Thromobosis and Targeted Synthetic Dmards: Is the Risk Real?? Learning Objectives

Thromobosis and Targeted Synthetic DMARDs: Is the Risk Real?? Learning Objectives

• Review data on the currently approved targeted synthetic DMARDs (tsDMARDs) for RA • Understand the potential risks of approved tsDMARDs • Assess the association between tsDMARDs and thromboembolic events Note: This presentation will include discussion of non-FDA approved drugs in the treatment of RA. The Concept of Intracellular Signaling Pathways

Cytokine, Immune complex, Antigen…

TNF Transduction Transcription Nucleus eg, STAT, MAPK DNA P Anti-TNF P P eg, STAT, NF-kB Ligand eg, JAK, SYK, BtK Binding mRNA

microRNA Translation Release/ Cell Membrane Secretion Effector Protein Expressed

STAT = signal transducers and activators of transcription; MAPK = mitogen-activated protein kinase; BtK = Bruton’s tyrosine kinase; NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells; mRNA = messenger ribonucleic acid; microRNA = micro ribonucleic acid. McInnes IB. Kelly’s Textbook of Rheumatology. 2011. Human Kinome

• A subset of the genome, consisting of the protein kinase genes

• Protein kinases act as key regulators of cell function by catalyzing the addition of a negatively charged phosphate group to proteins

• Regulates protein function in both normal and disease states

• Over 500 kinome genes have been identified

TK = tyrosine kinase; TKL = tyrosine kinase-like; STE = serine/threonine kinase; CKI = casein kinase I ; CAMK = Ca2+/calmodulin-dependent protein kinase; RGC = receptor guanylate cyclase Manning G, et al. Science. 2012;298:1912-1934. Oral Kinase Inhibitors Approved for RA

• Tofacitinib1 – Indicated for treatment of adult patients with moderately to severely active RA – May be used as monotherapy or in combination with MTX or other non-biologic DMARDs – Approved November 6, 2012 • Baricitinib2 – Indicated for treatment of adult patients with moderately to severely active RA who have had an inadequate response to ≥1 TNF antagonist – Approved June 4, 2018 • Upadacitinib3 – Indicated for the treatment of adults with moderately to severely active RA who have had an inadequate response or intolerance to MTX – Approved August 16, 2019

1. Available at: www1.pfizerpro.com/product/xeljanz. Accessed September 16, 2019; 2. Available at: https://www.olumiant.com/hcp. Accessed September 16, 2019; 3. Available at: https://www.rxabbvie.com/pdf/rinvoq_pi.pdf. Accessed September 16, 2019. Unapproved Kinase Inhibitor Being Investigated for Use in RA

• Filgotinib – Phase 3 programs ongoing in: – Rheumatoid arthritis – Ulcerative colitis – Crohn’s disease – Phase 2 studies in: – Small bowel Crohn’s disease – Fistulizing Crohn’s disease – Sjögren’s syndrome – Axial spondyloarthritis – Psoriatic arthritis – Cutaneous lupus – Lupus membranous nephritis – Uveitis

Available at: http://www.glpg.com/filgotinib. Accessed March 7, 2020. Cytokine Receptor Activation and JAK Pathway Signaling

• Cytokines bind to cell surface receptors Cytokine leading to receptor polymerization and activation of associated JAKs.1 The JAK family includes JAK1, JAK2, JAK3, JAK JAK 1-3 and TYK2 P P P P P

P STAT • Activated JAKs phosphorylate the cytokine STAT Phosphate group receptors. These receptors then dock

1 STAT (bind) STATs STAT

• Activated JAKs then phosphorylate the docked STATs. The now activated STATs dimerize and move to the nucleus to Gene transcription/ activate new gene transcription1,3 Cytokine production

P = phosphate; TYK2 = tyrosine kinase 2; JAK = Janus kinase; STAT = signal transducer and activator of transcription 1. Shuai K, Liu B. Nat Rev Immunol. 2003;3(11):900-911; 2. O’Sullivan LA, et al. Mol Immunol. 2007;44:2497-2506; 3. O’Shea JJ, et al. N Engl J Med. 2013;368:161-170. Targeting Cytokine Signaling Pathways Using Janus Kinase (JAK) Inhibitors

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

JAK independent IL-1 IL-17 IL-18 TGF-β TNF Ghoreschi K, et al. Nature Immunology. 2009;10(4):356-360. JAK Inhibitors: Comparison of Enzymatic Activity

Enzyme Assay IC50 (nM)*

Compound JAK1 JAK2 JAK3 Selectivity

Tofacitinib 15.1 77.4 55.0 JAK1 > JAK3 > JAK2

Baricitinib 6.4 8.8 487.0 JAK1/JAK2

Upadacitinib 14 593 1860 JAK1 Tofacitinib Baricitinib Filgotinib 363 2400 >104 JAK1

*Run in the presence of 1 mM ATP. Clark JD, et al. J Med Chem. 2014; 57: 5023-5038; Parmentier JM, et al. BMC Rheumatol. 2018; 2: 23. Filgotinib Upadacitinib Tofacitinib Inhibits JAK1 & JAK3 Signaling Pathways

Tofacitinib • Oral, reversible competitor of ATP binding site of JAK with chemical structure related to ATP

• t1/2  3 hours • Originally developed as a JAK3 inhibitor, tofacitinib was found to inhibit JAK3 and JAK1 with functional specificity over JAK2

JAK = Janus kinase; ATP = Adenosine triphosphate. O'Shea JJ, et al. Annu Rev Med. 2015. 66:311-28. JAK Inhibitors: Comparison of Enzymatic Activity

