Deucravacitinib

Identification

Summary

Deucravacitinib is a TYK2 inhibitor being investigated as a treatment for psoriasis.

Brand Names
Sotyktu
Generic Name
Deucravacitinib
DrugBank Accession Number
DB16650
Background

Deucravacitinib is a novel oral selective tyrosine kinase 2 (TYK2) inhibitor. Unlike other Janus kinase 1/2/3 inhibitors that bind to the conserved active domain of these non-receptor tyrosine kinases, deucravacitinib binds to the regulatory domain of TYK2 with high selectivity to this therapeutic target.1,2 This selectivity towards TYK2 may lead to an improved safety profile of deucravacitinib, as nonselective JAK inhibitors are associated with a range of adverse effects such as altered cholesterol and triglyceride levels and liver and kidney dysfunction.2

Deucravacitinib was first approved by the FDA in September 2022 to treat moderate-to-severe plaque psoriasis.5 It was later approved by Health Canada in November 2022 6 and by the European Medicines Agency in March 2023.8

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 425.467
Monoisotopic: 425.200316838
Chemical Formula
C20H22N8O3
Synonyms
  • Deucravacitinib
External IDs
  • BMS-986165
  • WHO 11342

Pharmacology

Indication

Deucravacitinib is a tyrosine kinase 2 (TYK2) inhibitor indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. It is not recommended for use in combination with other potent immunosuppressants.5,6,7

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofSevere plaque psoriasis••••••••••••••••••••••••••• ••• ••••••••••••••••••
Management ofSevere plaque psoriasis••••••••••••••••••••••••••• ••• •••••••• ••••••• ••• •••••••••••••••
Management ofModerate plaque psoriasis••••••••••••••••••••••••••• ••• ••••••••••••••••••
Management ofModerate plaque psoriasis••••••••••••••••••••••••••• ••• •••••••• ••••••• ••• •••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Deucravacitinib is a tyrosine kinase 2 (TYK2) inhibitor that works to suppress the immune signaling pathways in inflammatory disorders, such as plaque psoriasis. In clinical studies comprising patients with psoriasis, deucravacitinib reduced psoriasis-associated gene expression in psoriatic skin in a dose dependent manner, including reductions in IL-23-pathway and type I IFN pathway regulated genes. Following 16 weeks of once-daily treatment, deucravacitinib reduced inflammatory markers such as IL-17A, IL-19 and beta-defensin by 47 to 50%, 72%, and 81 to 84%, respectively.5 Deucravacitinib does not affect with JAK2-dependent hematopoietic functions.4

Mechanism of action

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of kinases, which are intracellular tyrosine kinases that activate the JAK–signal transducer and activator of the transcription pathway. Unlike other members of the JAK family that promote broader immune and extra-immune pathways, such as lipid metabolism, the TYK2 signalling pathway is responsible for selected immune pathways.1 TYK2 mediates the signalling of inflammatory cytokines of both adaptive (e.g., interleukin (IL) 12 and IL-23) and innate (e.g., type I interferons) immune responses.3 IL-23 has been implicated in the pathogenesis of immune-mediated disorders such as psoriasis and psoriatic arthritis.1 It activates and promotes the proliferation of Th17 cells: subsequently, Th17 cells secrete inflammatory mediators, such as IL-17 and tumour necrosis factor-alpha, that stimulate epidermal cells to produce cytokines and chemokines that attract and activate innate immune system cells.1,2 Enhanced activity of Th17 cells leads to sustained inflammatory responses in the skin and joints as manifested in psoriatic arthritis.1

Deucravacitinib inhibits TYK2 via an allosteric mechanism: it binds to the enzyme's regulatory domain - also known as the pseudokinase (JH2) domain - instead of the catalytic domain. This binding activity allows high selectivity towards TYK2 over other tyrosine kinase enzymes. In in vitro cellular assays, deucravacitinib showed a 100-fold to 2000-fold selectivity for TYK2 over JAK 1/2/3 and demonstrated minimal or no activity against JAK 1/2/3. Upon binding to TYK2, deucravacitinib induces a conformational change and locks the regulatory domain of TYK2 into an inhibitory confirmation with the catalytic domain, trapping TYK2 in an inactive state.1,2 Inhibiting TYK2 leads to the downregulation of the IL-23/TH17 pathway, IL-12 signalling, type 1 interferon pathway, and keratinocyte activation.3

TargetActionsOrganism
ANon-receptor tyrosine-protein kinase TYK2
inhibitor
Humans
Absorption

