New Treatments for Rheumatoid Arthritis

Professor Ernest Choy Head of Rheumatology and Translational Research Institute of Infection and Immunity Director of Arthritis Research UK and Health and Care Research Wales CREATE Centre EULAR 2016 recommendations

Smolen JS, et al. Ann Rheum Dis 2017;0:1–18. EULAR 2016 update on Management of RA

Smolen J et al. EULAR 2016 Congress oral presentation ADACTA Trial: Clinical Disease Activity Index (CDAI) Analysis at Week 24 (ITT) ADA (N = 162) TCZ (N = 163) † 50% 47.9%

40%

29.0% 30.7 30%

20% 19.8 Patients, % Patients,

10% 17.2* 9.3 0% Remission + Low DiseaseRemission Activity (>0 to <10) (>0 to <2.8)

*P = 0.0389, remission (unadjusted, no control for multiple testing). †P = 0.0003, remission + low disease activity (unadjusted, no control for multiple testing). Proportions of patients were compared using Cochran-Mantel-Haenzsel (CMH) analysis stratified by region and duration of RA. Data collected after withdrawal/initiation of escape therapy were set to missing. LOCF was used for missing data. Gabay C, et al. Lancet. 2013 May 4;381(9877):1541-50. Therapeutic targeting of IL-6 and its receptor

Hunter CA & Jones SA. Nature Immunology 16, 448–457 (2015) IL-6 inhibitors in rheumatology: At-a-glance

Tocilizumab and sarilumab are approved for RA treatment

Development phase completed (RA): Phase 1 Phase 2 Phase 3

Tocilizumab (Roche) [IL-6]

Sarilumab (Sanofi, Regeneron) [IL-6 ]

Sirukumab (GlaxoSmithKline, Johnson & Johnson)[ IL-6 ]

Clazakizumab (Alder, Vitaeris) [IL-6 ]

Olokizumab (R-Pharm) [IL-6 ]

Vobarilizumab (Ablynx) [IL-6R] SARIL-RA-MOBILITY: Study Flowchart Part A1: 12 weeks Part B2: 52 weeks Cohort 1 Cohort 2

N=1197: Efficacy population

N=1282 (88 – 3 + 1197): Safety population

Selected doses

n=52 Sar 200 mg q2w n=28 n=399 sarilumab 200 mg q2w

n=51 Sar 150 mg q2w n=30 n=400 sarilumab 150 mg q2w

n=52 placebo qw n=30 n=398 placebo qw / q2w Inadequate Rescue: From Week 16, patients with lack of efficacy defined as response to R Nonselected doses: MTX therapy less than 20% improvement from baseline in either SJC or TJC for 2 consecutive visits were eligible for rescue with open label n=51 Sar 100 mg q2w n=28 sar 100 mg q2w sarilumab.

n=50 Sar 100 mg qw n= 29 sar 100 mg qw Open label extension

n=50 Sar 150 mg qw n=27 sar 150 mg qw

Dose selection All IMP added to MTX (6-25 mg/week) background treatment; * 3 patients randomised but never treated. 52 weeks Sar=sarilumab; SJC=swollen joint count; TJC=total joint count. 1. Huizinga TW et al. Ann Rheum Dis. 2013 Dec 2. doi: 10.1136/annrheumdis-2013-204405. 2. Genovese M et al. Presented at: 15th Annual European 7 Congress of Rheumatology, European League Against Rheumatism; June 11-14, 2014; Paris, France. Oral presentation OP0028. Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study

Arthritis & Rheumatology Volume 67, Issue 6, pages 1424-1437, 25 MAY 2015 DOI: 10.1002/art.39093 http://onlinelibrary.wiley.com/doi/10.1002/art.39093/full#art39093-fig-0002 Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study

Arthritis & Rheumatology Volume 67, Issue 6, pages 1424-1437, 25 MAY 2015 DOI: 10.1002/art.39093 http://onlinelibrary.wiley.com/doi/10.1002/art.39093/full#art39093-fig-0003 SARILUMAB MONOTHERAPY IS SUPERIOR TO ADALIMUMAB IN MTX-IR/-INT PATIENTS