Enzyme Assay IC50 (nM)*

Compound JAK1 JAK2 JAK3 Selectivity

Tofacitinib 15.1 77.4 55.0 JAK1 > JAK3 > JAK2

Baricitinib 6.4 8.8 487.0 JAK1/JAK2

Upadacitinib 14 593 1860 JAK1 Tofacitinib Baricitinib Filgotinib 363 2400 >104 JAK1 t1/2  3 hours

*Run in the presence of 1 mM ATP. Clark JD, et al. J Med Chem. 2014; 57: 5023-5038; Parmentier JM, et al. BMC Rheumatol. 2018; 2: 23. Filgotinib Upadacitinib Tofacitinib Phase 3 Clinical Program in RA

Trial Patient Population N Unique feature Therapy Duration

Monotherapy / Radiographs • TOFA 5 mg PO BID (n=373) MTX-naïve ORAL Start1 MTX-naïve 958 Co-primary endpoints: • TOFA 10 mg PO BID (n=397) 24 months ACR70/ vdH-mTSS • MTX 10 mg→20 mg PO weekly (n=186)

Monotherapy • TOFA 5 mg PO BID (n=243) csDMARD-IR • TOFA 10 mg PO BID (n=245) ORAL Solo2 611 Co-primary endpoints: 6 months (bDMARD-IR: 16.2%) • Placebo  3 mo → TOFA 5 mg PO BID (n=61) ACR20/ HAQ-DI/DAS28 < 2.6 • Placebo  3 mo → TOFA 10 mg PO BID (n=61) DMARD-IR csDMARD-IR • TOFA 5 mg PO BID (n=318) Co-primary endpoints: • TOFA 10 mg PO BID (n=318) ORAL Sync3 (bDMARD-IR: 6.6%) 795 12 months ACR20/ HAQ-DI/DAS28 < 2.6 • Placebo  6 mo → TOFA 5 mg PO BID (n=79) (stable csDMARD dose) • Placebo  6 mo → TOFA 10 mg PO BID (n=80)

Radiographs • TOFA 5 mg PO BID (n=321) MTX-IR • TOFA 10 mg PO BID (n=316) ORAL Scan4 797 Co-primary endpoints: 24 months (stable MTX dose) • Placebo  6 mo → TOFA 5 mg PO BID (n=81) ACR20/ vdH-mTSS • Placebo  6 mo → TOFA 10 mg PO BID (n=79)

• TOFA 5 mg PO BID (n=204) MTX-IR Active comparator (adalimumab) ORAL • TOFA 10 mg PO BID (n=201) (bDMARD-IR: 7.5%) 717 Co-primary endpoints: • Adalimumab 40 mg SC every 2 wk (n=204) 12 months MTX-IR Standard5 (stable MTX dose) ACR20/ HAQ-DI/DAS28 < 2.6 • Placebo  3 or 6 mo → TOFA 5 mg PO BID (n=56) • Placebo  3 or 6 mo → TOFA 10 mg PO BID (n=52)

Primary endpoint: ACR50 ORAL MTX-IR TOFA monotherapy vs TOFA + MTX • TOFA 5 mg PO BID monotherapy (n=384) 6 1152 • TOFA 5 mg PO BID + MTX PO weekly (n=378) 12 months Strategy (stable MTX dose) TOFA + MTX vs ADA + MTX • Adalimumab 40 mg SC every 2 wk + MTX PO weekly (n=388) TOFA monotherapy vs ADA + MTX

• TOFA 5 mg PO BID (n=133) TNFi-IR Co-primary endpoints: • TOFA 10 mg PO BID (n=134) TNFi-IR ORAL Step7 399 6 months (stable MTX dose) ACR20/ HAQ-DI/DAS28 < 2.6 • Placebo  3 mo → TOFA 5 mg PO BID (n=66) • Placebo  3 mo → TOFA 10 mg PO BID (n=66) bDMARD, biologic disease-modifying antirheumatic drug; csDMARD, conventional synthetic disease-modifying antirheumatic drug; IR, inadequate responder; vdH-mTSS, van der Heijde modified total Sharp score; MTX, methotrexate; TNFi, tumor necrosis factor inhibitor; TOFA, tofacitinib 1. Lee EB, et al. N Engl J Med. 2014;370:2377–86; 2. Fleischmann R et al. N Engl J Med. 2012;367:495–507; 3. Kremer J, et al. Ann Intern Med. 2013;159:253–61; 4. van der Heijde D, et al. Arthritis Rheum. 2013;65:559–70; 5. van Vollenhoven R, et al. N Engl J Med. 2012;367:508–19; 6. Fleischmann R, et al. Lancet. 2017; 390:457-68; 7. Burmester G, et al. Lancet. 2013;381:451–60. Proportion of ACR20 Responders Across Tofacitinib Phase 3 Studies (FAS, NRI)

100 Placebo / MTX Tofacitinib 5 mg BID Tofacitinib 10 mg BID Adalimumab 90 *** *** ACR20 was a co-primary endpoint for all studies except ORAL Start 76 80 71 *** *** *** *** 66 70 62 60 *** *** ** *** 58 53 *** 60 51 51 52 *** 53 47 * 48 50 42

40 28 31 25 27 24 30 20

10 Proportion ACR20 SE)(%, Responders ACR20 Proportion 0 N= 186 373 397 154 309 309 106 196 196 199 157 311 309 120 241 242 131 132 133 ORAL Start1 ORAL Scan2 ORAL Standard3 ORAL Sync4 ORAL Solo5 ORAL Step6 (6 mos) (6 mos) (6 mos) (6 mos) (3 mos) (3 mos)