Following oral administration, deucravacitinib plasma Cmax and AUC increased proportionally over a dose range from 3 mg to 36 mg (0.5 to 6 times the approved recommended dosage) in healthy subjects. The steady state Cmax and AUC24 of deucravacitinib following administration of 6 mg once daily were 45 ng/mL and 473 ng x hr/mL, respectively. The steady state Cmax and AUC24 of the active deucravacitinib metabolite, BMT-153261, following administration of 6 mg once daily were 5 ng/mL and 95 ng x hr/mL, respectively. The absolute oral bioavailability of deucravacitinib was 99% and the median Tmax ranged from two to three hours.5

A high-fat, high-calorie meal decreased Cmax and AUC of deucravacitinib by 24% and 11%, respectively, and prolonged Tmax by one hour; however, this has clinically significant effects on drug absorption and exposure.5

Volume of distribution

The volume of distribution of deucravacitinib at steady state is 140 L.5

Protein binding

Protein binding of deucravacitinib was 82 to 90% and the blood-to-plasma concentration ratio was 1.26.5

Metabolism

Deucravacitinib undergoes N-demethylation mediated by cytochrome P-450 (CYP) 1A2 to form major metabolite BMT-153261, which has a comparable pharmacological activity to the parent drug. However, the circulating exposure of BMT-153261 accounts for approximately 20% of the systemic exposure of the total drug-related components. Deucravacitinib is also metabolized by CYP2B6, CYP2D6, carboxylesterase (CES) 2, and uridine glucuronyl transferase (UGT) 1A9.5

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Route of elimination

After a single dose of radiolabeled deucravacitinib, approximately 13% and 26% of the dose was recovered as unchanged in urine and feces, respectively. Approximately 6% and 12% of the dose was detected as BMT-153261 in urine and feces, respectively.5

Half-life

The terminal half-life of deucravacitinib was 10 hours.5

Clearance

The renal clearance of deucravacitinib ranged from 27 to 54 mL/minute.5

Adverse Effects
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Toxicity

No information regarding the acute toxicity profile and LD50 of deucravacitinib is available. There is no experience regarding human overdosage with deucravacitinib. There is no known antidote for deucravacitinib overdose and hemodialysis is unlikely to be effective, as the extent of deucravacitinib elimination by hemodialysis is small (5.4% of dose per dialysis treatment).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.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Deucravacitinib.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Deucravacitinib.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Deucravacitinib.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Deucravacitinib.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Deucravacitinib.
Food Interactions
  • Take with or without food. Food has no clinically significant effect on drug absorption and exposure.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Deucravacitinib hydrochloride95C5558CF41609392-28-0LILQGPVDQZORJG-NIIDSAIPSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SotyktuTablet, film coated6 mgOralBristol Myers Squibb Pharma Eeig2023-04-04Not applicableEU flag
SotyktuTablet, film coated6 mgOralBristol Myers Squibb Pharma Eeig2023-04-04Not applicableEU flag
SotyktuTablet, film coated6 mgOralBristol Myers Squibb Pharma Eeig2023-04-04Not applicableEU flag
SotyktuTablet6 mgOralBristol Myers Squibb2023-02-14Not applicableCanada flag
SotyktuTablet, film coated6 mgOralBristol Myers Squibb Pharma Eeig2023-04-04Not applicableEU flag

Categories

ATC Codes
L04AF07 — Deucravacitinib
Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
N0A21N6RAU
CAS number
1609392-27-9
InChI Key
BZZKEPGENYLQSC-FIBGUPNXSA-N
InChI
InChI=1S/C20H22N8O3/c1-21-20(30)16-14(9-15(25-26-16)24-19(29)11-7-8-11)23-13-6-4-5-12(17(13)31-3)18-22-10-28(2)27-18/h4-6,9-11H,7-8H2,1-3H3,(H,21,30)(H2,23,24,25,29)/i1D3
IUPAC Name
6-cyclopropaneamido-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}-N-(2H3)methylpyridazine-3-carboxamide
SMILES
[2H]C([2H])([2H])NC(=O)C1=C(NC2=CC=CC(C3=NN(C)C=N3)=C2OC)C=C(NC(=O)C2CC2)N=N1

