Identification

Summary

Ivarmacitinib is a selective JAK1 inhibitor under investigation for the treatment of immuno-inflammatory diseases.

Generic Name
Ivarmacitinib
DrugBank Accession Number
DB16756
Background

Ivarmacitinib (SHR0302) is a selective inhibitor of Janus kinase 1 (JAK1) under investigation for the treatment of various immuno-inflammatory conditions. While ivarmactinib has yet to receive marketing authorization, as of February 2022 clinical trials are ongoing or completed evaluating its use in atopic dermatitis,11,14,16 ankylosing spondylitis,7 rheumatoid arthritis,8 psoriatic arthritis,9 graft-versus-host disease,2,10 vitiligo,12 ulcerative colitis,13 alopecia areata,15 and primary membranous nephropathy.17

Type
Small Molecule
Groups
Experimental, Investigational
Structure
Weight
Average: 414.49
Monoisotopic: 414.158643154
Chemical Formula
C18H22N8O2S
Synonyms
  • Ivarmacitinib
External IDs
  • SHR-0302
  • SHR-0302 free base
  • SHR0302
  • SHR0302 free base

Pharmacology

Indication

Not Available

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Autoimmune inflammatory diseases are thought to arise from a complex interplay of genetics, microbiota, and environmental factors that ultimately lead to dysregulated T- and B-cell activity against the host. Therapeutic interventions are therefore aimed at suppressing T-cell activity and/or blocking cytokine activity.3 A therapeutic target of particular interest is the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, the dysregulation of which has been implicated in a variety of immune disorders.4 Put simply, the JAK-STAT pathway plays a significant role in the transduction of signals from cell membrane receptors to the nucleus, and is essential for the transcription of a range of cytokines and growth factors, including those responsible for orchestrating innate and adaptive immune responses.4 The JAK family of non-receptor tyrosine kinases includes JAK1, JAK2, JAK3, and TYK2, each of which comprise several distinct domains and serve distinct functions.4

Ivarmacitinib is a highly selective inhibitor of JAK1 - which modulates IL-4, IL-5, IL-13, and IFN-γ, amongst other cytokines - while sparing inhibition of JAK2 in order to decrease the risk of adverse effects like anemia and neutropenia.1 By inhibiting this pathway, ivarmacitinib may help to prevent the immune dysregulation responsible for a number of inflammatory conditions, including atopic dermatitis and rheumatologic diseases (e.g. rheumatoid arthritis).

TargetActionsOrganism
ATyrosine-protein kinase JAK1
inhibitor
Humans
Absorption

Following oral administration, the median Tmax of ivarmacitinib is approximately one hour.1

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

The half-life of ivarmacitinib following oral administration is 8.33 - 9.87 hours and increases slightly with increasing dosage.1

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

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.
Not Available
Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Ivarmacitinib sulfateCN7B3Z5G041639419-51-4XVVWQCLRGHYWPI-OOWXMNGOSA-N

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
K6K4B9Z5TV
CAS number
1445987-21-2
InChI Key
DNBCBAXDWNDRNO-GDNZZTSVSA-N
InChI
InChI=1S/C18H22N8O2S/c1-25(15-13-3-4-19-14(13)20-9-21-15)12-5-10-7-26(8-11(10)6-12)18(27)23-17-22-16(28-2)24-29-17/h3-4,9-12H,5-8H2,1-2H3,(H,19,20,21)(H,22,23,24,27)/t10-,11+,12+
IUPAC Name
(3aR,5S,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-[methyl({7H-pyrrolo[2,3-d]pyrimidin-4-yl})amino]-octahydrocyclopenta[c]pyrrole-2-carboxamide
SMILES
[H][C@@]12C[C@H](C[C@]1([H])CN(C2)C(=O)NC1=NC(OC)=NS1)N(C)C1=NC=NC2=C1C=CN2

