Updates in Systemic Lupus Erythematosus by Integritas Communications

Learning Objectives • Describe SLE pathophysiology, with a focus on novel treatment targets • Evaluate patients with SLE using consensus classification criteria, measures of disease activity, and clinical trial endpoints • Discuss new clinical trial data and regulatory status for current and emerging targeted therapies in moderate-to-severe SLE • Manage patients with moderate-to-severe SLE based on a treat-totarget approach, evolving clinical evidence, unresolved symptoms, and patient preferences

SLE, systemic lupus erythematosus.

SLE: LET’S GET STARTED!

SLE

Incidence and Prevalence • Majority of incident SLE cases are aged 16-55 years – Mean age at SLE diagnosis is 35 years – 20% of patients receive a diagnosis before age 16 years – 4-12 women:1 man

• More common among certain racial and ethnic groups compared with Whites1-3 • Female predominance and increased incidence/prevalence among individuals of African, Asian, Latinx, and Native American ancestry4 – African American women ~1:250 – Hispanic and Asian American women ~1:700 – White women ~1:1000

Approximately 200,000 people are living with Classifiable SLE in the United States, based on CDC population-based registries5 CDC, US Centers for Disease Control and Prevention. 1. Dall’Era M, et al. Arthritis Rheumatol. 2017;69(10):1996-2005; 2. Izmirly PM, et al. Arthritis Rheumatol. 2017;69(10):2006-2017; 3. Somers EC, et al. Arthritis Rheumatol. 2014;66(2):369-378; 4. Maningding E, et al. Arthritis Care Res (Hoboken). 2020;72(5):622-629; 5. Somers E, et al. Arthritis Rheumatol. 2019;71(suppl 10).

SLE Is a Leading Cause of Death in Women 2000-2015

By Race/Ethnicity

• Overall, SLE is the1

• Among Black and Hispanic women, SLE is the1

– Fifth leading cause among women aged 15-24 years – Sixth leading cause in women aged 25-34 years – Eighth leading cause in women aged 35-44 years

Relative Risk of Death From SLE

– Seventh leading cause of death in women aged 15-24 years – 11th among women aged 25-44 years

3 2

1 0

White

Black

Hispanic

Asian and other

Mortality among patients with SLE remains high compared with individuals who do not have SLE, with racial and ethnic disparities.2 aStatistically

significant relative to the reference group. Population-based study using nationwide mortality counts for all female residents of US (2000-2015), after excluding external causes of death (eg, homicide, suicide, unintentional injury). 1. Yen E, et al. Arthritis Rheumatol. 2018;70(8):1251-1255; 2. Singh RR, et al. Lupus. 2018;27(10):1577-1581.

Common Comorbidities Associated With SLE

• Hypertension • Cardiovascular disease • Renal disease • Cancer • Cerebrovascular disease • Osteoporosis • Diabetes • Sterility • Cataracts • Infection

UK study of 7732 prevalent cases of SLE compared with 28,079 matched controls. 1. Rees F, et al. Arthritis Care Res (Hoboken). 2016;68(6):819-827.

Incidence Rates of Comorbidities in SLE1

Comorbidity

Unadjusted Incidence Rate Ratios

Cardiovascular disease

1.98

Stroke

1.81

End-stage renal failure

7.81

Cancer

1.28

Osteoporosis

2.53

Infection

1.49

50-Fold Greater Risk of MI in Young Women With SLE

• Traditional risk factors alone do not account for the increased risk of CAD in SLE • Dysregulation of innate and adaptive immune systems AND glucocorticoids play a large role in increased risk

Cumulative Incidence

Compared With Age-Matched Controls MI/Stroke

0.14

0.12

SLE Non-SLE

0.10 0.08 0.06 0.04 0.02 0

Year

9 10 11 12 13 14 15

It is imperative that we identify and mitigate CAD risk factors in patients with SLE when feasible. Matched cohort study of 4863 patients with incident SLE and 49,316 age-, sex-, entry time–matched controls. Hazard ratio=2.28. CAD, coronary artery disease; MI, myocardial infarction. Aviña-Zubieta JA, et al. Arthritis Care Res (Hoboken). 2017;69(6):849-856.