MTX-IR/INT patients MONARCH: Week 241,2 Monotherapy

Adalimumab Sarilumab Week 24 40 mg q2wa 200 mg q2w p-value (n=185) (n=184)

Change from baseline in DAS28-ESR, -2.20 (0.106) -3.28 (0.105) <0.0001 mean (SE) DAS28-ESR remission (<2.6), % 7.0 26.6 <0.0001

ACR20 response rate, % 58.4 71.7 0.0074

ACR50 response rate, % 29.7 45.7 0.0017

ACR70 response rate, % 11.9 23.4 0.0036

Change from baseline in HAQ-DI, mean -0.43 (0.045) -0.61 (0.045) 0.0037 (SE)

Sarilumab was superior to adalimumab in reducing disease activity and improving physical function1,2. aIncludes patients who increased the frequency of dosing of adalimumab 40 mg to qw because of an inadequate response. 1. KEVZARA Summary of Product Characteristics. Sanofi Genzyme/Regeneron Pharmaceuticals, 2017; 2. Burmester GR, et al. Ann Rheum Dis. 2017;76(5):840–7. SAFETY PROFILE OF SARILUMAB IS CONSISTENT WITH IL-6 BLOCKADE AND IS STABLE OVER >5 YEARS OF EXPOSURE

TNF-IR of MTX-IR/INT patients EXTEND: [DURATION] Combination therapy Raw incidence Exposure-adjusted incidence Most common AE (≥5%) rate rate n (%) nE (nE/100 PYs)a Neutropenia 527 (18.3) 1090 (14.3) Upper respiratory tract infection 376 (13.0) 592 (7.8) Accidental overdoseb 362 (12.5) 518 (6.8) Urinary tract infection 301 (10.4) 450 (5.9) Alanine aminotransferase 300 (10.4) 396 (5.2) increased Viral upper respiratory tract 281 (9.7) 393 (5.2) infection Bronchitis 238 (8.2) 325 (4.3) Hypertension 238 (8.2) 255 (3.4) RA 236 (8.2) 331 (4.4) Injection-site erythema 216 (7.5) 1071 (14.1) Diarrhea 161 (5.6) 202 (2.7) AE, adverse event; csDMARDs, conventional synthetic disease-modifying antirheumatic drugs; nE, number of events; PY, patient- years; TEAE, treatment-emergent adverse events; RA, rheumatoid arthritis Cytokine receptor signaling through intracellular tyrosine kinases • Many cytokine receptors lack intrinsic kinase activity, instead relying on associated tyrosine kinases, such as JAKs, to transmit signals from the extracellular environment to the nucleus1,2

1. Leonard WJ. Nat Rev Immunol. 2001;1(3):200-208; 2. Mavers M et al. Curr Rheum Rep. 2009;11(5):378-385. 12 JAK inhibitors in rheumatology: At-a-glance

Tofacitinib and are approved for RA treatment

Development phase completed (RA): Phase 1 Phase 2 Phase 3 and Approved

Tofacitinib (Pfizer) [JAK3, JAK2, JAK1]

Baricitinib (Eli Lilly) [JAK1, JAK2]

VX-509 (Vertex) [JAK3]

Filgotinib (Galapagos, Gilead) [JAK1]

ASP-015K (Astellas) [JAK1, JAK3]

ABT-494 (AbbVie) [JAK1]

Adapted from Norman et al. Expert Opin Investig Drugs 2014;23(8):1067-77 Janus family kinases (JAKs)

Cytokine A subgroup of non-receptor protein tyrosine kinases: JAK1, JAK2, JAK3, and TYK21,2

Characterised by two adjacent kinase Cytokine domains, resembling the face of the receptor Roman god Janus2