References

General References
  1. Zhao Y, Zhang L, Ding Y, Tao X, Ji C, Dong X, Lu J, Wu L, Wang R, Lu Q, Goh AH, Liu R, Zhang Z, Zhang J: Efficacy and Safety of SHR0302, a Highly Selective Janus Kinase 1 Inhibitor, in Patients with Moderate to Severe Atopic Dermatitis: A Phase II Randomized Clinical Trial. Am J Clin Dermatol. 2021 Nov;22(6):877-889. doi: 10.1007/s40257-021-00627-2. Epub 2021 Aug 9. [Article]
  2. Sun X, He Q, Yang J, Wang A, Zhang F, Qiu H, Zhou K, Wang P, Ding X, Yuan X, Li H, Zhang Y, Song X: Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease. Cell Transplant. 2021 Jan-Dec;30:9636897211033778. doi: 10.1177/09636897211033778. [Article]
  3. Shalabi MMK, Garcia B, Coleman K, Siller A Jr, Miller AC, Tyring SK: Janus Kinase and Tyrosine Kinase Inhibitors in Dermatology: A Review of Their Utilization, Safety Profile and Future Applications. Skin Therapy Lett. 2022 Jan;27(1):4-9. [Article]
  4. Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M: The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017 Jun 21;15(1):23. doi: 10.1186/s12964-017-0177-y. [Article]
  5. BioSpace: Reistone Announces Positive Results from a Phase II Study Evaluating SHR0302 Ointment for Patients with Mild-to-Moderate Atopic Dermatitis [Link]
  6. PR Newswire: Reistone Biopharma Announces Positive Topline Results from Phase 2 Clinical Trial Evaluating SHR0302, a JAK1 Inhibitor for the Treatment of Moderate-to-Severe Atopic Dermatitis [Link]
  7. NCT04481139: A Study to Evaluate the Efficacy and Safety of SHR0302 in Patients With Ankylosing Spondylitis [Link]
  8. NCT04333771: A Study to Evaluate the Efficacy and Safety of SHR0302 in Patients With Rheumatoid Arthritis [Link]
  9. NCT04957550: To Evaluate the Efficacy and Safety of SHR0302 Tablet in Subjects of Active Psoriatic Arthritis [Link]
  10. NCT04146207: SHR0302 and Steroid as First Line Therapy for Chronic GVHD [Link]
  11. NCT04717310: Evaluate the Efficacy and Safety of Topical SHR0302 Ointment in Patients With Mild-to-Moderate Atopic Dermatitis (MARBLE-23) [Link]
  12. NCT04774809: Assess the Efficacy and Safety of SHR0302 Ointment in Adult Patients With Vitiligo [Link]
  13. NCT05181137: A Phase 3 Study to Investigate the Efficacy and Safety of SHR0302 With Moderately to Severely Active Ulcerative Colitis [Link]
  14. NCT04162899: A Phase II Study in Adult Patients With Moderate to Severe Atopic Dermatitis [Link]
  15. NCT04346316: A Phase II Study in Patients With Alopecia Areata [Link]
  16. NCT04875169: Evaluate Efficacy and Safety of Oral SHR0302 in Subjects Aged 12 Years and Older With Moderate to Severe Atopic Dermatitis [Link]
  17. NCT05136456: Evaluate the Efficacy and Safety of SHR1459 Tablets in Patients With Primary Membranous Nephropathy [Link]
ChemSpider
103820841

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentAlopecia Areata (AA)1
3RecruitingTreatmentAtopic Dermatitis1
3RecruitingTreatmentNon-radiographic Axial Spondyloarthritis1
3RecruitingTreatmentRheumatoid Arthritis1
3RecruitingTreatmentUlcerative Colitis1
2CompletedTreatmentAlopecia Areata (AA)1
2CompletedTreatmentAtopic Dermatitis1
2CompletedTreatmentCrohn's Disease (CD)1
2CompletedTreatmentRheumatoid Arthritis1
2CompletedTreatmentUlcerative Colitis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0228 mg/mLALOGPS
logP1.96ALOGPS
logP1.82Chemaxon
logS-4.3ALOGPS
pKa (Strongest Acidic)6.91Chemaxon
pKa (Strongest Basic)6.27Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area112.16 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity111.49 m3·mol-1Chemaxon
Polarizability42.58 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Ubiquitin protein ligase binding
Specific Function
Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.
Gene Name
JAK1
Uniprot ID
P23458
Uniprot Name
Tyrosine-protein kinase JAK1
Molecular Weight
133275.995 Da
References
  1. Zhao Y, Zhang L, Ding Y, Tao X, Ji C, Dong X, Lu J, Wu L, Wang R, Lu Q, Goh AH, Liu R, Zhang Z, Zhang J: Efficacy and Safety of SHR0302, a Highly Selective Janus Kinase 1 Inhibitor, in Patients with Moderate to Severe Atopic Dermatitis: A Phase II Randomized Clinical Trial. Am J Clin Dermatol. 2021 Nov;22(6):877-889. doi: 10.1007/s40257-021-00627-2. Epub 2021 Aug 9. [Article]

Drug created at February 23, 2022 21:47 / Updated at February 26, 2022 15:23