Why the 2019 ACR/EULAR SLE Classification Criteria Matter to Rheumatologists • Positive ANA result at least once, plus additive weighted (from 2-10) criteria grouped in 10 clinical and immunologic domains • Patients accumulating ≥10 points are classified as having SLE • Criteria had a sensitivity of 96.1% and specificity of 93.4% – Compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and – 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria

ACR, American College of Rheumatology; ANA, antinuclear antibodies; dsDNA, double-stranded deoxyribonucleic acid; EULAR, European League Against Rheumatism; GP, glycoprotein. Aringer M, et al. Arthritis Rheumatol. 2019;71(9):1400-1412.

Domain

Constitutional Hematologic

Neuropsychiatric

Mucocutaneous

Relative Weights of Additive Classification Criteria Items Item

Score

Fever Leukopenia Thrombocytopenia Autoimmune hemolysis Delirium Psychosis Seizure Alopecia Oral ulcers SCLE/DLE ACLE

2 3 4 4 2 3 5 2 2 4 6

Domain Serosal

Musculoskeletal Renal Antiphospholipid antibodies Complements SLE-specific antibodies

Item

Score

Antiphospholipid

C3 or C4 low C3 and C4 low Anti-Sm Anti-dsDNA

3 4 6 6

Effusion Acute pericarditis Joint involvement Proteinuria Class II or IV Class III or V

5 6 6 4 8 10

Together with ANA titer of 1:80 on HEp-2 cells or an equivalent positive test (ever), and score of ≥10, classify disease as SLE. ACLE, acute cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; dsDNA, double-stranded DNA; HEp-2, human larynx epithelioma cancer; SCLE, subacute cutaneous lupus erythematosus; Sm, Smith. Aringer M, et al. Arthritis Rheumatol. 2019;71(9):1400-1412.

SLE PATHOGENESIS A Brief Overview

Pathogenesis of SLE and Therapeutic Targets

• B cells • Cytokines and signaling • Type 1 IFN

JAK

Cytokines

Tissue Inflammation

Macrophage

Type I IFN

BAFF Treg

JAK

Th cell

B cell

pDC

Cytoplasmic Nucleic Acid Sensors

TLRs Immune Complexes

BAFF, B-cell-activating factor; IFN, interferon; JAK, Janus kinase; pDC, plasmacytoid dendritic cell; Th, T helper; TLR, Toll-like receptor; Treg, regulatory T cell. Adapted from: Kasper D, et al., eds. Harrison’s Principles of Internal Medicine, 19th ed. New York, NY: McGraw-Hill Education; 2015.

Pathogenic Mechanisms in SLE Innate Immunity and IFN

Why is IFN stimulated in SLE? Virus

Early Endosome

Late Endosome MyD88 NF-κB

MyD88 IRF7

Late Endosome MyD88 LysosomeRelated Organelle

NF-κB

AP Complex Nucleus

AP, adaptor protein; IRF7, interferon regulatory factor 7; IL, interleukin; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa B; TNF, tumor necrosis factor. Lee BL, et al. Trends Cell Biol. 2014;24(6):360-369.

IFN-α, IFN-β (antiviral genes)

NF-κB

TNF-a, IL-12p40, IL-6 (proinflammatory genes)

Host defense: IFN is induced by viral nucleic acids

Pathogenic Mechanisms in SLE Innate Immunity and IFN

Why is IFN stimulated in SLE? DNA-Immune Complex

CpG ODNs

FcRγ

Virus

LAP Pathway?

“Interferonopathies”: IFN is induced by host nucleic acids via same mechanism

ATG7 LAP Pathway

Early Endosome

MyD88 IRF7

Mature DNA-IC Endosome MyD88 IRF7

Late Endosome MyD88 NF-κB

MyD88 IRF7

Late Endosome MyD88 LysosomeRelated Organelle

NF-κB

AP Complex Nucleus

ATG7, autophagy-related 7; CpG ODN, CpG oligodeoxynucleotide; IRF7 FcRγ, Fc receptor common γ signaling chain; LAP, LC3-associated phagocytosis. Lee BL, et al. Trends Cell Biol. 2014; 24(6):360-369.