Implicated in cell growth, survival, JAK development and cell differentiation1

Essential for immune cells and Phosphate 1 haematopoietic cells ions

1. Ghoreschi K et al. Immunol Rev 2009;228:273–87; 2. Thomas SJ et al. Br J Cancer 2015;113:365–71. Cytokines activate JAK signalling pathways leading to transcription of inflammatory mediators

Cytokine • Rapid membrane-to-nucleus signalling: ‒ Cytokines bind trans-membrane receptors that are associated with JAKs1 • Binding activates JAKs • JAKs phosphorylate receptors Cell • STATs bind to receptors membrane • JAKs phosphorylate STATs • STATs translocate to the nucleus

• STATs bind DNA and activate or Cytoplasm repress transcription of target genes Nucleus

Activation of the JAK pathway Gene transcription regulates transcription of genes involved in many cellular processes1

15

Coskun M et al. Pharmacol Res 2013;76:1–8. P, phosphate. The JAK/STAT signalling pathways

• There are four JAK family members: JAK1, JAK2, JAK3, and TYK2

Example of cytokines that signal through JAK/STAT combinations1

γ-chain IFN-γ IL-10 IL-12 IL-6† EPO cytokines2 IL-22 IL-23 IL-11 TPO GM-CSF

STAT STAT STAT STAT STAT STAT 1, 3, 5, 6 1, 3, 5 1, 3, 5 3, 4 1, 3, 5 5

EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; 1. O’Sullivan LA et al. Mol Immunol 2007;44:2497–2506. IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and 2. Ghoreschi K et al. Immunol Rev 2009;228:273-287. activator of transcription; TPO, thrombopoietin; TYK, tyrosine kinase. Differences in JAK Inhibitor Selectivity Necessitates Independent

Characterisation of Each1,2 Molecule In vitro JAK selectivity of JAK inhibitors (IC50, nM; [ATP] = 1 mM)

Tofacitinib Baricitinib (XELJANZ; Pfizer) (Olumiant; Eli Lilly) (Galapagos)

JAK1 15 4 363

JAK2 77 7 2400

JAK3 55 787 >10,000

TYK2 489 61 2600

IL-2, IL-4, IL-7, IL-9, IL-6, IL-11, IL-27, CNTF, EPO, TPO, IL-3, IFN IL-12/23 IL-22 IL-15, IL-21 LIF, OSM GM-CSF γ IL-10 Prolactin IFNα/β

g c JAK JAK JAK TYK JAK JAK TYK JAK TYK JAK JAK JAK JAK 1 3 2 2 Jak 1 2 2 1 2 1 2 22 2

ATP=adenosine triphosphate; EPO=erythropoietin; IC50=half maximal inhibitory concentration; IL=interleukin; IFN=interferon; JAK=Janus kinase; STAT=signal transducer and activator of transcription; TPO=thrombopoietin; TYK2=tyrosine kinase 2. 1. Clark JD, et al. J Med Chem. 2014;57(12):5023-5038. 2. O‘Sullivan LA, et al. Mol Immunol. 2007;44(10):2497-2506. 17 In vitro JAK isoform selectivity

Enzyme essay IC50(nM) Compound JAK1 JAK2 JAK3 TyK2 JAK2:JAK1 JAK3:JAK1 TyK2:JAK1 Tofacitinib 15.1 77.4 55.0 489 5.1 3.6 32.4 Baricitinib 4.0 6.6 787 61 1.5 196.8 15.3 Filgotinib 363 2400 >10,000 2,600 6.6 >27.5 7.2 8 600 139 NA 75 17.4 NA 3.9 5.0 0.7 4.8 1.3 0.2 1.2 Decernotinib 112 619 74.4 >10,000 5.5 0.67 >89

Choy EH. Rheumatology (Oxford). 2019 Jan 28. epub Common beta chain cytokines & hormones gp130 cytokines IL-3, 5, G-CSF, GM-CSF Common g chain IL-6, 11,12, 27 Erythropoietin Interferon-a/b cytokines Leukemia inhibitory Leptin IL-10 cytokine IL-2, 4, 7, 9, 13 factor Thrombopoetin family: IL12, 23 &15 Oncostatin M Growth hormone IL-10, 20, 22, Interferon-g Type III interferon Prolactin 28