MTX-naïve MTX-IR DMARD-IR TNFi-IR

*p≤0.05; **p<0.001; ***p<0.0001 vs. placebo/MTX. ACR=American College of Rheumatology; BID=twice daily; DMARD=disease-modifying antirheumatic drug; FAS=full analysis set; IR=inadequate response; MTX=methotrexate; NRI=non-responder imputation; SE=standard error; TNFi=tumor necrosis factor inhibitor. 1. Lee EB et al. N Engl J Med. 2014;370:2377–86; 2. van der Heijde D et al. Arthritis Rheum. 2013;65:559–70; 3. van Vollenhoven R et al. N Engl J Med. 2012;367:508–19; 4. Kremer J et al. Ann Intern Med. 2013;159:253–61; 5. Fleischmann R et al. N Engl J Med. 2012;367:495–507; 6. Burmester G et al. Lancet. 2013;381:451–60. Tofacitinib: ORAL Strategy (MTX-IR)

• 12-month, phase 3b/4, double-blind, head-to-head, randomized controlled trial • 1146 patients with active RA: – Inadequate response to MTX • Patients randomly assigned 1:1:1 to – Tofacitinib 5 mg PO BID monotherapy (n=384) – Tofacitinib 5 mg PO BID + MTX PO weekly (n=378) – Adalimumab 40 mg SC every 2 wk + MTX PO weekly (n=388)

MTX-IR Tofacitinib 5 mg BID + MTX (N=376) patients with active RA Tofacitinib 5 mg BID (N=384)

(N=1152)*

Randomis Screening ation 1:1:1 Adalimumab 40 mg Q2W + MTX (N=386)

Day -42 Day 1 Month 6 (primary endpoint) Month 12 • Primary endpoint at month 6: Proportion of patients achieving ACR50

Fleischmann R, et al. Lancet. 2017; 390:457-68. ORAL Strategy: Concomitant Medications

• MTX  25 mg/week – Dose maintained throughout study unless modification was clinically indicated – Doses < 15 mg/week allowed only in presence of documented intolerance or toxicity – Doses > 25 mg/week were not permitted • Background arthritis therapy – Subjects continued on stable background arthritis therapy, including MTX (or placebo MTX; required), NSAIDs, analgesics, and/or low-dose glucocorticoids (≤ 10 mg/d prednisone or equivalent) – Stable dose for ≥ 4 weeks prior to baseline and during study period

• Primary efficacy analysis: Noninferiority of ACR50 at month 6 (independent treatment comparisons)

Tofacitinib + MTX Tofacitinib monotherapy Tofacitinib monotherapy vs vs vs ADA + MTX ADA + MTX Tofacitinib + MTX

Fleischmann R, et al. Lancet. 2017; 390:457-68. ORAL Strategy: ACR Response Rates at Month 6 (FAS)

Tofacitinib monotherapy (n=384) Tofacitinib + MTX (n=376) Adalimumab + MTX (n=386) 100

80 Primary endpoint

Response rate (%) rate Response 20 65.0 73.0 71.0 38.0 46.0 44.0 18.0 25.0 21.0 0 ACR20 ACR50 ACR70

ACR, American College of Rheumatology; FAS, full analysis set; MTX, methotrexate. Fleischmann R, et al. Lancet. 2017;390:457–468. ORAL Strategy: Statistical Analysis

Non-inferiority margin • Per standard practice, a non-inferiority margin of ~50% of the observed treatment A Superior difference in clinical trials of Lower bound of CI >0 adalimumab + MTX vs placebo B Non-inferior was calculated1,2 Lower bound of CI >NI margin – Margin = −13%3 Non-inferiority not C demonstrated • Bonferroni corrections suggested an alpha Lower bound of CI ≤NI margin value of 0.0166; therefore, non-inferiority D Inferior would be confirmed if the lower bound Upper bound of CI <0 of the 98.34% CI was > −13%3 0 • If non-inferiority was shown, superiority Treatment difference was declared if the lower bound of the 98.34% CI of the difference was > 03

CI, confidence interval; MTX, methotrexate; NI, non-inferiority. 1. Machado, et al. Rev Bras Reumatol. 2013;53:419–430; 2. van Vollenhoven, et al. N Engl J Med. 2012;367:508–519; 3. Fleischmann R, et al. Lancet. 2017;390:457–468; Figure adapted from: Piaggio, et al. JAMA. 2006;295: 1152–160. ORAL Strategy: Analysis of Primary Endpoint (Non-inferiority of ACR50 at 6 Months) (FAS)

• Non-inferiority is demonstrated if lower bound of CI is larger than –13% (to right of dashed line) • Superiority is demonstrated if lower bound of CI is larger than 0 • Inferiority is demonstrated when upper bound of CI is less than 0 (dark gray bar) ACR, American College of Rheumatology; CI, confidence interval; FAS, full analysis set; MTX, methotrexate. FleischmannFleischmann R, et R al. et Lancet al. Lancet. 2017;390:457. 2017;390:457–468.–468. ORAL Strategy: Safety and Conclusions

• Similar discontinuations because of AEs: – 23 (6%) of 384 patients receiving tofacitinib monotherapy – 26 (7%) of 376 patients receiving tofacitinib + MTX – 36 (9%) of 386 patients receiving adalimumab + MTX • 2 deaths among 384 patients receiving tofacitinib monotherapy (urosepsis; H1N1 influenza) • Conclusion: Tofacitinib + MTX was non-inferior to adalimumab + MTX for treatment of RA in patients inadequately responsive to MTX – Tofacitinib monotherapy was not shown to be non-inferior to either combination.

