Olumiant ® (baricitinib) tabletter

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Olumiant® (baricitinib): Jämförelse av JAK-selektivitetsprofiler för baricitinib och filgotinib

Baricitinib och JAK-hämmare filgotinib har inte jämförts i kliniska prövningar.

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JAK-STAT Pathway in Rheumatoid Arthritis

The JAK-STAT pathway is a key regulator of signaling from pro-inflammatory cytokines implicated in the pathogenesis of RA.1 Inhibiting specific JAK-STAT pathways may reduce the activity of cytokines that signal through that pathway. 2

Cytokine Signaling Through JAK Pathways3,4

JAK Pairing

Cytokines Signaled

JAK1/JAK3

IL-2, IL-4, IL-7, IL-9, IL-15, IL-21

JAK1/JAK2

IFN-γ

JAK1/TYK2

IL-10, IL-20, IL-22, IFNα, IFNβ

JAK2/TYK2

IL-12, IL-23

JAK1/JAK2 or TYK2

IL-6, IL-11, IL-27, CTF-1, CNTF, G-CSF, LIF, OSM

JAK2/JAK2

EPO, TPO, GM-CSF, GH, IL-3, IL-5

Abbreviations: CNTF = human ciliary neurotrophic factor; CTF-1= cardiotrophin 1; EPO = erythropoietin; G-CSF = granulocyte colony–stimulating factor; GH = growth hormone; GM-CSF = granulocyte-macrophage colony–stimulating factor; IFN = interferon; IL = interleukin; JAK = Janus kinase; LIF = leukemia inhibitory factor; OSM = oncostatin M; TPO = thrombopoietin; TYK = tyrosine kinase.

Janus Kinase Selectivity Profiles

Baricitinib and filgotinib have varying selectivities for the JAK isoforms, including JAK1, JAK2, JAK3, and TYK2, based upon the biochemical assays evaluating the concentration of drug necessary to inhibit 50% of the cytokine signaling activity (IC50).5,6

JAK Selectivity of Baricitinib

Baricitinib selectively inhibits JAK1 and JAK2. Reported IC50 values for BARI are

  • 5.9 nM for JAK1
  • 5.7 nM for JAK2
  • >400 nM for JAK3, and
  • 53 nM for TYK2.5

JAK Selectivity of Filgotinib

Filgotinib is proposed to selectively inhibit JAK1. Based on a JAK biochemical assay, the reported IC50 values are

  • 10 nM for JAK1
  • 28 nM for JAK2
  • 810 nM for JAK3, and
  • 116 for TYK2.6

Another study has shown conflicting evidence of JAK selectivity for filgotinib. In an in vitro cell-based assay, at efficacious doses used in RA, authors noted that filgotinib demonstrated a similar cytokine inhibition profile as BARI.7

Cytokine Signaling of Baricitinib and JAK Inhibitors Based on ex vivo Comparisons

A comparison of the ex vivo pharmacologic profile of BARI and filgotinib was conducted to assess the specific cytokines each compound modulates in the JAK-STAT pathway.8

Potency of JAK Signaling of Baricitinib Compared to Filgotinib

The IC50 values for filgotinib indicate lower potency compared to the other JAK inhibitors for JAK1/3 dependent signaling stimulated by IL-2, 4, 15, and 21.8

Filgotinib did not modulate

  • JAK1/2 dependent signaling stimulated by IFN-γ, and
  • JAK2/2 dependent signaling stimulated by GM-CSF.8

Filgotinib inhibited JAK1/TYK2 dependent signaling stimulated by IL-6, IL-10, and IFN-α to a lesser degree compared to BARI.8 Additional details presented in IC50 Values for Baricitinib and Filgotinib in Cytokine-Stimulated Human Peripheral Blood Mononuclear Cell Preparations.

IC50 Values for Baricitinib and Filgotinib in Cytokine-Stimulated Human Peripheral Blood Mononuclear Cell Preparations8


CD4+ T cells

CD4+ T cells

NK Cells

NK Cells

Monocytes

Monocytes

Stimulation/pSTAT

BARI (nM)

Filgo (nM)

BARI (nM)

Filgo (nM)

BARI (nM)

Filgo (nM)

JAK1/3 dependent cytokines

IL-2/ pSTAT5

29

330a

44

422a

NI

NI

IL-4/ pSTAT6

48

457a

22

183a

45

540a

IL-15/ pSTAT5

40

462a

67

687a

NI

NI

IL-21/ pSTAT3

64

642a

62

597a

NI

NI

JAK2/2 or JAK2/TYK2 dependent cytokines

IL-3/ pSTAT5

NI

NI

NI

NI

30

859a

G-CSF/ pSTAT3

NI

NI

NI

NI

65

1359a

GM-CSF/ pSTAT5

NI

NI

NI

NI

33

1253a

JAK1/JAK2/TYK2 dependent cytokines

IL-6/ pSTAT3

61

428b

NI

NI

48

466a

IL-10/ pSTAT3

68

715c

87

482a

142

1484a

IFN-γ/ pSTAT1

NI

NI

NI

NI

38

897a

IFN-α/ pSTAT1

95

779a

93

670a

94

994a

IFN-α/ pSTAT3

NI

NI

NI

NI

17

197a

IFN-α/ pSTAT5

36

317a

NI

NI

16

204a

Abbreviations: BARI = baricitinib; CD = cluster of differentiation; Filgo = filgotinib; G-CSF = granulocyte-colony stimulating factor; GM-CSF = granulocyte macrophage-colony stimulating factor; IC50 = half maximum inhibitory concentration; IFN = interferon; IL = interleukin; JAK = Janus kinase; NI = no induction; NK = natural killer; nM = nanomolar; pSTAT = phosphorylated signal transducer and activator of transcription; TYK = tyrosine kinase.

ap<.0001 vs BARI.

bp<.001 vs BARI.

cp<.01 vs BARI.

