JAK-INHIBITORER MODE OF ACTION

Transcription

1 JAK-INHIBITORER MODE OF ACTION DANBIO KURSUS 19. JANUAR 2018 Uffe Møller Døhn Center for Rheumatology and Spine Diseases & COPECARE Rigshospitalet, Glostrup Denmark

2 RA PATHOGENESIS

3 Rheumatoid arthritis TARGETED THERAPIES Intracellular pathways can be targeted by small molecules Biologics target cytokines and extracellular signalling Small molecules target intracellular signalling pathways Cytokines IL-1, IL-6 TNF Dendritic cell B cell Co-stimulation T cell T cell T cell Rheumatoid factor and other antibodies T cell Macrophage The inflammatory cascade continues downstream into the cell Figure adapted from

4 TARGETED SYNTHETIC VS. MONOCLONAL Monoclonal Antibody Biological DMARDS Targeted Synthetic DMARDs Size: ~ Da ~500 Da Structure: Immunoglobulin Chemical entity Production: Made from cell culture media; very complex Controlled chemical synthesis; not complex Target: Extracellular Intracellular or extracellular Target specificity: High Low(er) Metabolism: RES Hepatic/renal Administration: Parenteral Oral Antidrug antibodies Yes No Dosing: ~Q2W-Q4W ~QD Cross blood-brain barrier: ANTIBODY BIOLOGICAL DMARDS No Potentially Price: High High

5 Smolen J et al.: Ann Rheum Dis 2016

6 JAK/STAT SYSTEM The JAK/STAT system: Is a signaling pathway transmitting information from extracellular cytokines to the nucleus Signaling results in DNA transcription and expression of genes involved in immune system, proliferation, differentiation, apoptosis and oncogenesis. Consists of three main components: 1. Cell surface receptor 2. Janus kinase (JAK) 3. Signal Transducer and Activator of Transcription (STAT) proteins Disrupted or dysregulated JAK-STAT system can result in immune deficiency syndromes and cancers

7 CYTOKINE SIGNALLING PATHWAYS IN RA Cytokines act via receptor binding BTK 3 JAK JAK AC, adenylyl cyclase; BTK, Bruton tyrosine kinase; camp, cyclic adenosine monophosphate; ERK, extracellular-signal-regulated kinases; IKK, κb kinase; JAK, Janus kinase; JNK, c-jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PDE4, phosphodiesterase 4; PIK3, phosphatidylinositol-4,5-bisphosphate 3-kinase; PKC, protein kinase C; STAT, signal transducer and activator of transcription; Syk, spleen tyrosine kinase. 1. Mavers M, et al. Curr Rheum Rep 2009;11: Rommel C, et al. Nat Rev Immunol 2007;7: Taskén K, et al. Physiol Rev2004; 84: Baier G, et al. Curr Opin Cell Biol 2009;21: O Sullivan LA, et al. Molec Immunol 2007; 44:

8 JANUS KINASES (JAKS) A subgroup of non-receptor protein tyrosine kinases 1,2 JAK1, JAK2, JAK3, and TYK2 Characterised by two adjacent kinase domains (JH1 and JH2) 3 Implicated in cell growth, survival, development and cell differentiation 1 Essential for immune and hematopoietic cells 1 JAK, Janus family kinase; TYK2, tyrosine kinase Ghoreschi K, et al. Immunol Rev 2009;228: Wilks AF. Proc Natl Acad Sci USA 1989;86: Thomas SJ, et al. Br J Cancer 2015; 113:

9 JAK, Janus kinase; P, phosphate; STAT, signal transducer and activator of transcription. 1. Shuai K, et al. Nat Rev Immunol 2003;3: BINDING OF CYTOKINE RECEPTORS ACTIVATES JAK SIGNALLING PATHWAYS JAKs activate STATs, which then act as transcription factors Rapid membrane to nucleus signalling: Cytokines bind trans-membrane receptors that are associated with JAKs Binding activates JAKs JAKs phosphorylate receptors STATs bind to receptors JAKs phosphorylate STATs STATs translocate to the nucleus STATs bind to DNA and activate gene transcription to produce proteins mediating immune response/inflammation Gene transcription

10 BINDING OF CYTOKINE RECEPTORS ACTIVATES JAK SIGNALLING PATHWAYS Frøling M et al: Ugeskr Læger 2017

11 BINDING OF CYTOKINE RECEPTORS ACTIVATES JAK SIGNALLING PATHWAYS Winthrop KL. Nat Rev Rheumatol Mar 2. doi:

12 CELLULAR DISTRIBUTION OF JAKS JAK1, JAK2, and TYK2 are expressed ubiquitously in mammals 1 JAK3 has restricted expression, predominately in cells of hematopoietic origin 2,3 At the cellular level, JAKs reside in the cytosol, endosome and plasma membrane, along with their associated receptors 4 Synovial biopsy specimen stained for JAK3 5 JAK3 has been localised in cells with dendritic morphology in the RA synovium 5 JAK, Janus family kinase; TYK2, tyrosine kinase Ghoreschi K, et al. Immunol Rev 2009;228: O Sullivan LA, et al. Molec Immunol 2007;44: Kawamura M, et al. Proc Natl Acad Sci USA 1994;91: Yamaoka A, et al. Genome Biol 2004;5: Walker JG, et al. Ann Rheum Dis 2006:65: Figure Reproduced from Annals of the Rheumatic Diseases, Walker JG, et al. 65, , 2006 with permission from BMJ Publishing Group Ltd.