IFN-α, IFN-β (antiviral genes)

NF-κB

TNF-a, IL-12p40, IL-6 (proinflammatory genes)

Host defense: IFN is induced by viral nucleic acids

Pathogenesis of SLE and Therapeutic Targets Type I IFN

• B cells • Cytokines and signaling • Type 1 IFN

JAK

Cytokines

Tissue Inflammation

Macrophage

Type I IFN

BAFF Treg

Th cell

JAK

B cell

pDC

IFN Inhibitor Targeted Therapies Anifrolumab2 Anti BDCA-23 Anti ILT74 Cytoplasmic Nucleic Acid Sensors

TLRs Immune Complexes

BDCA-2, blood dendritic cell antigen 2; ILT7, immunoglobulin-like transcript 7. 1. Adapted from: Kasper D, et al., eds. Harrison’s Principles of Internal Medicine, 19th ed. New York, NY: McGraw-Hill Education; 2015; 2. Rönnblom L, Leonard D. Lupus Sci Med. 2019;6(1):e000270; 3. Chaichian Y, et al. J Clin Invest. 2019;129(3):958-961.

Pathogenesis of SLE and Therapeutic Targets

• B cells • Cytokines and signaling • Type 1 IFN

B Cell Targeted Therapies Rituximab2 Obinutuzumab2 Th 2 Treg Belimumab cell 2 Atacicept Telitacicept3

JAK

Cytokines

Tissue Inflammation

Macrophage

Type I IFN

BAFF B cell

pDC

Cytoplasmic Nucleic Acid Sensors

TLRs Immune Complexes

JAK, Janus kinase; pDC, plasmacytoid dendritic cell; Th, T helper; TLR, Toll-like receptor; Treg, regulatory T cell. 1. Adapted from: Kasper D, et al., eds. Harrison’s Principles of Internal Medicine, 19th ed. New York, NY: McGraw-Hill Education; 2015; 2. Bag-Ozbek A, Hui-Yuen JS. Ther Clin Risk Manag. 2021;17:39-54; 3. Wu D, et al. Arthritis Rheumatol. 2019; 71(suppl 10); Abstract L18.

• B cells • Cytokines and signaling • Type 1 IFN

Pathogenesis of SLE and Therapeutic Targets JAK Inhibitors2 Baricitinib Upadacitinib Tofacitinib

JAK

Cytokines

Tissue Inflammation

Macrophage

Calcineurin-Inhibitor Voclosporin3 Treg

JAK

Th cell

Type I IFN

BAFF B cell

pDC

Cytoplasmic Nucleic Acid Sensors

TLRs Immune Complexes

1. Adapted from: Kasper D, et al., eds. Harrison’s Principles of Internal Medicine, 19th ed. New York, NY: McGraw-Hill Education; 2015; 2. Tektonidou MG. Lancet. 2019;394(10214):2047-2048; 3. Kuglstatter A, et al. Acta Crystallogr D Biol Crystallogr. 2011;67(Pt 2):119-123.

THERAPEUTIC APPROACHES FOR PATIENTS WITH MODERATE-TO-SEVERE SLE

TRADITIONAL TREATMENT MODALITIES

Therapies Currently Used in SLE • FDA approved for SLE

– NSAIDs – Steroids (low dose to “pulse”) – Antimalarials (hydroxychloroquine; chloroquine) – Biologics (belimumab)

• Not FDA approved for SLE

– Immunosuppressives (MMF; AZA, MTX; CNI) – Chemotherapy (cyclophosphamide) – Biologics (rituximab) – Miscellaneous (thalidomide/lenalidomide; quinacrine) – Adjunctive therapies (ACEi; bisphosphonates)

ACEi, angiotensin-converting enzyme inhibitor; AZA, azathioprine, CNI, calcineurin inhibitor; FDA, US Food and Drug Administration; MMF, mycophenolate mofetil; MTX, methotrexate; NSAID, nonsteroidal anti-inflammatory drug.