P JAK1 JAK3 JAK1 JAK2 JAK2 JAK2 JAK1 TyK2 JAK1 JAK2 JAK2 TyK2 P P P P P P P P P P TyK2 P P

Tofacitinib Tofacitinib Baricitinib Tofacitinib Tofacitinib Baricitinib Baricitinib Baricitinib Baricitinib Baricitinib Upadacitinib Upadacitinib Upadacitinib Upadacitinib Filgotinib Filgotinib Filgotinib Filgotinib Peficitinib Decernotinib Choy EH. Rheumatology (Oxford). 2019 Jan 28. epub Phase 3 Tofacitinib and Baricitinib Programs Tofacitinib (N~5,000) Baricitinib (N~3,000)

MTX-naïve / limited ORAL Start BEGIN MTX-naive Biologic / DMARD-naïve, ≤3 doses MTX allowed 5mg BID vs. 10mg BID vs. MTX 4mg QD + MTX vs 4mg QD vs MTX N=958 N=581 MTX-IR, Humira H2H ORAL Standard ORAL Strategy BEAM 5mg vs. 10mg vs. ADA vs. pbo Phase 4 biologic-naïve N=717 5mg + MTX vs. 5mg vs. 4mg vs. 40mg ADA vs. pbo ADA MTX background N=1080 N=1304 DMARD-IR ORALScan MTX-IR ORAL Sync BUILD 5mg vs. 10mg vs. pbo (MTX 5mg vs. 10mg vs. pbo biologic-naïve bgrd.) DMARD bgrd. 2mg QD vs. 4mg QD vs. pbo pbo X to 5/10 N=792 DMARD background N=611 N=684 DMARD-IR, monotherapy ORAL Solo ORAL Strategy DMARD-IR Phase 4 5mg vs. 10mg vs. pbo 5mg + MTX vs. 5mg vs. pbo X-over to 5mg/10mg ADA N=611 N=1080 Biologic-IR ORAL Step BEACON TNF-IR TNF-IR 5 mg vs. 10 mg vs. pbo 2mg vs. 4mg vs. pbo MTX background DMARD background N=396 N=525 Extension ORAL Sequel BEYOND 10mg / 5mg 2mg vs. 4mg N=4385 DMARD background allowed from originating study N=3073

Source: clinicaltrials.gov, company presentations / publications MTX/DMARD-IR JAK inhibitor MTX-IR Tofacitinib – ORAL Standard study

Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID Adalimumab 40 mg sc Q2W

100 ACR20 (NRI)

• The study was not powered for 80 superiority or non-inferiority *** *** ** between active treatments, 60 and comparisons should not 51.5 52.6 47.2 be made between tofacitinib

40 and adalimumab 28.3 • Advancement penalty

20 Patients with response response with(%) Patients

0 n=30/106 101/196 103/196 94/199 **p<0.001; ***p<0.0001 vs placebo

van Vollenhoven R, et al. NEJM 2012;367:508–519. van Vollenhoven R, et al. NEJM 2012;367:suppl 1–18. RA-BEAM: ACR Response Rate at Weeks 12, 24, and 52

PBO + MTX (n=488) Baricitinib 4 mg + MTX (n=487) ADA 40 mg + MTX (n=330) 100 Wk 12 Wk 24 Wk 52 Primary endpoint + 80 + *** ++ *** 74 70 *** 71 *** 66 61 62 + *** 60 ++ 56 *** 51 *** 45 45 47 40 *** 37 + 37 40 35 ***

Response Rate (%) Rate Response 30 31 + *** *** 22 19 *** 19 20 17 13 8 5 0 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