Fleischmann R, et al. Lancet. 2017;390:457–468. JAK Inhibitors: Comparison of Enzymatic Activity

Enzyme Assay IC50 (nM)*

Compound JAK1 JAK2 JAK3 Selectivity

Tofacitinib 15.1 77.4 55.0 JAK1 > JAK3 > JAK2

Baricitinib 6.4 8.8 487.0 JAK1/JAK2

Upadacitinib 14 593 1860 JAK1

Filgotinib 363 2400 >104 JAK1 Tofacitinib Baricitinib t1/2  12 hours

*Run in the presence of 1 mM ATP. Clark JD, et al. J Med Chem. 2014; 57: 5023-5038; Parmentier JM, et al. BMC Rheumatol. 2018; 2: 23. Filgotinib Upadacitinib Baricitinib Phase 3 Clinical Program in RA

Trial Patient Population N Unique feature Therapy Duration

• BARI 4 mg PO daily (n=159) csDMARD-naïve & • BARI 4 mg PO daily + MTX 10 mg→20 mg PO RA-BEGIN1 588 Early RA 52 weeks bDMARD-naïve weekly (n=215) • MTX 10 mg→20 mg PO weekly (n=210) bDMARD-naïve csDMARD-IR • BARI 2 mg PO daily (n=229) Radiographs RA-BUILD2 (stable csDMARD 684 • BARI 4 mg PO daily (n=227) 24 weeks Primary endpoint: ACR20 dose) • Placebo PO daily (n=228) at week 12 Active comparator (adalimumab) • BARI 4 mg PO daily (n=487) MTX-IR RA-BEAM3 1307 Radiographs • Adalimumab 40 mg SC every 2 wk (n=330) 52 weeks (stable MTX dose) Primary endpoint: ACR20 • Placebo  24 wk → BARI 4 mg PO daily (n=488) at week 12 bDMARD-IR • BARI 2 mg PO daily (n=174) Primary endpoint: ACR20 RA-BEACON4 (stable csDMARD 527 • BARI 4 mg PO daily (n=177) 24 weeks at week 12 dose) • Placebo PO daily (n=176)

BARI, baricitinib; bDMARD, biologic disease-modifying antirheumatic drug; csDMARD, conventional synthetic disease-modifying antirheumatic drug; IR, inadequate responder; MTX, methotrexate. 1. Fleischmann R et al. Arthritis Rheum. 2017;69:506-17; 2. Dougados M et al. Ann Rheum Dis. 2017;76:88-95; 3. Taylor PC et al. N Engl J Med. 2017;376:652-62; 4. Genovese MC et al. N Engl J Med. 2016;374:1243-52. Baricitinib: RA-BEAM (MTX-IR)

• 52-week, phase 3, double-blind, randomized placebo- and active-controlled trial • 1307 patients with active RA: – Previous inadequate response or intolerance to MTX – Receiving concomitant background MTX – ≥3 joint erosions on hand, wrist, or foot radiographs, or ≥1 joint erosion + IgM RF or + anti-CCP antibodies • Patients randomly assigned 3:3:2 to – Placebo PO daily + MTX  24 weeks → baricitinib 4 mg PO daily + MTX (n=488) – Baricitinib 4 mg PO daily + MTX (n=487) – Adalimumab 40 mg SC every 2 weeks + MTX (n=330) • Primary endpoint at week 12: Proportion of patients achieving ACR20

Taylor PC, et al. N Engl J Med. 2017;376:652-62. RA-BEAM: Baricitinib + MTX Is Superior to Adalimumab + MTX in RA Patients Inadequately Responsive to MTX

***p<0.001 for baricitinib 4 mg or adalimumab vs. placebo, without adjustment for multiple comparisons. +p0.05, ++p0.01, +++p0.001 for baricitinib 4 mg vs. adalimumab, without adjustment for multiple comparisons. † statistical significance for baricitinib 4 mg vs. adalimumab or baricitinib 4 mg vs. placebo with studywise error rate strongly controlled at =0.05 for multiple comparisons. Taylor PC, et al. N Engl J Med. 2017;376:652-62. RA-BEAM: Baricitinib + MTX Is Superior to Adalimumab + MTX in RA Patients Inadequately Responsive to MTX

***p<0.001 for baricitinib 4 mg or adalimumab vs. placebo, without adjustment for multiple comparisons. +p0.05, ++p0.01, +++p0.001 for baricitinib 4 mg vs. adalimumab, without adjustment for multiple comparisons. † statistical significance for baricitinib 4 mg vs. adalimumab or baricitinib 4 mg vs. placebo with studywise error rate strongly controlled at =0.05 for multiple comparisons. Taylor PC, et al. N Engl J Med. 2017;376:652-62. RA-BEAM: Baricitinib + MTX & Adalimumab + MTX Inhibit Progression of Structural Damage at Week 24

**p0.01, ***p0.001 for baricitinib 4 mg or adalimumab vs. placebo. † statistical significance for baricitinib 4 mg vs. adalimumab or baricitinib 4 mg vs. placebo with studywise error rate strongly controlled at =0.05 for multiple comparisons. Taylor PC, et al. N Engl J Med. 2017;376:652-62. RA-BEAM: Safety and Conclusions

• AEs were more frequent through week 24 with baricitinib 4 mg + MTX & adalimumab + MTX vs placebo + MTX • Baricitinib was associated with  neutrophil counts,  creatinine, &  LDL cholesterol • In RA patients inadequately responsive to MTX, baricitinib 4 mg + MTX exhibited significantly greater efficacy than adalimumab + MTX or placebo + MTX at week 12 – ACR20 response rate –  DAS28-CRP • Significant inhibition of progression of structural damage at week 24 with both baricitinib 4 mg + MTX & adalimumab + MTX • Conclusion: Baricitinib 4 mg + MTX is superior to adalimumab + MTX in RA patients inadequately responsive to MTX

Taylor PC, et al. NEJM. 2017;376:652-62. JAK Inhibitors: Comparison of Enzymatic Activity