13 CELLULAR DISTRIBUTION OF JAKS JAK1 and JAK2 are ubiquitous in tissue expression and JAK3 has limited distribution Tao Wei TS&T June 2012 Data generated by Neurocrine Biosciences, Inc. and downloaded from GEO (GSE7307).

14 CYTOKINES REQUIRING JAKS FOR INTRACELLULAR SIGNALLING Key cytokines in the pathogenesis of RA IFNα and IFNβ IL-6 IL-7 IL-10 IL-12 IL-15 IL-21 IL-23 GM-CSF IL-1 IL-17 IL-18 TGF-β TNF Key cytokines in RA that utilise JAK 1,2 IFNα and IFNβ IL-6 IL-7 IL-10 IL-12 IL-15 IL-21 IL-23 GM-CSF GM-CSF, granulocyte-macrophage colony-stimulating factor, IFN, interferon; IL, interleukin; JAK, Janus kinase; TGF, transforming growth factor; TNF, tumour necrosis factor. 1. O Sullivan LA, et al. Mol Immunol 2007;44: Riese RJ, et al. Best Pract Clin Res Rheumatol 2010;24:

15 JAK/STAT SIGNALLING PATHWAYS Four JAK family members: JAK1, JAK2, JAK3, and TYK2 Example of cytokines that signal through JAK combinations 1 4 γ-chain cytokines 2 IFN-γ Type1 interferons, IL-10, IL-22 IL-12 IL-23 IL-6 IL-11 EPO, TPO GM-CSF, IL-3, IL-5 STAT 1, 3, 5, 6 STAT 1, 3, 5 STAT 1, 3, 5 STAT 3, 4 STAT 1, 3, 5 STAT 5 T-cell growth and differentiation B-cell function NK growth and cytolytic activity TH1 differentiation Macrophage activity NK, CD8 cytolytic activity Antiviral response NK cytolytic activity TH1 and TH17 differentiation EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TPO, thrombopoietin; TYK, tyrosine kinase. Acute phase response Lymphocyte groth and differentiation Catabolic metabolism Lipid metabolism Bone resoprtion Hematopoisis Thrombopoiesis Myelopoiesis Growth Anabolic metabolism 1. O Sullivan LA, et al. Mol Immunol 2007;44: Ghoreschi K, et al. Immunol Rev 2009;228: Sanjabi S, et al. Curr Opin Pharmacol 2009;9: Chizzolini C, et al. Arthritis Res Ther 2009;11: Gadina M et al, Arthritis Rheumatol Jan; 68(1):

16 1. Ruxolitinib JAK/STAT INHIBITORS JAK1/JAK2 inhibitor FDA approval 2011 & 2014 for myelofibrosis and PCV Being investigated for plaque psoriasis, alopecia areata, relapsed diffuse large B-cell lymphoma, and peripheral T-cell lymphoma 2. Tofacitinib JAK1/JAK3 inhibitor FDA & EMA approval (2012 & 2017) for rheumatoid arthritis. FDA approval december 2017 for psoriatic arthritis Being investigated for ankylosing spondylitis, ulcerative colitis, psoriasis, atopic dermatitis, alopecia areata, vitiligo, JIA, SLE 3. Baricitinib JAK1/JAK2 inhibitor EMA approval 2017 for rheumatoid arthritis Being investigated for psoriatic arthritis, GCA, SLE, atopic dermatitis

17 THE JAK/STAT SIGNALLING PATHWAYS Furumoto et al. BioDrugs. 2013; 27:

18 ATP-binding site of protein kinases Paul MK, Mukhopadhyay AK: Int J Med Sci (2004) Adenosin-tri-phosphat (ATP)

19 Methotrexate Sulfasalazin Adenosin-tri-phosphat (ATP)

20 JAK/STAT INHIBITORS Methotrexate were independently identified as strong inhibitors of the Drosophila JAK/STAT pathway, an effect conserved to human cells. Methotrexate did not affect protein phosphorylation in other intracellular signalling pathways. Methotrexate caused significant suppression of JAK/STAT activation at a concentration equivalent to that seen in patients taking low-dose oral methotrexate (p 0.001). Thomas S.: The Lancet, Volume 385, Supp. 1, 2015, Page S98

