraSolution200 mgSubcutaneousSanofi AventisNot applicableNot applicableCanada
KevzaraSolution150 mgSubcutaneousSanofi Aventis2017-03-29Not applicableCanada
KevzaraInjection, solution200 mg/1.14mLSubcutaneousSanofi Aventis2017-05-22Not applicableUs
KevzaraSolution150 mgSubcutaneousSanofi AventisNot applicableNot applicableCanada
KevzaraInjection, solution200 mg/1.14mLSubcutaneousSanofi Aventis2017-05-22Not applicableUs
KevzaraInjection, solution150 mg/1.14mLSubcutaneousSanofi Aventis2017-05-22Not applicableUs
KevzaraSolution200 mgSubcutaneousSanofi Aventis2017-02-08Not applicableCanada
KevzaraInjection, solution150 mg/1.14mLSubcutaneousSanofi Aventis2017-05-22Not applicableUs
Categories
UNII
NU90V55F8I
CAS number
1189541-98-7

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.

Associated Conditions
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].

TargetActionsOrganism
AInterleukin-6 receptor subunit alpha
antagonist
antibody
Human
UHigh affinity immunoglobulin gamma Fc receptor I
unknown
Human
ULow affinity immunoglobulin gamma Fc region receptor II-a
unknown
Human
ULow affinity immunoglobulin gamma Fc region receptor II-b
unknown
Human
ULow affinity immunoglobulin gamma Fc region receptor III-A
unknown
Human
ULow affinity immunoglobulin gamma Fc region receptor III-B
unknown
Human
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].

Toxicity

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

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Sarilumab.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Sarilumab.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Sarilumab.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Sarilumab.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Sarilumab.
5-androstenedioneThe metabolism of 5-androstenedione can be increased when combined with Sarilumab.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be increased when combined with Sarilumab.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Sarilumab is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Sarilumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Sarilumab.
Food Interactions
Not Available

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. [PubMed:24297381]
  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. [PubMed:25733246]
  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. [PubMed:26860742]
  4. Kaufman MB: Pharmaceutical Approval Update. P T. 2017 Sep;42(9):562-580. [PubMed:28890641]
  5. ema.europa [Link]
  6. Kevzara product monograph [Link]
External Links
PubChem Substance
347911238
Wikipedia
Sarilumab
AHFS Codes
  • 92:36.00 — Disease-modifying Antirheumatic Agents
FDA label
Download (1.31 MB)
MSDS
Download (90.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingTreatmentMorphea, Plaque Form1
1CompletedBasic ScienceRheumatoid Arthritis1
1CompletedHealth Services ResearchRheumatoid Arthritis1
1CompletedTreatmentRheumatoid Arthritis6
2CompletedTreatmentAnkylosing Spondylitis (AS)1
2RecruitingTreatmentJuvenile Idiopathic Arthritis (JIA)2
2TerminatedTreatmentAnkylosing Spondylitis (AS)1
2TerminatedTreatmentRheumatoid Arthritis1
2, 3CompletedTreatmentRheumatoid Arthritis1
3Active Not RecruitingTreatmentRheumatoid Arthritis2
3CompletedTreatmentRheumatoid Arthritis6
3RecruitingTreatmentPolymyalgia Rheumatica1
3RecruitingTreatmentRheumatoid Arthritis1
3TerminatedTreatmentRheumatoid Arthritis1
4RecruitingTreatmentRheumatoid Arthritis1
Not AvailableNot Yet RecruitingNot AvailableRheumatoid Arthritis -Exposure During Pregnancy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous150 mg/1.14mL
Injection, solutionSubcutaneous200 mg/1.14mL
SolutionSubcutaneous150 mg
SolutionSubcutaneous200 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
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 point6.6 - 7.2Jin, et al. Electrophoresis. Sep;23(19):3385-91. (2002).

Taxonomy

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

Targets

Kind
Protein
Organism
Human
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. [PubMed:24297381]
  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. [PubMed:27464017]
  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. [PubMed:28264816]
  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. [PubMed:28707587]
  5. Lin P: Targeting interleukin-6 for noninfectious uveitis. Clin Ophthalmol. 2015 Sep 11;9:1697-702. doi: 10.2147/OPTH.S68595. eCollection 2015. [PubMed:26392750]
Kind
Protein
Organism
Human
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]
Kind
Protein
Organism
Human
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]
Kind
Protein
Organism
Human
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]
Kind
Protein
Organism
Human
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]
Kind
Protein
Organism
Human
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]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
General Function
Pyridoxal phosphate binding
Specific Function
Catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate. Participates in cellular nitrogen metabolism and also in liver gluconeogenesis starting wi...
Gene Name
GPT
Uniprot ID
P24298
Uniprot Name
Alanine aminotransferase 1
Molecular Weight
54636.415 Da
References
  1. Kevzara product monograph [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
General Function
Pyridoxal phosphate binding
Specific Function
Catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate.
Gene Name
GPT2
Uniprot ID
Q8TD30
Uniprot Name
Alanine aminotransferase 2
Molecular Weight
57903.11 Da
References
  1. Kevzara product monograph [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
General Function
Pyridoxal phosphate binding
Specific Function
Not Available
Gene Name
GIG18
Uniprot ID
Q2TU84
Uniprot Name
Aspartate aminotransferase
Molecular Weight
46319.2 Da
References
  1. Kevzara product monograph [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. ema.europa [Link]

Drug created on October 20, 2016 14:46 / Updated on November 16, 2018 11:29