Enzyme Assay IC50 (nM)*

Compound JAK1 JAK2 JAK3 Selectivity

Tofacitinib 15.1 77.4 55.0 JAK1 > JAK3 > JAK2

Baricitinib 6.4 8.8 487.0 JAK1/JAK2

Upadacitinib 14 593 1860 JAK1

Filgotinib 363 2400 >104 JAK1 Tofacitinib Baricitinib

*Run in the presence of 1 mM ATP. Clark JD, et al. J Med Chem. 2014; 57: 5023-5038; Parmentier JM, et al. BMC Rheumatol. 2018; 2: 23. Filgotinib Upadacitinib Upadacitinib (ABT-494) Phase 3 Clinical Program in RA

Trial Patient Population N Unique feature Therapy Duration

• UPA 15 mg PO daily + MTX matching placebo PO weekly SELECT-EARLY MTX-naïve 945 MTX-naïve • UPA 30 mg PO daily + MTX matching placebo PO weekly 48 weeks • MTX PO weekly + UPA matching placebo PO daily • UPA 15 mg once daily  240 wk SELECT- • UPA 30 mg once daily  240 wk MTX-IR 648 Monotherapy 240 weeks MONOTHERAPY • MTX PO weekly  14 wk → UPA 15 mg PO daily  226 wk • MTX PO weekly  14 wk → UPA 30 mg PO daily  226 wk Active comparator • UPA 15 mg PO daily SELECT- MTX-IR 1629 (adalimumab) • Adalimumab 40 mg SC every 2 wk 5 years COMPARE (stable MTX dose) Radiographs • Placebo  26 wk → UPA 15 mg PO daily

SELECT- bDMARD-IR Active comparator • UPA PO daily 614 5 years CHOICE (stable csDMARD dose) (abatacept) • Abatacept IV every 2 wk  24 wk → UPA PO daily

• UPA 15 mg PO daily csDMARD alone-IR • UPA 30 mg PO daily SELECT-NEXT 661 csDMARD alone-IR 5 years (stable csDMARD dose) • Placebo PO daily  12 wk → UPA 15 mg PO daily • Placebo PO daily  12 wk → UPA 30 mg PO daily • UPA 15 mg PO daily SELECT- bDMARD-IR • UPA 30mg PO daily 499 bDMARD-IR 240 weeks BEYOND (stable csDMARD dose) • Placebo PO daily  12 wk → UPA 15 mg PO daily  228 wk • Placebo PO daily  12 wk → UPA 30 mg PO daily  228 wk http://www.clinicaltrials.gov Accessed August 24, 2019. Upadacitinib: SELECT-COMPARE (MTX-IR)

• 5-year, phase 3, double-blind, randomized • Two separate primary endpoints at week 12 controlled trial – Proportion of patients achieving ACR20 – 26-week placebo-controlled period – Proportion of patients achieving DAS28(CRP) – Double-blind extension of up to 5 years <2.6 • 1629 patients with active RA: • Inhibition of radiographic progression – Stable MTX dose assessed at week 26 – Inadequate response to MTX • Study powered to test for noninferiority & • Patients randomly assigned 2:2:1 to superiority of upadacitinib vs. adalimumab – Placebo  26 wk → UPA 15 mg PO daily (n=651) – UPA 15 mg PO daily (n=651) – Adalimumab 40 mg SC every 2 weeks (n=327)

Fleischmann R, et al. Arthritis Rheumatol. 2019; 71(11):1788-1800. Upadacitinib: SELECT-COMPARE (MTX-IR)

Fleischmann R, et al. Arthritis Rheumatol. 2019; 71(11):1788-1800. Upadacitinib: SELECT-COMPARE ACR20 & DAS28(CRP) Responders

For upadacitinib vs placebo, **p ≤ 0.01 and ***p ≤ 0.001. For upadacitinib vs adalimumab, #p ≤ 0.05, ##p ≤ 0.01, ###p ≤ 0.001. Multiplicity-controlled comparisons: †upadacitinib vs adalimumab; ¶upadacitinib vs placebo. Fleischmann R, et al. Arthritis Rheumatol. 2019; 71(11):1788-1800. UpadacitUpadacitinibinib: SELEC:T SELECT-COMPA-COMPARE:RE: RadiogRadiographicraphic Progre Progressionssion at We eatk Week26 26

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Least-squares (LS) mean change from baseline in the modified total Sharp/van der Heijde score (mTSS) of radiographic progression, erosion, Leandast -jointsqua spaceres (L Snarrowing) mean c h(JSN)ange atfr oweekm ba s26el i(withne in linearthe m extrapolation).odified total Sh aForrp/ vupadacitiniban der Heijdvse splacebo,core (m T***SSp)≤ o 0.001.f radio g¶multiplicityraphic pro-gcontrolledression, e rosion, ¶ ancomparison,d joint spac eupadacitinib narrowing (vsJSplacebo.N) at we eComparisonsk 26 (with lin ebetweenar extrapupadacitinibolation). Foandr up adalimumabadacitinib ve forrsu radiographics placebo, ** progression*p ≤ 0.001. weremulti pnotlici tprespecified.y-controlled comparison, upadacitinib vs placebo. Comparisons between upadacitinib and adalimumab for radiographic progression were not prespecified. Fleischmann R, et al. Arthritis Rheumatol. 2019; 71(11):1788-1800. Fleischmann R, et al. Arthritis Rheumatol. 2019 Jul 9. doi: 10.1002/art.41032. [Epub ahead of print] JAK Inhibitors: Comparison of Enzymatic Activity

