d z ] u } µ o ] } ( À ] } o ] Ç ( µ ] v p ï ] ] } v o p u v x · 2019. 10. 30. · ð î ì í...

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© 2019 PRIME® Education, LLC. All Rights Reserved.

TREATMENT AFTER ANTI-TNF FAILURE:

CYCLING VS SWITCHING MECHANISM OF ACTION

Sandeep K Agarwal, MD, PhD

This activity is provided by PRIME Education and is supported by an educational grant from Gilead Sciences, Inc. There is no fee to participate in this activity.


This module is part of a video library featuring 3 additional segments.

(4 of 4)

Please note that to claim credit, participants must complete

all four modules.

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Accreditation

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This activity was planned by and for the healthcare team, and learners will receive 2.0 Interprofessional Continuing Education (IPCE) credits for learning and change.

Physician Credit Designation StatementPRIME Education, LLC (PRIME®) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.PRIME® designates this Enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only credit commensurate with the extent of their participation in the activity.

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PRIME Education, LLC (PRIME®) endorses the standards of the ACCME, as well as those of the AANP, ANCC, and ACPE, which require everyone in a position of controlling the content of a CME/CE activity to disclose all financial relationships with commercial interests related to the activity content. CME/CE activities must be balanced, independent of commercial bias, anddesigned to improve quality in health care. All recommendations involving clinical medicine must be based on evidence accepted within the medical profession. A conflict of interest is created when individuals in a position of controlling the content of CME/CE activities have a relevantfinancial relationship with a commercial interest which therefore may bias his/her opinion and teaching. This may include receiving a salary, royalty, intellectual property rights, consulting fee, honoraria, stocks, or other financial benefits. PRIME® will identify, review, and resolve all conflicts of interest that speakers, authors, course directors, planners, peer reviewers, or relevant staff disclose prior to an educational activity being delivered to learners. Disclosure of a relationship is not intended to suggest or condone bias in any presentation but is made to provide participants with information that might be of potential importance to their evaluation of a presentation. Disclosure information for speakers, authors, course directors, planners, peer reviewers, and/or relevant staff is provided with this activity.Presentations that provide information in whole or in part related to non-FDA-approved uses of drugs and/or devices will disclose the unlabeled indications or the investigational nature of their proposed uses to the audience. Participants should refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity. The opinions expressed in the educational activity are those of the presenting faculty and do not necessarily represent the views of PRIME®, ACCME, AANP, ACPE, ANCC, or other relevant accreditation bodies.

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Faculty Disclosures

The following individuals have identified relevant financial relationships with commercial interests to disclose:• William FC Rigby, MD (Speaker)

Advisory Board/Panel – Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, RocheConsultant – Bristol-Myers Squibb, Pfizer, RochePrincipal Investigator of Research Grant – PfizerSpeaker's Bureau Promotional Education – Bristol-Myers Squibb

The following individuals have no relevant financial relationships with commercial interests to disclose:• Sandeep K Agarwal, MD, PhD (Lead Faculty, Speaker)• Rebecca L Manno, MD, MHS (Speaker)• Kristi Kay Orbaugh, RN, MSN, RNP, AOCN (Planner/Reviewer)

All PRIME staff participating in planning and content development have no relevant financial relationships with commercial interests to disclose.


Learning Objectives

• Incorporate strategies for assessing and monitoring disease activity, prognostic factors, and patient-reported outcomes to guide clinical decisions

• Assess new research findings on the pathogenesis of RA, focusing on the TNF-α, JAK/STAT, and interleukin-6 inflammatory pathways

• Differentiate the latest evidence on the efficacy and safety of new and emerging small-molecule and biologic therapies for moderately to severely active RA

• Apply treat-to-target approaches and evidence on switching mechanism of action for patients with inadequate therapy responses

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Primary and Secondary Anti-TNF Failure Rates

Keystone EC, et al. ACR/ARHR 2015. San Francisco, CA. Abstract 2783.

