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.

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. 

Table 1. Cytokine Signaling Through JAK Pathways2,3

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).4,5

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 TYK2.4

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 TYK2.5

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.6

Cytokine Signaling of Baricitinib and JAK Inhibitors Based on in vitro 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.7

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 21.7

Filgotinib did not modulate

  • JAK1/2 dependent signaling stimulated by IFN-γ, and

  • JAK2/2 dependent signaling stimulated by GM-CSF.7

Filgotinib inhibited JAK1/TYK2 dependent signaling stimulated by IL-6, IL-10, and IFN-α to a lesser degree compared to BARI.7 Additional details presented in Table 2.

Table 2. IC50 Values for Baricitinib and Filgotinib in Cytokine-Stimulated Human Peripheral Blood Mononuclear Cell Preparations7








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


CD4+ T cells

NK Cells

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.

a p<.0001 vs BARI.

b p<.001 vs BARI.

c p<.01 vs BARI.

References

1. O'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

2. O’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

3. Ghoreschi 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

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

5. Rompaey 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

6. Dowty 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

7. McInnes 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/

Glossary

BARI = baricitinib

GM-CSF = granulocyte/macrophage colony-stimulating factor

IC50 = inhibitory concentration of 50%

IFN = interferon

IL = interleukin

JAK = Janus kinase

RA = rheumatoid arthritis

STAT = signal transducers and activators of transcription

TYK = tyrosine kinase

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn 2019 M07 30

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