Enzyme Assay IC50 (nM)*

Compound JAK1 JAK2 JAK3 Selectivity

Tofacitinib 15.1 77.4 55.0 JAK1 > JAK3 > JAK2

Baricitinib 6.4 8.8 487.0 JAK1/JAK2

Upadacitinib 14 593 1860 JAK1

Filgotinib 363 2400 >104 JAK1 Tofacitinib Baricitinib

*Run in the presence of 1 mM ATP. Clark JD, et al. J Med Chem. 2014; 57: 5023-5038; Parmentier JM, et al. BMC Rheumatol. 2018; 2: 23. Filgotinib Upadacitinib Filgotinib Phase 3 Clinical Program in RA

Trial Patient Population N Unique feature Therapy Duration

• Filgotinib 100 mg PO daily + MTX (n=480) MTX-IR Active comparator • Filgotinib 200 mg PO daily + MTX (n=475) FINCH 1 1,759 52 weeks (stable MTX dose) (adalimumab) • Adalimumab 40 mg SC every 2 wk + MTX (n=325) • Placebo + MTX (n=475)

bDMARD-IR • Filgotinib 100 mg PO daily (n=153) FINCH 2 448 bDMARD-IR • Filgotinib 200 mg PO daily (n=148) 24 weeks (stable csDMARD dose) • Placebo PO daily (n=148) • Filgotinib 100 mg PO daily + MTX (n=207) • Filgotinib 200 mg PO daily + MTX (n=416) FINCH 3 MTX-naïve 1,249 Monotherapy 52 weeks • Filgotinib 200 mg PO daily (monotherapy) (n=210) • Placebo + MTX (n=416)

http://www.clinicaltrials.gov Accessed August 24, 2019. Filgotinib Phase 3: FINCH 1 (MTX-IR) Week 12 Efficacy Results

100 Filgotinib 200 mg + MTX (n=475) 100 *p<0.001 vs. placebo * Filgotinib 100 mg + MTX (n=480) †p<0.001 non-inferiority to adalimumab 76.6 * 80 80 ‡p<0.01 non-inferiority to adalimumab 69.8 70.8 Adalimumab 40 mg + MTX # p<0.01 superiority to adalimumab (n=325) 60 Placebo + MTX (n=475) * 60 *† 49.9 47.2 49.7 * * 43.4 *# 40 36.3 35.1 38.8 * 40 33.9 * 26.3 ‡ * 19.8 18.5 23.4 23.8 23.7 20

% Patients with response with Patients % 14.2 20 6.7 response with Patients % 9.3

0 ACR20 ACR50 ACR70 0 DAS28(CRP) <3.2 DAS28(CRP) <2.6

Combe B, et al. Ann Rheum Dis. 2019; 78(Suppl 2): A77. Increased Risk of Pulmonary Embolism & Deep Vein Thrombosis in RA

• Cohort analyses of incident venous thromboembolism (pulmonary embolism or deep vein thrombosis) using data from a population-based cohort representative of the UK general population – 9,589 patients with incident RA – 95,776 age-, sex-, & entry-time-matched individuals without RA

Pulmonary Embolism Deep Vein Thrombosis

Choi HK, et al. Ann Rheum Dis. 2013;72:1182-1187. Thromboembolic Adverse Events and JAK Inhibitors: Analysis of Spontaneous Postmarketing Case Reports Submitted to FDA

‘Primary suspect’ Reporting Odds Ratio Empirical Bayesian Drug Adverse event cases (95% CI) Geometric Mean (95% CI) Ruxolitinib Pulmonary thrombosis 9 1.46 (0.76–2.80) 1.25 (0.70) Pulmonary embolism 55 0.59 (0.45–0.77) 0.57 (0.45) Portal vein thrombosis 11 4.08 (2.25–7.38) 3.04 (1.79) Deep vein thrombosis 40 0.57 (0.42–0.78) 0.54 (0.42) Thrombosis 75 1.22 (0.97–1.53) 1.16 (0.96) Tofacitinib Pulmonary thrombosis 18 2.46 (1.55–3.91) 2.46 (1.64) Pulmonary embolism 36 0.33 (0.23–0.45) 0.37 (0.28) Portal vein thrombosis 0 – – Deep vein thrombosis 18 0.22 (0.14–0.34) 0.24 (0.16) Thrombosis 43 0.59 (0.43–0.79) 0.66 (0.51) Tofacitinib XR Pulmonary thrombosis 3 2.48 (0.80–7.71) 1.56 (0.57) Pulmonary embolism 3 0.16 (0.05–0.51) 0.18 (0.06) Portal vein thrombosis 0 – – Deep vein thrombosis 1 0.07 (0.01–0.52) 0.08 (0.01) Thrombosis 5 0.41 (0.17–1.00) 0.43 (0.20) Reporting odds ratios (RORs) with a two-sided lower 95% confidence bound >1.0 were considered significant. Empirical Bayesian Geometric Means (EBGMs) with a one-sided 95% lower confidence bound >1.0 were considered significant. Where both ROR and EBGM were >1.0, but one lower bound CI was <1.0, were considered to be a ‘trend.’ Verden A, et al. Drug Saf. 2018;41: 357–361. Increased Risk of Thromboembolism with JAK Inhibitors: All Diseases

• Meta-analysis of 9 published randomized, placebo-controlled trials (Phase II & III) that evaluated JAK inhibitor therapies in any disease and had reported safety data

• Patients receiving JAK inhibitors (n=9,496) had higher risk of thromboembolic events Odds Ratio 4.09 (95% CI 1.91-8.48, p < 0.001)

Bilal J, et al. Risk of Thromboembolism with Janus Kinase Inhibitors: A Systematic Review and Meta-Analysis of Randomized Placebo Controlled Trials [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/risk-of-thromboembolism-with-janus-kinase-inhibitors-a-systematic- review-and-meta-analysis-of-randomized-placebo-controlled-trials/. Accessed May 22, 2020. No Increased Incidence of Thromboembolic Events in Tofacitinib Rheumatoid Arthritis, Psoriasis, Psoriatic Arthritis and Ulcerative Colitis Development Programs