Cohort study in 953 patients with RA treated with an anti-TNF agent

After a mean follow-up period of 33 months:• 27% patients were discontinued

due to some type of failure• 20% due to non-response• 8% due to safety reasons

Mean time to failure was 9.3 years

Failure Definition% of Patients Time Criteria Response Criteria Time & Response Criteria

Primary Failure <6 mos 5.6% No LDA 14.9% No LDA 14.9%

Partial Response 6–12 mos 4.5% - -

<12 mos + LDAOR

>12 mos + LDA after 12 mos

2.0%

SecondaryFailure >12 mos 9.5% LDA 4.7% >12 mos + LDA

before 12 mos 2.7%

Safety - - AE 7.6% -

Early Safety <6 mos 3.3% - - <6 mos + AE 3.3%

Intermediate Safety 6–12 mos 1.7% - - 6–12 mos + AE 1.7%

Late Safety >12 mos 2.6% - - >12 mos + AE 2.6%

Rates of Primary and Secondary Anti-TNF FailureBased on Different Definitions


ACR RA Guidelines: Treatment Strategy

Singh JA, et al. Arthritis Care Res. 2016;68:1-25.

Treat to Target#

Moderate or High Disease Activity*†

Strong RecommendationsConditional Recommendations

Disease ActivityTreatment Options or Strategy

Algorithm Pathway for Most Patients Disease or Prior Treatment State

Single TNFiFailure

Single Non-TNF Biologic Failure

Another Non-TNF Biologic +/- MTX

Non-TNF Biologic +/- MTXOR

TNFi +/- MTX

Multiple Non-TNF Biologic Failure

TNF +/- MTX (in TNFi-naïve)OR

Tofacitinib +/- MTX

Dual Failure: TNFi and Non-TNF Biologic

Multiple TNFi FailureNon-TNF Biologic +/- MTX

ORTofacitinib +/- MTX

Another Non-TNF Biologic +/-MTXOR

Tofacitinib +/- MTX

Low Disease Activity, But Not Remission, Continue RA

Treatments

In Remission, Consider Tapering

RA Treatments

Do Not Discontinue All RA Treatments

Failure defined as patients with moderate or high disease activity despite biologic DMARD therapy

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© 2019 PRIME® Education, LLC. All Rights Reserved. 9

After TNFi Failure—Cycle or Swap?

• Optimal treatment after TNFi failure remains unclear Mostly registry studies and observational research

• Switching to another TNFi May offer clinical benefit in some RA patients Antidrug antibodies and seropositivity/negativity may guide choice of second biologic

• Switching to non-TNFi biologic with different mode of action Sarilumab, tocilizumab, tofacitinib, rituximab, abatacept, upadacitinib effective after

TNFi-IR

• Choice may be driven by contraindications and safety factors

Nam JL, et al. Ann Rheum Dis. 2014;74(3):516-528; Schoels M, et al. Ann Rheum Dis. 2012;71(8):1303-1308; Favalli EG, et al. Rheumatology. 2014;53(9):1664-1668; Sullivan SD, et al. J Med Econ. 2013;16(3):391-396; Chatzidionysiou K, et al. Ann Rheum Dis. 2015;74(5):890-889; Emery P, et al. Ann Rheum Dis. 2015;74(6):979-984; Smolen JS, et al. Ann Rheum Dis. 2017;0:1-18;Smolen JS, et al. Lancet. 2016;388(10061):2763-2774.


Head-to-Head Comparison of TNF Inhibitorsin MTX-IR and TNF-IR Patients

Schiff M, et al. Ann Rheum Dis. 2014;73(1):86-94; Smolen JS, et al. Lancet. 2016;388(10061):2763-2774.

EXXELERATE:Certolizumab (TNF) vs Adalimumab (TNF)

Week

In some patients, after primary failure of each of the two TNF therapies, the switch to the other therapy was associated with a potential response

First TNF Failure

Patie

nts

(%)

100

80

60

40

20

00 8 16 24 32 40 48 56 64 72 80 88 96 104

Non-responders switch treatment at week 12

Double non-responders withdrawn at week 24

6


70%60%

52%43%

0%

20%

40%

60%

80%

24 Weeks 52 WeeksNon-TNF biologic Group (N=146) 2nd Anti-TNF Group (N=146)

Non-TNF vs TNF Treatment Efficacy After 1st TNF Failure

*The choice of non-TNF biologic was left to the treating clinicianGottenberg JE, et al. JAMA. 2016;316(11):1172-1180.

