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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Deucravacitinib (DB16650)

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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

• Severe Plaque psoriasis
• Moderate 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

Target	Actions	Organism
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 C_max 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 T_max ranged from two to three hours.⁵

A high-fat, high-calorie meal decreased C_max and AUC of deucravacitinib by 24% and 11%, respectively, and prolonged T_max 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

Hover over products below to view reaction partners

• Deucravacitinib
  • BMT-153261
  • Deucravacitinib M11 metabolite
  • BMT-158170
  • BMT-334616

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.

• 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 Deucravacitinib.
Acetaminophen	The serum concentration of Acetaminophen can be increased when it is combined with Deucravacitinib.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Deucravacitinib.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Deucravacitinib.
Aldesleukin	The risk or severity of adverse effects can be increased when Aldesleukin is combined with Deucravacitinib.
Alefacept	The risk or severity of adverse effects can be increased when Alefacept is combined with Deucravacitinib.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Deucravacitinib.
Allogeneic processed thymus tissue	The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Deucravacitinib.
Altretamine	The risk or severity of adverse effects can be increased when Altretamine is combined with Deucravacitinib.
Amsacrine	The risk or severity of adverse effects can be increased when Amsacrine is combined with Deucravacitinib.

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Food Interactions

• Take with or without food. Food has no clinically significant effect on drug absorption and exposure.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Deucravacitinib hydrochloride	95C5558CF4	1609392-28-0	LILQGPVDQZORJG-NIIDSAIPSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Sotyktu	Tablet, film coated	6 mg	Oral	Bristol Myers Squibb Pharma Eeig	2023-04-04	Not applicable
Sotyktu	Tablet, film coated	6 mg/1	Oral	E.R. Squibb & Sons, L.L.C.	2022-09-09	Not applicable
Sotyktu	Tablet, film coated	6 mg	Oral	Bristol Myers Squibb Pharma Eeig	2023-04-04	Not applicable
Sotyktu	Tablet, film coated	6 mg	Oral	Bristol Myers Squibb Pharma Eeig	2023-04-04	Not applicable
Sotyktu	Tablet, film coated	6 mg	Oral	Bristol Myers Squibb Pharma Eeig	2023-04-04	Not applicable
Sotyktu	Tablet, film coated	6 mg	Oral	Bristol Myers Squibb Pharma Eeig	2023-04-04	Not applicable
Sotyktu	Tablet, film coated	6 mg	Oral	Bristol Myers Squibb Pharma Eeig	2023-04-04	Not applicable
Sotyktu	Tablet, film coated	6 mg	Oral	Bristol Myers Squibb Pharma Eeig	2023-04-04	Not applicable
Sotyktu	Tablet	6 mg	Oral	Bristol Myers Squibb	2023-02-14	Not applicable
Sotyktu	Tablet, film coated	6 mg	Oral	Bristol Myers Squibb Pharma Eeig	2023-04-04	Not applicable

Categories

ATC Codes

L04AA56 — Deucravacitinib

• L04AA — Selective immunosuppressants
• L04A — IMMUNOSUPPRESSANTS
• L04 — IMMUNOSUPPRESSANTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Antineoplastic and Immunomodulating Agents
• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2B6 Substrates
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 Substrates
• Dermatologicals
• Enzyme Inhibitors
• Immunosuppressive Agents
• Janus Kinase Inhibitor
• Janus Kinase Inhibitors
• OATP1B3 inhibitors
• OCT1 substrates
• P-glycoprotein substrates
• Protein Kinase Inhibitors
• Selective Immunosuppressants
• Tyrosine Kinase 2 Inhibitor
• Tyrosine Kinase Inhibitors
• UGT1A9 Substrates

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]

External Links

ChemSpider

72380005

BindingDB

50507816

RxNav

2612087

ChEMBL

CHEMBL4435170

Wikipedia

Deucravacitinib

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Psoriasis	1
4	Not Yet Recruiting	Basic Science	Psoriasis Vulgaris (Plaque Psoriasis)	1
4	Recruiting	Treatment	Palmoplantar Psoriasis / Psoriasis Genital	1
4	Recruiting	Treatment	Palmoplantar Pustulosis (PPP)	1
4	Recruiting	Treatment	Psoriasis	1
3	Active Not Recruiting	Treatment	Psoriasis	1
3	Active Not Recruiting	Treatment	Psoriatic Arthritis	1
3	Completed	Treatment	Psoriasis	4
3	Not Yet Recruiting	Treatment	Psoriasis Vulgaris (Plaque Psoriasis)	1
3	Recruiting	Treatment	Psoriasis Vulgaris (Plaque Psoriasis)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	6 mg
Tablet, film coated	Oral	6 mg/1
Tablet, film coated	Oral	6 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US11021475	No	2021-06-01	2033-11-07
USRE47929	No	2020-04-07	2033-11-07
US10000480	No	2018-06-19	2033-11-07

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.159 mg/mL	ALOGPS
logP	1.8	ALOGPS
logP	2.1	Chemaxon
logS	-3.4	ALOGPS
pKa (Strongest Acidic)	11.09	Chemaxon
pKa (Strongest Basic)	2.38	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	8	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	135.95 Å2	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	138.38 m3·mol-1	Chemaxon
Polarizability	44.49 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. Non-receptor tyrosine-protein kinase TYK2

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]

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