Placebo-controlled cohort Dose-comparison cohort IR (95% CI) Tofacitinib Tofacitinib Tofacitinib Tofacitinib Adalimumab Methotrexate Placebo n/N 5 mg BID 10 mg BID 5 mg BID 10 mg BID 40 mg SC Q2W 20 mg QW Rheumatoid arthritis (N=5368; PY=4440) 0.0 (0.0, 0.9) 0.0 (0.0, 0.8) 0.4 (0.0, 2.4) 0.1 (0.0, 0.3) 0.1 (0.0, 0.3) 0.0 (0.0, 1.9) 0.7 (0.1, 2.5) DVT 0/1849 0/2024 1/1079 1/1849 1/2024 0/257 2/223 0.0 (0.0, 0.9) 0.0 (0.0, 0.8) 0.4 (0.0, 2.4) 0.1 (0.0, 0.4) 0.2 (0.0, 0.4) 0.0 (0.0, 1.9) 0.0 (0.0, 1.3) PE 0/1849 0/2024 1/1079 2/1849 3/2024 0/257 0/223 Psoriasis (N=3662; PY=8763) 0.0 (0.0, 1.0) 0.0 (0.0, 1.0) 0.0 (0.0, 2.1) 0.0 (0.0, 0.4) 0.0 (0.0, 0.4) DVT – – 0/1123 0/1120 0/530 0/1217 0/1219 0.0 (0.0, 1.0) 0.0 (0.0, 1.0) 0.0 (0.0, 2.1) 0.0 (0.0, 0.4) 0.0 (0.0, 0.4) PE – – 0/1123 0/1120 0/530 0/1217 0/1219 Psoriatic arthritis (N=783; PY=791) 0.0 (0.0, 6.8) 0.0 (0.0, 6.8) 0.0 (0.0, 6.9) 0.0 (0.0, 1.8) 0.5 (0.0, 2.8) 0.0 (0.0, 4.0) DVT – 0/238 0/236 0/236 0/347 1/344 0/106 0.0 (0.0, 6.8) 0.0 (0.0, 6.8) 0.0 (0.0, 6.9) 0.0 (0.0, 1.8) 0.0 (0.0, 1.9) 0.0 (0.0, 4.0) PE – 0/238 0/236 0/236 0/347 0/344 0/106 Ulcerative colitis (N=1156; PY[DVT]=1420; PY[PE]=1418) 0.0 (0.0, 2.2) 2.0 (0.1, 11.0) 0.0 (0.0, 2.5) 0.0 (0.0, 2.4) – DVT N/A – 0/938 1/282 0/198 0/196 0.0 (0.0, 2.2) 2.0 (0.1, 11.0) 0.0 (0.0, 2.5) 0.0 (0.0, 2.4) PE N/A – – 0/938 1/282 0/198 0/196

IR = incidence rate (patients with event/100 PY0; N = # of patients in group; n= # of patients with event Mease PJ, et al. Arthritis Rheumatol. 2017; 69 (suppl 10). Abstract 16L, ACR 2017 Annual Meeting. Similar Risk of VTE in RA Patients Initiating Treatment With Tofacitinib 5 mg BID or TNF Inhibitors

Incidence rate per Unadjusted Propensity score- Data source & No. of VTE Total person-years 100 person-years hazard ratio adjusted hazard ratio exposure group events of follow-up (95% CI) (95% CI) (95% CI) Truven TNF inhibitor initiators 98 28,951 0.34 (0.27-0.41) Reference Reference (n = 32,164) Tofacitinib initiators 8 1,326 0.60 (0.26-1.19) 1.70 (0.82-3.49) 1.55 (0.75-3.18) (n = 1,910) Medicare TNF inhibitor initiators 117 12,660 0.92 (0.76-1.11) Reference Reference (n = 16,091) Tofacitinib initiators <111 625 1.12 (0.45-2.31) 1.16 (0.54-2.49) 1.12 (0.52-2.40) (n = 995) Pooled TNF inhibitor initiators 215 41,611 0.52 (0.45-0.59) Reference Reference (n = 48,255) Tofacitinib initiators 15 1,951 0.77 (0.43-1.27) 1.42 (0.84-2.40) 1.33 (0.78-2.24) (n = 2,905) Desai RJ, et al. Arthritis Rheumatol. 2019; 71:892-900. Phase 3B/4 Randomized Safety Endpoint Study of Tofacitinib 5 mg or 10 mg BID in Comparison to a TNF Inhibitor in Subjects With RA (A3921133)

• Inclusion Criteria: – Age ≥ 50 years – Moderate to severe rheumatoid arthritis – Taking MTX without adequate control of symptoms – Have at least one cardiovascular risk factor (e.g., current smoker, BP,  cholesterol, diabetes mellitus, Hx of MI, FHx of CAD, extra-articular RA) • DSMB identified safety concern about tofacitinib10 mg BID treatment group – Subjects who received tofacitinib 10 mg dose “had a statistically and clinically important difference in the occurrence of pulmonary embolism, compared with patients in this study who were treated with a TNFi.” – Increase in overall mortality in tofacitinib10 mg BID treatment group compared to tofacitinib10 5 mg BID & TNFi treatment arms. – Subjects taking tofacitinib 10 mg BID to were shifted to tofacitinib 5 mg BID treatment group

ClinicalTrials.gov Identifier: NCT02092467 https://www.biospace.com/article/high-dose-of-pfizer-s-xeljanz-raises-red-flag-in-a-post-marketing-study/ Tofacitinib Package Insert

http://labeling.pfizer.com/ShowLabeling.aspx?id=959 Baricitinib: Thrombosis During Placebo-Controlled Period (Weeks 0-16) of Phase 3 Clinical Trials