• HAQ Scores did not differ between the two groups at week 12, 24, and 52• ~50% of patients with insufficient response to a TNFi might respond to a second anti-TNF agent• However, a therapeutic response was more frequent with non–TNF-targeted biologics

Response Criteria in the Non-TNF Biologic and Second Anti-TNF Groups

45% 41%28% 23%

24 Weeks 52 Weeks

EULARGood or Moderate Response

Low Disease ActivityDAS28-ESR <3.2

27% 27%19% 14%

24 Weeks 52 Weeks

DAS28 RemissionDAS28-ESR <2.6

Patie

nts

(%)

Pragmatic, open-label study of 300 patients with insufficient response to a TNFi who were randomized to either a second TNFi or a non-TNF drug


Efficacy and Safety of Tocilizumab (IL-6R) in TNFi-IR Patients

*P <0.001; IR = Inadequate Response.Emery P, et al. Ann Rheum Dis. 2008;67(11):1516-1523.

***

60

50

40

30

20

10

0

Patie

nts

(%)

Time (weeks)

PBO + MTX(n = 158)

4 mg/kg TCZ + MTX (n = 161)

8 mg/kg TCZ + MTX (n = 170)

***

ACR20 at Week 24

0 4 8 12 16 20 24

Secondary endpoints(24 wks)

TCZ 8 mg/kg + MTX

Placebo+ MTX

P value

ACR50 (%) 28.8 3.8 ≤0.001

ACR70 (%) 12.4 1.3 0.001

DAS28 <3.2 (%) 51.2 4.9

DAS28 <2.6 (%) 30.1 1.6 0.001

HAQ-DI (change from baseline)

‒0.39 ‒0.05 <0.001

EULAR good or moderate (%)

67.7 16.5 <0.001

Secondary Endpoints at Week 24

Overall incidence of AEs was similar across all groups. AEs were mostly mild to moderate. Serious AEs occurred more frequently in the PBO arm, and most were related to RA complications.

Rate of serious infections per 100 patient years was lowest in the 4mg/kg group and similar between the 8mg/kg and placebo groups. Prior anti-TNF exposure or number of previous therapies did not impact safety outcomes.

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Efficacy and Safety of Sarilumab (IL-6R) in TNFi-IR Patients

*P <0.001; †P <0.001 ‡P <0.01; ◊P <0.05Fleischmann R, et al. Arthritis Rheumatol. 2017;69(2):277-290; Strand V, et al. RMD Open. 2017;3(1):e000416.

34%

18%7%

14%

32%

56%

37%

20%

33%43%

61%

41%

16%

40%47%

0%

20%

40%

60%

80%

100%

ACR20 ACR50 ACR70 DAS28-CRP HAQ DI

PBO + csDMARD (n = 181) Sarilumab 150 mg + csDMARD (n = 181) Sarilumab 200 mg + csDMARD (n = 184)

TARGET Phase 3 Trial: Clinical Outcomes at Week 24

Patie

nt R

espo

nse

* *

* *

‡†

≤3.2 Change ≥0.3

** ◊

‡

Sarilumab resulted in a higher incidence of TEAEs, with infections being the most frequently reported event. Serious AEs were reported most frequently in the sarilumab 200 mg treatment arm.

No reported cases of GI perforation, lupus-like syndrome, or demyelinating disorders.


Efficacy and Safety of Tofacitinib (JAK 1/3) + MTXin TNFi-IR Patients

Burmester GR, et al. Lancet. 2013;381(9865):451-460; Wollenhaupt J, et al. ACR/ARHP 2017. San Diego, CA. Abstract 522; Kremer J, et al. EULAR 2019. Madrid, Spain. Abstract OP0028

P ≤ .05 vs placebo. †P < .0001 vs placebo.

ACR20 Response Rate (3 mos)

Months Months

Change in HAQ-DI (3 mos) DAS28 <2.6 (3 mos)

0 3

60

40

20

0

ACR2

0 Re

spon

se R

ate

(SE)

, Pat

ient

s (%

)

LSM

HAQ

-DI (

SE),

(Cha

nge

from

Bas

elin

e)

0

--0.2

--0.4

--0.6

DA

S28-

4(ER

S) <

2-6

(SE)

, Pat

ient

s (%

)

20

15

10

5

0

Treatments (n = numbers at month 3)Tofacitinib 5 mg (n = 132)Tofacitinib 10 mg (n = 133)PBO (n = 131)