Primary endpoint: ACR20 vs PBO at Wk 12. Data are % patients achieving response (NRI). ***P≤0.001 vs PBO. +P≤0.05 vs ADA. ++P≤0.01 vs ADA; +++P≤0.01 vs ADA ACR20/50/70=20%, %50, or 70% improvement in American College of Rheumatology; ADA=adalimumab; MTX=methotrexate; NRI=nonresponder imputation; PBO=placebo; wk=week. Taylor P et al. N Engl J Med. Supplement. 2017;376(7):652-662. doi:10.1056/NEJMoa1608345. 23 BIOLOGIC-IR JAK inhibitor BIOLOGIC-IR Tofacitinib – ORAL Step study

Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID

100 ACR20 (Month 3)

80 *** 60 * 48.1 41.7 40 24.4

20 Patients with response (%) response with Patients

0 n=32/131 55/132 64/133 *p<0.05; ***p<0.0001 vs placebo

Burmester GR, et al. Lancet 2013;381:451–60. RA BEACON: ACR Responses at Weeks 12 and 24 PBO Bari 2 mg Bari 4 mg

100 Week 12 Week 24 80 *** ***55 60 49 ****** 45 46 40 *** * *** 27 28 27 29 *** Patients, % Patients, ** 23 20 *** *** 17 20 13 *** 13 13 8 11 2 3 0 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

Data are % patients achieving response (NRI); *p≤0.05, **p≤0.01, ***p≤0.001 vs. PBO

Genovese MC, et al. EULAR 2015. OP0029. MONOTHERAPY JAK inhibitor MTX-IR Tofacitinib – ORAL Solo study

Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID Placebo 5 mg BID Placebo 10 mg BID ACR20

*** ***

Month 3 Month 6 ***p<0.0001 vs placebo; there are no p values at Month 6 as there is no placebo

Fleischmann R, et al. NEJM 2012;367:495–507. Fleischmann R, et al. NEJM 2012;367:Suppl 1–24. ORAL – START 6 month

80 ** ** 70

60 ** 50 ** MTX 40 ** Tofacitinib 5 mg BID 30 ** Tofacitinib 10 mg BID 20

10

0 ACR20 ACR50 ACR70

***p<0.001 vs methotrexate Lee EB et al. N Engl J Med 2014;370:2377-86 RA-BEGIN

Fleischmann R et al. Arthritis Rheumatol. 2017 Mar;69(3):506-517 RADIOGRAPHIC OUTCOME ORAL-SCAN

van der Heijde D, et al. Arthritis Rheum. 2013 Mar;65(3):559-70. Baricitinib Radiographic Data

RA BUILD1 RA BEAM2 RA BEGIN3

PBO Bari 2 mg Bari 4 mg PBO Bari 4 mg ADA 40 mg MTX Bari 4 mg Bari 4 mg + MTX 0.8 2 1.5 0.70 Week 24 1.80 Week 52 Week 24 Week 52

0.6 1.5 1.02

0.47 1.23 Baseline 1 0.80 * 0.81 0.4 0.33 1 0.90 *** 0.61 0.30 0.55 0.71 *** 0.23 *** 0.47 ** 0.61 0.60 0.58 0.39 ** ** *** 0.51*** 0.5 0.40 0.41 * 0.33 0.34 0.15 ** *** *** 0.42 *** * 0.25 0.2 0.5 0.29 0.29 0.26 0.11 * 0.33 *** 0.29 0.21 0.21 * 0.24 ** ** Mean Change fromBaseline MeanChange 0.19 0.14 0.03 0.04 0.12 ** 0.06 0.10 0.03 0.06

0 0 0 LS Mean Change from Mean LS Change mTSS Erosion JSN fromBaseline Mean LS Change mTSS Erosion JSN mTSS Erosion JSN mTSS Erosion JSN mTSS Erosion JSN *p≤0.05, **p≤0.01, ***p≤0.001 vs. PBO *p≤0.05, **p≤0.01, ***p≤0.001 vs. PBO *p≤0.05, **p≤0.01, ***p≤0.001 vs. MTX