21 PHARMAKOKINETICS TOFACITINIB BARICITINIB Bioavailability: ~75% ~80% Peak plasma concentration: min min Plasma half-life: ~3 hours ~12 hours Steady state: ~24-48 hours ~72 hours Plasma protein bound: ~40% ~50% Elimination: Liver: 70% Renal: 30% Faeces: 20% Renal: 75%

22 TOFACITINIB BARICITINIB Mode of action: JAK1, JAK3, (JAK2) JAK1, JAK2 Indication: Mono therapy or in combination with MTX or other csdmards Mono therapy or in combination with MTX Dosing 5 mg BID 4 mg QD Elimination: Hepatic Renal Reduced dose: Moderate liver impairment Moderate kidney impairment Age >75 yrs Drug interactions: Recommended lab tests: PHARMAKOKINETICS CYP3A4, CYP2C (Clarithromycin, Ketoconazole ) Neutrophiles, leukocytes, Hgb, transaminases, lipids OAT3 (Probenecid) Neutrophiles, leukocytes, Hgb, transaminases, lipids, creatinine

23 MODE-OF-ACTION JAK inhibitors has high in-vitro passive permeability properties and entries intracellularly by transcellular diffusion Hodge et al.: Clin Exp Rheumatol 2016; 34:

24 MODE-OF-ACTION Inhibitory effect (10 mg): ~89-95% Inhibitory effect (5 mg): ~80-90% Inhibitory effect (10 mg): ~42-60% Inhibitory effect (5 mg): ~26-43% Hodge et al.: Clin Exp Rheumatol 2016; 34:

25 TOFACITINIB & BARICITINIB: IN VITRO COMPARISON (IL-6) IL-6: signals via JAK1/JAK2, TYK2 a McInnes I et al.: EULAR 2016, Poster number THU0182

26 TOFACITINIB & BARICITINIB: IN VITRO COMPARISON (IL-15) IL-15: signals via JAK1/JAK3 McInnes I et al.: EULAR 2016, Poster number 26 THU0182

27 TOFACITINIB & BARICITINIB: IN VITRO COMPARISON (IL-21) IL-21: signals via JAK1/JAK3 McInnes I et al.: EULAR 2016, Poster number THU0182

28 Safety population: TOFACITINIB 1 BARICITINIB patient years (5 mg & 10 mg) patient years (2 mg & 4 mg) Follow-up period: 8.5 years 5.5 years 1) Cohen et al. Ann Rheum Dis ) Genovese et al. ACR 2017; poster 511 SAFETY

29 INFECTIONS IR (100 pt. years) TOFACITINIB 1 BARICITINIB 2 Serious infections Herpes zoster Herpes zoster serious ) Cohen et al. Ann Rheum Dis ) Genovese et al. ACR 2017; poster 511 3) Eli Lilly data on file MALIGNANCIES IR (100 pt. years) TOFACITINIB 1 BARICITINIB 2 Malignancies (excl. NMSC) ) Cohen et al. Ann Rheum Dis ) Genovese et al. ACR 2017; poster 511 SAFETY

30 TOFACITINIB & BARICITINIB: HAEMOGLOBIN Hemoglobin Schulze-Koops H et al.: Rheumatology; 2017, 56:46-57 Taylor P et al.: NEJM; 2017, 376: (suppl.)

31 TOFACITINIB & BARICITINIB: Neutrophiles WHITE BLOOD CELLS Lymphocytes Schulze-Koops H et al.: Rheumatology; 2017, 56:46-57 Taylor P et al.: NEJM; 2017, 376: (suppl.)

32 TOFACITINIB & BARICITINIB: HEMATOLOGICAL EFFECTS MEAN CHANGES TOFACITINIB BARICITINIB Hemoglobin then Neutrophils Lymphocyte count then then NK cells then Thrombocytes References: Yamanaka et al. Arthritis Res Ther. 2016; 18: 34. Tanaka.THU.0209 EULAR 2016 Poster.

33 TOFACITINIB & BARICITINIB: LIPIDS LDL HDL Schulze-Koops H et al.: Rheumatology; 2017, 56:46-57 Taylor P et al.: NEJM; 2017, 376: (suppl.)

34 JAK INHIBITORS ON THE WAY Name: JAK inhibition: Disorders under investigation: Filgotinib JAK1 RA, AS, PsA, Sjogren, CD, UC, uveitis Upadacitinib JAK1 RA, AS, PsA, UC, CD Peficitinib JAK3 RA PF JAK1 Atopic dermatitis, Psoriasis Gandotinib JAK2 Myeloproliferative neoplasms Lestaurtinib JAK2 AML Momelotinib JAK1/JAK2 Myeloproliferative disorders, metastatic pancreatic cancer Pacricitinib JAK2 Relapsed lymphoma, advanced myeloid malignancies, myelofibrosis, myeloproliferative neoplasms, MDS Fedratinib JAK2 Primary myelofibrosis, PCV, essential thrombocythemia

35 Coffeecitinib Chococitinib