0 3

Phase 3 Trial Outcomes

• Tofacitinib has a consistent, manageable safety profile across studies, with no new safety signals identified. • It was associated with consistent safety through 114 months and sustained clinical efficacy through 96 months.• 5-year analysis of AEs with tofacitinib vs bDMARDS reported in the CORRONA RA Registry show higher incidence of HZ but not MACE or other serious infections

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• Baricitinib led to more AEs (including infections) than placebo.• Most common infections: respiratory and urinary tract; bronchitis.• Rates of serious AEs through week 24 were similar among patient groups.• Post-hoc analysis of RA-BEACON:OR favor use of baricitinib over PBO regardless of bDMARD history

(number or type)• 7-year integrated safety analysis from phase 3 trials show increased risk for herpes zoster and deep

vein thrombosis/pulmonary embolism, but not malignancy

Efficacy and Safety of Baricitinib (JAK 1/2) in bDMARD-IR Patients

Genovese MC, et al. N Engl J Med. 2016;374(13):1243-1252; Fautrel B, et al. ACR/ARHP 2017. San Diego, CA. Abstract 508; Genovese MC, et al. Rheumatology (Oxford). 2018;57(5):900-908; Genovese MC, et al. EULAR 2019. Madrid, Spain. Abstract THU0078.

RA-BEACON Phase 3 Trial RA-BEAM Phase 3 Trial

62

73

5964

74

64

38

48

73

52

61 59 58

4237

53

3340

48

37 37

0

20

40

60

80

PBO to BARI (n = 103)ADA to BARI (n = 33)BARI to BARI (n = 30)

Patients who met/exceeded clinically relevantimprovement thresholds at week 12 after rescue

0

20

40

60

80

0 2 4 8 12 14 16 20 24

Patie

nts

(%)

ACR20 Response

55%

50%

27%

-2

-1.5

-1

-0.5

0

0 2 4 8 12 14 16 20 24

Chan

ge fr

om B

asel

ine

DAS28-CRP

Patie

nts

(%)


Efficacy and Safety of Upadacitinib (JAK 1) in bDMARD-IR Patients

*P < 0.001 relative to PBO.UPA = upadacitinib; QD = once daily; bDMARD= biologic DMARD; VTE = venous thromboembolic events; MACE = major adverse cardiovascular events; PRO = patient-reported outcomes.Genovese MC, et al. Lancet. 2018 Jun 23;391(10139):2513-2524; Kremer J, et al. EULAR 2019. Madrid, Spain. Abstract FRI0155; Cohen SB, et al. EULAR 2019. Madrid, Spain. Abstract THU0167; Genovese MC, et al. EULAR 2019. Madrid, Spain. Abstract THU0172.

Patie

nts

(%)

28

14

65

43

56

42

0

20

40

60

80

ACR20 DAS28-CRP ≤3.2

PBO (n = 169) UPA 15 mg (n = 164) UPA 30 mg (n = 165)

61

39

6356

6252

5952

0

20

40

60

80

ACR20 DAS28-CRP ≤3.2

PBO → 15 mg UPA (n = 85) PBO → 30 mg UPA (n = 84)UPA 15 mg (n = 164) UPA 30 mg (n = 165)

% o

f Pat

ient

s w

ith re

spon

se

*

*

*

*

Phase 3 Trial SELECT-BEYONDPrimary Outcomes at 12 Weeks Primary Outcomes at 24 Weeks

• In a post-hoc analysis, upadacitinib showed comparable efficacy whether administered with MTX vs other non-MTX csDMARDs• UPA treatment also resulted in significant, clinically meaningful improvements in PROs among patients. • Pooled safety analysis across phase 3 trials show higher risk for serious infections and herpes zoster, but not VTE, MACE, and malignancy (vs comparators) • Safety and efficacy remain consistent after 60 weeks of treatment

9


Efficacy and Safety of Filgotinib (JAK 1) in bDMARD-IR Patients

*P<0.01 vs placebo; **P<0.001 vs placeboFIL = Filgotinib; HAQ-DI = Health Assessment Questionnaire–Disability Index; FACIT = Functional Assessment of Chronic Illness Therapy; BL = baseline;Genovese MC, et al. JAMA. 2019;322(4):315-325; Genovese MC, et al. EULAR 2019. Madrid, Spain. Abstract FRI0092; Kalunian K, et al. EULAR 2019. Madrid, Spain. Abstract FRI0154.