RA BUILD: RA BEAM: RA BEGIN: • Significant inhibition of • Significant inhibition of • Significant inhibition of radiographic progression for radiographic progression was radiographic progression both baricitinib 2 and 4 mg vs observed for both baricitinib observed for baricitinib 4 mg placebo 4 mg and adalimumab vs + MTX vs MTX placebo • There was no significant difference in change from baseline in mTSS between baricitnib monotherapy and MTX Safety of JAKi Meta-analysis of Serious Infections in Tofacitinib, Baricitinib, and Biologic DMARDs Agent Trial types Number Incidence rate (95% CI), Patients of trials per 100 PY (N) Tofacitinib 5 mg bid RCT† 15 2.71 2989 Tofacitinib 10 mg bid RCT† 15 2.72 3152 Tofacitinib (all doses) RCT+LTE 17 2.74 6194 Baricitinib 2 mg qd RCT 6 4.75 1657 Baricitinib 4 mg qd RCT 6 . 3.67 3546 TNF inhibitors RCT+LTE 57 4.90 26,492 Adalimumab RCT+LTE 18 5.04 6570 Certolizumab pegol RCT+LTE 5 7.59 3212 RCT+LTE 17 4.06 7141 Golimumab RCT+LTE 6 5.31 2820 Infliximab RCT+LTE 11 6.11 4592 Non-TNF bDMARDs Abatacept RCT+LTE 11 3.04 5953 Rituximab RCT+LTE 8 3.72 2926 Tocilizumab RCT+LTE 13 5.45 5547

Tofacitinib LTE data as of March 2015. Bars indicate 95% CIs. 0 2 4 6 8 10 †Estimate from pooled patient-level data. Patients with events per 100 PY (95% CI) bid=twice daily; CI=confidence interval; bDMARD=biologic disease-modifying antirheumatic drug; LTE=long-term extension; PY=patient year; qd=once daily; RCT=randomized controlled trial; TNF=tumour necrosis factor. Strand V et al. Poster presentation at EULAR 2017. Abstract THU0211. Incidence Rates of Serious and Nonserious Herpes Zoster

8 Phase I, II, III and LTE Phase II, III LTE studies 7 6 5 4 3.63 3.48 3.43 3.73 (95% CI) (95% 3 2.64 2 2.11

Incidence rate per 100 PY 100 per rate Incidence 1 0.69 0 Overall 5 mg 5 mg Placebo ± ADA MTX Overall tofacitinib Tofacitinib Tofacitinib csDMARDs tofacitinib

Patients 7061 3066 3995 1849 2024 1079 257 223 4967 Total PY 21,519 7735 13,784 1777 1903 285 189 290 16,441 Patients with events 782 269 513 61 79 6 5 2 621

Data as of March 2017. Incidence rate of patients per 100 PY. Bars indicate 95% CI. ADA=adalimumab; CI=confidence interval; csDMARDs=conventional synthetic disease-modifying antirheumatic drugs; LTE=long-term extension; MTX=methotrexate; PY=patient-years. Data on file. Pfizer Inc. Incidence Rate of Serious and Non-serious Herpes Zoster with Tofacitinib by Region

Incidence rate per 100 PY (95% CI) Unique patients with Total number of HZ events, n patients, N Global RA program1 3.6 782 7061 By Region2 US/Canada 4.1 190 1745 Europe 2.3 192 2382 Latin America 3.4 123 1221 Asia 5.6 277 1673 Japan 7.8 120 556 7.4 Korea 63 316 India 2.9 16 197 4.3 Thailand/Malaysia/Philippines 27 208 2.9 China/Taiwan 26 260 5.5 Australia/New Zealand 25 136 0 4 8 12 Data from Phase I, II, III and LTE studies for tofacitinib all doses, as of March 2017. CI=confiden,ce interval; HZ=Herpes zoster; PY=patient-years; RA=rheumatoid arthritis. 1. Cohen SB, et al. Ann Rheum Dis. 2017;76(7):1253-1262. 2. Supplement to: Cohen SB, et al. Ann Rheum Dis. 2017;76(7):1253-1262. 3. XELJANZ/XELJANZ XR [prescribing information]. New York, NY: Pfizer Inc; 2017. Incidence Rate of Serious and Non-serious Herpes Zoster with Tofacitinib Monotherapy or Combination ± GCs