References

General References
  1. Mease PJ, Deodhar AA, van der Heijde D, Behrens F, Kivitz AJ, Neal J, Kim J, Singhal S, Nowak M, Banerjee S: Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann Rheum Dis. 2022 Mar 3. pii: annrheumdis-2021-221664. doi: 10.1136/annrheumdis-2021-221664. [Article]
  2. Chimalakonda A, Burke J, Cheng L, Catlett I, Tagen M, Zhao Q, Patel A, Shen J, Girgis IG, Banerjee S, Throup J: Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors. Dermatol Ther (Heidelb). 2021 Oct;11(5):1763-1776. doi: 10.1007/s13555-021-00596-8. Epub 2021 Aug 30. [Article]
  3. Catlett IM, Hu Y, Gao L, Banerjee S, Gordon K, Krueger JG: Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis. J Allergy Clin Immunol. 2021 Nov 10. pii: S0091-6749(21)01690-0. doi: 10.1016/j.jaci.2021.11.001. [Article]
  4. Le AM, Puig L, Torres T: Deucravacitinib for the Treatment of Psoriatic Disease. Am J Clin Dermatol. 2022 Aug 12. pii: 10.1007/s40257-022-00720-0. doi: 10.1007/s40257-022-00720-0. [Article]
  5. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]
  6. Health Canada Approved Drug Products: SOTYKTU (deucravacitinib) Oral Tablets [Link]
  7. EMA Approved Drug Products: Sotyktu (deucravacitinib) Oral Tablets [Link]
  8. Bristol Myers Squibb: Bristol Myers Squibb Receives European Commission Approval of Sotyktu (deucravacitinib), a Once-Daily Oral Treatment for Adults With Moderate-to-Severe Plaque Psoriasis [Link]
ChemSpider
72380005
BindingDB
50507816
RxNav
2612087
ChEMBL
CHEMBL4435170
Wikipedia
Deucravacitinib

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
4Active Not RecruitingTreatmentPsoriasis2somestatusstop reasonjust information to hide
4CompletedTreatmentPsoriasis1somestatusstop reasonjust information to hide
4RecruitingBasic SciencePsoriasis Vulgaris (Plaque Psoriasis)1somestatusstop reasonjust information to hide
4RecruitingTreatmentModerate Plaque psoriasis1somestatusstop reasonjust information to hide
4RecruitingTreatmentPalmoplantar Psoriasis / Psoriasis Genital1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral6 mg
TabletOral6.000 mg
Tablet, film coatedOral6 mg
Tablet, film coatedOral6 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11021475No2021-06-012033-11-07US flag
USRE47929No2020-04-072033-11-07US flag
US10000480No2018-06-192033-11-07US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.159 mg/mLALOGPS
logP1.8ALOGPS
logP2.1Chemaxon
logS-3.4ALOGPS
pKa (Strongest Acidic)11.09Chemaxon
pKa (Strongest Basic)2.38Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count8Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area135.95 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity138.38 m3·mol-1Chemaxon
Polarizability44.49 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0001900000-a66ffc24d04789987c14
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00ei-0019200000-780f6d8a0e47c880ff66
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00r6-0009300000-02405db2c838b5b62d8e
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0009000000-c353dca0ca346d16dd77
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0kov-0039200000-5474ab3cffaa5dc56650
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-0029000000-c81a5fa1dca92c9d8d24
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.
Gene Name
TYK2
Uniprot ID
P29597
Uniprot Name
Non-receptor tyrosine-protein kinase TYK2
Molecular Weight
133648.77 Da
References
  1. Mease PJ, Deodhar AA, van der Heijde D, Behrens F, Kivitz AJ, Neal J, Kim J, Singhal S, Nowak M, Banerjee S: Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann Rheum Dis. 2022 Mar 3. pii: annrheumdis-2021-221664. doi: 10.1136/annrheumdis-2021-221664. [Article]
  2. Chimalakonda A, Burke J, Cheng L, Catlett I, Tagen M, Zhao Q, Patel A, Shen J, Girgis IG, Banerjee S, Throup J: Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors. Dermatol Ther (Heidelb). 2021 Oct;11(5):1763-1776. doi: 10.1007/s13555-021-00596-8. Epub 2021 Aug 30. [Article]
  3. Catlett IM, Hu Y, Gao L, Banerjee S, Gordon K, Krueger JG: Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis. J Allergy Clin Immunol. 2021 Nov 10. pii: S0091-6749(21)01690-0. doi: 10.1016/j.jaci.2021.11.001. [Article]
  4. Le AM, Puig L, Torres T: Deucravacitinib for the Treatment of Psoriatic Disease. Am J Clin Dermatol. 2022 Aug 12. pii: 10.1007/s40257-022-00720-0. doi: 10.1007/s40257-022-00720-0. [Article]
  5. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
The alternate name for this enzyme is carboxylesterase (CES) 2.
General Function
Methylumbelliferyl-acetate deacetylase activity
Specific Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Shows high catalytic efficiency for hydrolysis of cocaine, 4-methylumbelliferyl acetate, heroin and ...
Gene Name
CES2
Uniprot ID
O00748
Uniprot Name
Cocaine esterase
Molecular Weight
61806.41 Da
References
  1. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drug Products: SOTYKTU (deucravacitinib) tablets, for oral use [Link]

Drug created at March 24, 2021 22:54 / Updated at April 07, 2023 13:12