FINCH 2 Phase 3 Trial

Placebo(n = 148)

FIL 200 mg(n = 147)

FIL 100 mg(n = 153)

ACR50 19% 46%** 35%*

ACR70 8% 32%** 20%*

DAS28(CRP) < 2.6 12% 31%** 26%*

CDAI, mean ΔBL -25.4 -30.9 -27.8

SDAI, mean ΔBL -24.9 -32.1 -28.8

HAQ-DI, mean ΔBL (SD) -0.42 (0.6) -0.75 (0.62) -0.60 (0.66)

FACIT-Fatigue, mean ΔBL (SD) 7.0 (10.23) 11.6 (11.67) 9.8 (10.39)

Primary Endpoint: ACR20 Response Other Efficacy Measures (Week 24)

• The most common adverse events were nasopharyngitis, headache, and upper respiratory infection for filgotinib and RA for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib; there were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths

• Efficacy and safety were comparable among patients who had <3 or ≥3 prior bDMARDs• Sub-analysis among patients aged ≥65 vs <65 years show no association of age with incidence of safety effects, and comparable efficacy among groups

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24

% o

f Pat

ient

s

Time Since Baseline, week

FIL 200mg

FIL 100mg

Placebo

69%

55%

35%


Rates per 100 Patient-Years

Any AE / SAE 147 / 9.6AE leading to Deaths 0.4AE leading to discontinuations 9.1All Infections 54.7Serious Infections 3.7Opportunistic Infections 0.9Injection site Reactions 24.9All Malignancies 0.7Primary / Narrow MACE 0.4 / 0.5GI Perforation 1

Long-Term Safety of IL-6 Inhibitors in RA

Systematic Review of IL-6s in RA(Oton, AB0469)

• 64 articles covering >8,000 patients with RA• Most of them with established RA with high disease activity and

severity criteria• More than a half of the studies are of tocilizumab

• Rate of adverse events: increased over time and with the concomitant use of DMARDs

• Most frequent AE: infections and hypersensitivity reactions • Most frequent serious AE: infections • AEs of interest

• associated with a rapid and subsequently sustainable increase in serum lipid parameters

• not associated with a higher prevalence of cardiovascular events and related mortality, nor neoplasms

• Transaminase elevations were generally mild and without serious disorders.

• Low incidence of gastrointestinal perforations (associated with history of diverticulitis)

5-year Pooled Safety Data of Sarilumab(Burmester, SAT0172)

• Long term data from 6 trials of sarilumab + csDMARDs in 2887 patients with RA

• Safety profile remained stable over >5 years’ treatment

AE = adverse event; MACE = major adverse cardiac event; GI = gastrointestinal. Oton T, et al. EULAR 2018. Amsterdam, Netherlands. Abstract AB0469; Burmester GR, et al. EULAR 2018. Amsterdam, Netherlands. Abstract SAT0172

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Long-Term Safety of JAK Inhibitors in RA

Tofacitinib – 9 year data(Wollenhaupt, SAT0234)

Filgotinib – 108 week data(Westhovens, SAT0200)

* Treatment groups with fewer than 10 subjects were omitted for clarity; **Single patient DVT leading to PE. NMSC = Non-melanoma skin cancer

Wollenhaupt J, et al. EULAR 2018. Amsterdam, Netherlands. Abstract SAT0234; Westhovens R, et al. EULAR 2018. Amsterdam, Netherlands. Abstract SAT0200

• Pooled data from 2 OLE studies of patients participating in qualifying phase 1/2/3 trials

• Total tofacitinib exposure was 17,738.5 patient-years• 51% of patients discontinued

• 24% due to AEs, 4% insufficient clinical response

• Most common AEs: nasopharyngitis, URTIs, bronchitis, and UTIs

• 739 patients from two 24-week Phase 2B trials enrolled in OLE • Cumulative patient years of exposure (PYE) was 1931

Tofacitinib (5 and 10 mg BID); ± background csDMARDSs; N=4967AEs of interest IR per 100 py (95% CI)

Serious adverse eventsSerious infectionsMalignances (excluding NMSC)

9.13 (8.67, 9.61)2.46 (2.23, 2.70)0.83 (0.71, 0.98)

Confirmed laboratory abnormalities n (%) IR per 100 py (95% CI)