Inhibition Time by Baricitinib and Filgotinib Doses

Levels of pSTAT were measured in cytokine-stimulated PBMCs from 6 healthy donors. Average daily percent inhibition of pSTAT (%SI) for selected cytokines was determined for BARI 2 mg once daily, BARI 4 mg once daily, filgotinib 100 mg once daily, and filgotinib 200 mg once daily using calculated mean concentration time profiles over 24 hours. Filgotinib calculations included parent drug plus metabolite.9,10

Overall, %SI in JAK2/2 or JAK2/Tyk2 cytokines were

  • higher for BARI 4 mg than filgotinib 100mg and 200 mg, and 
  • higher for BARI 2 mg than filgotinib 100mg and 200 mg.9

Overall, %SI in JAK1/JAK2/Tyk2 cytokines were

  • higher for BARI 4 mg than filgotinib 100 mg
  • similar for BARI 4 mg and filgotinib 200 mg
  • similar for BARI 2 mg and filgotinib 100 mg, and
  • lower for BARI 2 mg than filgotinib 200 mg .9

Overall, %SI in JAK1/JAK3 cytokines were

  • higher for BARI 4 mg than filgotinib 100mg and 200 mg
  • similar for BARI 2 mg and filgotinib 100 mg, and
  • lower for BARI 2 mg than filgotinib 200 mg.9

Neither BARI or filgotinib continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. 9

Baricitinib and filgotinib have different in vitro pharmacologic profiles and may modulate distinct cytokine pathways to differing degrees and durations over 24 hours.9,10

References

1O'Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161-170. http://dx.doi.org/10.1056/NEJMra1202117

2O’Shea JJ, Schwartz DM, Villarino AV, et al. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311-28. http://dx.doi.org/10.1146/annurev-med-051113-024537

3O’Sullivan LA, Liongue C, Lewis RS, et al. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol. 2007;44(10):2497-2506. http://dx.doi.org/10.1016/j.molimm.2006.11.025

4Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228(1):273-287. http://dx.doi.org/10.1111/j.1600-065X.2008.00754.x

5Data on file, Eli Lilly and Company and/or one of its subsidiaries.

6Rompaey LV, Galien R, van der Aar EM, et al. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J Immunol. 2013;191(7):3568-3577. http://www.jimmunol.org/content/191/7/3568

7Dowty ME, Lin T, Wang L, et al. Lack of differentiation of Janus kinase inhibitors in rheumatoid arthritis based on Janus kinase pharmacology and clinically meaningful concentrations [abstract OP0147]. Ann Rheum Dis. 2014;73:116. http://dx.doi.org/10.1136/annrheumdis-2014-eular.2490

8McInnes IB, Higgs R, Lee J, et al. Ex vivo comparison of baricitinib, upadacitinib, filgotinib, and tofacitinib for cytokine signaling in human leukocyte subpopulations [abstract 2870]. Arthritis Rheumatol. 2017;69(suppl 10). http://acrabstracts.org/abstract/ex-vivo-comparison-of-baricitinib-upadacitinib-filgotinib-and-tofacitinib-for-cytokine-signaling-in-human-leukocyte-subpopulations/

9McInnes IB, Rocha G, Higgs RE, et al. Baricitinib, tofacitinib, upadacitinib, filgotinib, and cytokine signaling in human leukocyte subpopulations: an updated ex-vivo comparisons. Ann Rheum Dis. 2020;79 (suppl 1):1. European League Against Rheumatism abstract OP0001. http://scientific.sparx-ip.net/archiveeular/?searchfor=McInnes&c=a&view=4&item=2020OP0001

10McInnes IB, Rocha G, Higgs RE, et al. Baricitinib, tofacitinib, upadacitinib, filgotinib, and cytokine signaling in human leukocyte subpopulations: an updated ex-vivo comparisons. Poster presented at: European League Against Rheumatism (EULAR Virtual); June 3-6, 2020.

Glossary

BARI = baricitinib

GM-CSF = granulocyte/macrophage colony-stimulating factor

IC50 = inhibitory concentration of 50%

IFN = interferon

IL = interleukin

JAK = Janus kinase

PBMC = peripheral blood mononuclear cell

RA = rheumatoid arthritis

%SI = percent inhibition of pSTAT

STAT = signal transducers and activators of transcription

TYK = tyrosine kinase

Datum fӧr senaste ӧversyn May 05, 2020


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