Incidence Rate Difference (95% CI) Baricitinib Baricitinib Baricitinib All Baricitinib Placebo All Baricitinib 4 mg vs 2 mg 4 mg vs N=1070 N=1479 Baricitinib N=479 N=997 Placebo 2 mg Patient-Year Exposure 308 140 298 438 Overall thrombosis n (rate/100 patient-years) 1 (0.3) 2 (1.4) 7 (2.4) 9 (2.1) 1.6 (0.1, 3.1) 1.4 (-2, 4.8) Arterial thrombosis n (rate/100 patient-years) 1 (0.3) 2 (1.4) 2 (0.7) 4 (0.9) 0.4 (-0.7, 1.4) 0 (-2.8, 2.7) Venous thrombosis n (rate/100 patient-years) 0 0 5 (1.7) 5 (1.1) 1.2 (0.1, 2.3) 1.4 (-0.6, 3.4)

Studies JADA, JADC, JADN, JADV, JADW, and JADX CI = confidence interval; N = number of subjects; n = number of patients with event Nikolov NP. FDA Opening Remarks at FDA Arthritis Advisory Committee Meeting: NDA 207924: Baricitinib for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have inadequate response to methotrexate. April 23, 2018. https://www.fda.gov/media/113101/download. Accessed August 31, 2019. 7-Year Safety Profile of Baricitinib in Rheumatoid Arthritis: Adverse CV Events of Special Interest, n (IR)

Placebo-controlled (to Wk 24) 2/4 mg extended dataset All Bari RA

Placebo Bari 2 mg Bari 4 mg Bari 2 mg Bari 4 mg All Bari RA (n=1215) (n=479) (n=1142) (n=479) (n=479) (n=3770)

Total patient-years 450.8 185.8 471.8 675.6 698.6 10,127

Major adverse CV events 2 (0.5) 0 3 (0.7) 2 (0.3) 2 (0.3) 51 (0.5)

Deep vein thrombosis 0 0 3 (0.6) 4 (0.6) 2 (0.3) 35 (0.4)

Pulmonary embolism 0 0 3 (0.6) 1 (0.2) 2 (0.3) 24 (0.2)

Bari = baricitinib; CV = cardiovascular; IR = incidence rate “Incidence rates for deep vein thrombosis/pulmonary embolism were numerically higher in baricitinib 4-mg versus placebo; incidence rates were similar in 2/4-mg-extended dataset.” Genovese M, et al. Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 7 Years: An Updated Integrated Safety Analysis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/safety-profile-of-baricitinib-for-the-treatment-of-rheumatoid-arthritis-up-to-7-years- an-updated-integrated-safety-analysis/. Accessed May 22, 2020. RA Patients Treated With Upadacitinib Have Comparable Rates of Adjudicated MACE & VTEs to Placebo, & Active Controls

Choy E, et al. MACE and VTE Across Multiple Upadacitinib Studies in Rheumatoid Arthritis: Integrated Analysis from the SELECT Phase 3 Clinical Program [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/mace-and-vte-across-multiple-upadacitinib-studies-in-rheumatoid- arthritis-integrated-analysis-from-the-select-phase-3-clinical-program/. Accessed May 22, 2020. JAK Inhibitors: Thromboembolic Events

• FDA has approved JAK inhibitors for RA with boxed safety warnings about thromboembolic events

Company Drug Boxed language on thrombosis

"Rheumatoid arthritis patients with at least one cardiovascular (CV) risk factor Pfizer Tofacitinib had a higher rate of all-cause mortality and thrombosis with Xeljanz 10 mg twice daily vs. 5 mg twice daily or TNF blockers."

"Thrombosis, including deep venous thrombosis, pulmonary embolism, and Eli Lilly Baricitinib arterial thrombosis, some fatal, have occurred in patients treated with Olumiant. Patients with symptoms of thrombosis should be evaluated promptly."

"Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial AbbVie Upadacitinib thrombosis, have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions." Forest Plots for Incidence Risk Ratios of Herpes Zoster Infections Between JAK Inhibitor or Placebo

Tofacitinib • Greater risk of herpes zoster with baricitinib than with placebo • Not observed with

Baricitinib tofacitinib 5 mg BID or upadacitinib 15 mg daily

Upadacitinib

Bechman K, et al. Rheumatology. 2019; 58:1755-1766. JAK Inhibitors: Safety

• Despite differences in selectivity, a large overlap exists in JAK inhibitor safety profiles

• All are associated with  neutrophil number, although changes in numbers of lymphocytes and natural killer cells vary between compounds

• Increased risk of thrombosis with tofacitinib & baricitinib

– Not yet observed with upadacitinib or filgotinib (but FDA boxed warning for class)

• Greater risk of herpes zoster with baricitinib than with placebo

– Not observed with tofacitinib 5 mg BID or upadacitinib 15 mg daily

• To date, no increased risk of malignancy has been reported with JAK inhibitors in RA; however, experience is limited

– Risk of malignancy must be evaluated over the long term with all JAK inhibitors

Winthrop K, et al. Nature Reviews Rheumatology. 2017; 13:234-243. JAK Inhibitors: Summary

• Tofacitinib, baricitinib, upadacitinib, & filgotinib are each more effective than placebo in MTX-naïve, MTX-IR, & bDMARD-IR RA patients • Baricitinib + MTX, filgotinib + MTX, & upadacitinib + MTX are each superior to adalimumab + MTX in MTX-IR RA patients • Increased risk of thrombosis with tofacitinib & baricitinib 4 mg – Mechanism unknown – Must determine risk factors to identify patients who can use JAK inhibitors without increased risk of venous thromboembolic events