Decrease from baseline in hemoglobin≥3 g/dL or hemoglobin ≤7 g/dLNeutropenia, ANC <0.5 x 103/mm3

Lymphopenia, ALC <0.5 x 103/mm3

AminotransferasesALT >3x ULNAST <3 x ULN

104 (2.1)0 (0. 0)70 (1. 4)

285 (5. 7)166 (3.3)

0.59 (0.48, 0.71)0 (0.0, 0.0)0.39 (0.30, 0.49)

1.62 (1.44, 1.82)0.93 (0.79, 1.08)

Serum creatinine increase >50% from baseline 138 (2.8) 0.77 (0.65, 0.91)

Key Safety Events and Lab Abnormalities Per 100 PYE*Filgotinib + MTX Filgotinib

MonotherapyTotal*

(N=739)

Events per 100 PYE 100 mg BID (N=249)

200 mg QD(N=250)

200 mg QD(N=222)

Treatment-emergent AEs (TEAEs) 146.7 141.7 150.3 146.2

Serious TEAEs 5.9 3.9 7.4 5.7

TEAEs for Infections 44.5 39.3 37.2 40.0

Serious TEAEs for Infections 1.2 0.6 2.2 1.3

Malignancy (excluding NMSC) 0.8 0.4 0.7 0.6

Herpes Zoster 1.2 1.5 1.1 1.2

Deep Vein Thrombosis** 0.2 0 0 0.1

Pulmonary Embolism** 0.2 0 0 0.1

Active Tuberculosis 0 0 0 0

≥ Grade 3 Laboratory AbnormalitiesHemoglobin ↓Lymphocytes ↓Neutrophils ↓Platelets ↓ALT ↑Creatinine ↑LDL ≥ 190 mg/dLHDL <40 mg/dL

0.51.20.300.20.317.05.4

0.10.90.10.30.105.57.3

00.40.200.2018.46.9

0.20.80.20.10.20.113.17.1


Long-Term Safety of JAK Inhibitors in RA (cdt)

• 494 patients from two phase 2 trials entered the OLE • Patients switched to 6 mg UPA from original trial dose, titrated to 12mg as needed • 150 pts (30.4%) were discontinued

o 8.5% withdrew consento 7.5% due to AE o 4.9% due to lack of efficacy

• Cumulative exposure was 725.1 PY

PY = patient years; E/100PT, events/100 PY; AE = adverse events; NMSC = non-melanoma skin cancer, CPK = creatinephosphokinase. a. Multiple events occurring in the same patients are counted in the E/100PY calculation. Includes patients from never-titrated, titrated-up, and titrated-up and back down groups. b. One sudden death, likely due to cardiac disease (undetermined or unknown cause of death); one death due to Hodgkin’s lymphoma (non-cardiovascular death) c. One patient with coccidiomycosis (from an endemic area); Two patients with oral candidiasis. d. Three patients with basal cell carcinoma; One patient with 2 events of squamous cell carcinoma e. Two patients with breast cancer (One patient had bilateral cancer); Two patients with lymphoma; One patient with prostate cancer. f. Not symptomatic. g. All isolated elevations of ALT/AST or bilirubin; no Hy’s Law cases. h. Serious vs non-serious VTE as determined by investigator (typically based on hospitalizations) Genovese MC, et al. EULAR 2018. Amsterdam, Netherlands. Abstract SAT0236.

Upadacitinib – 72 week data(Genovese, SAT0236)

Summary of Adverse Events in Patients who Entered the OLE

As of 1/13/17; N=493; PYs=725.1; Eventsa (E/100PY)

Any AE 1236 (170.5)

Serious AE 68 (9.4)

AE leading to discontinuation 42 (5.8)

AE leading to deathb 2 (0.3)

Infections-Serious infections- Opportunistic infectionsc

- Herpes Zoster

427 (58.9)17 (2.3)3 (0.4)27 (3.7)

Anemia 19 (2.6)

Neutropenia 10 (1.4)

Lymphopenia 17 (2.3)

GI perforation 0

NMSCd 5 (0.7)

Malignancy other than NMSCe 6 (0.8)

CPK elevationf 36 (5.0)

Hepatic disordersg 37 (5.1)

VTE- Serious VTEh

5 (0.7)4 (0.6)

Adjudicated CV events- MACE- Other CV events

5 (0.7)3 (0.4)2 (0.3)

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