Tofacitinib 5 mg bid 8

6

4.8 4 (95% CI) (95% 3.7 3.4

2

Crude incidence rate incidence Crudeper100 PY 0.6 0 +nbDMARD +nbDMARD -nbDMARD -nbDMARD +GCs -GCs +GCs -GCs

Patients 579 394 320 296 PY 603 412 367 361 Patients with events 28 15 12 2 Crude incidence rates (patients with events per 100 PY) were calculated to examine if differences exist. bid=twice daily; CI=confidence interval; GC=glucocorticoid; HZ=Herpes zoster; nbDMARD=non-biologic disease-modifying antirheumatic drug; PY=patient-years. 1. Winthrop K, et al. [abstract]. Arthritis Rheumatol. 2015;67(suppl 10). http://acrabstracts.org/abstract/herpes-zoster-and-tofacitinib- the-risk-of-concomitant-nonbiologic-therapy/. Accessed March 28, 2017. 2. Kivitz AJ et al. Presented at: American College of Rheumatology Annual Meeting; November 6-11, 2015; San Francisco, CA. Poster 2143. The JAK/STAT signalling pathways There are four JAK family members: JAK1, JAK2, JAK3, and TYK2

Key cytokines that signal through JAK/STAT combinations

IL-2, IL-4, IL-6, IL-2, IL-4, IL-5, IL-2, IL-4, IL-6, IL-3, IL-5, IL-6, IL-2, IL-4, IL-3, IL-5, IL-6, IL-12, IL-23, IL-10, IL-11, IL-6, IL-10, IL-11, IL-10, IL-11, IL-10, IL-11, IL- IL-10, IL-11, IL-12, IL-23, EPO, TPO, GM- IFN-β, IFN-γ IFN-β, IFN-γ, IFN-β, IFN-γ 12, IL-23, IFN- IFN-α, IFN-β, IFN-γ CSF, IFN-γ GM-CSF α, IFN-β, IFN-γ

STAT phosphorylation and translocation to the nucleus

Gene transcription and production of inflammatory factors

1. O’Sullivan LA, et al. Mol Immunol 2007;44:2497–506; 2. Ghoreschi K, et al. Immunol EPO, erythropoietin; GM-CSF, granulocyte-macrophage Rev 2009;228:273–87; 3. Sanjabi S, et al. Curr Opin Pharmacol 2009;9:447–53. colony-stimulating factor; TPO, thrombopoietin. Changes in Laboratory Tests with JAKi

Tofacitinib (5mg) Baricitinib (4mg) (JAK, JAK3) (JAK1, JAK2) Haemoglobin (g/dl) +0.47+0.05 -0.17

Neutrophil (x103/mm3) -1.09+0.1 -1.08 +0.07

Lymphocyte count (x103/mm3) -0.24+0.03 -0.05

Platelets -30% Increase

Choy EH. Rheumatology (Oxford). 2019 Jan 28. epub Conclusions

• Recent approved therapeutic agents in Europe for the treatment of RA in 2017: – IL-6 inhibitor: sarlimumab – Janus Kinase inhibitors: Tofacitinib and Baricitinib • Sarlimumab has similar efficacy and safety profile as Tocilizumab • JAKi selectively is relative and not absolute. • Current approved JAKi and those in development significantly inhibit JAK1 isoform. • JAK1 is an effective target in RA although zoster reactivation is a class effect. • The balance of benefit and risk of inhibiting JAK2, JAK3 and TYK2 is uncertain and should be evaluated in the future.