Measures of Disease Activity Currently Used in SLE Trials

• Global endpoints

– SLEDAI (one score, partial improvement not captured) – BILAG (each organ system assessed separately)

• Organ-specific endpoints – CLASI (skin) – Joint counts

• Composite endpoints

– SRI (anchored on the SLEDAI) – BICLA (anchored on the BILAG)

All indices require the experienced clinician to distinguish symptoms due to active disease vs symptoms due to another cause. BICLA, BILAG-Based Combined Lupus Assessment; BILAG, British Isles Lupus Assessment Group; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; SLEDAI, SLE Disease Activity Index; SRI, SLE Responder Index.

How Are Current Therapies Performing Now? SLE

Study Drug

Year

Endpoint

Placebo Response Standard of Care, %

Belimumab1,2

2011

SRI

43.6 (B-52); 33.5 (B-76)

Tabalumab3

2015

mSRI(5)

Sifalimumab4

2016

SRI

Rituximab5

2010

Major clinical

Epratuzumab6

2016

BICLA

Blisibimod7

2018

mSRI(6)

Anifrolumab8

2017

SRI and steroid taper

Ustekinumab9

2018

SRI

Anifrolumab10

2019

SRI

Anifrolumab11

2020

BICLA

mSRI, modified SRI. 1. Navarra SV, et al. Lancet. 2011;377(9767):721-731; 2. Furie R, et al. Arthritis Rheum. 2011;63(12):3918-3930; 3. Merrill JT, et al. Ann Rheum Dis. 2016;75(2):332-340; 4. Khamashta M, et al. Ann Rheum Dis. 2016;75(11):1909-1916; 5. Merrill JT, et al. Arthritis Rheum. 2010;62(1):222-233; 6. Clowse ME, et al. Arthritis Rheumatol. 2017;69(2):362-375; 7. Merrill JT, et al. Ann Rheum Dis. 2018;77(6):883-889; 8. Furie R, et al. Arthritis Rheumatol. 2017;69(2):376-386; 9. van Vollenhoven RF, et al. Lancet. 2018;392(10155):1330-1339; 10. Furie R, et al. Lancet Rheumatol. 2019;1(4):E208-E219; 11. Morand EF, et al. N Engl J Med. 2020;382(3):211-221.

How Are Current Therapies Performing Now? LN

Study Drug

Rituximab1 MMF2 Abatacept3 Abatacept4 Sirukumab5 BIIB0236 Voclosporin7 Abatacept8 R, CTX, B9 Voclosporin10 Obinutuzumab11 Belimumab12

Year

Metric

Placebo Response Standard of Care, %

2012 2009 2014 2014 2016 2016 2016 2018 2018 2019 2019 2020

CR CR CR CR CR CR + >50% protein reduction CR (+ prednisone <10 mg/d) CR CR RR CR PERR

31 9 3; 12 (CR revised) 30 0 6 (+ 14% CR 3 m run-in) 19 (6 mo); 24 (12 m) 33 32 23 23 32

B, belimumab; CR, complete response; LN, lupus nephritis; PERR, primary efficacy renal response; PR, partial response; R, rituximab. 1. Rovin BH, et al. Arthritis Rheum. 2012;64(4):1215-1226; 2. Appel GB, et al. J Am Soc Nephrol. 2009;20(5):1103-1112; 3. Furie R, et al. Arthritis Rheumatol. 2014;66(2):379-389; 4. ACCESS Trial Group. Arthritis Rheumatol. 2014;66(11):3096-3104; 5. Rovin BH, et al. Arthritis Rheumatol. 2016;68(9):2174-2183; 6. Furie R, et al. Arthritis Rheumatol. 2016;68(suppl 10); 7. Dooley MA, et al. Arthritis Rheumatol. 2016;68(suppl 10). Abstract 5L; 8. Furie R, et al. European League Against Rheumatism Annual Congress; June 13-16, 2018; Amsterdam, Netherlands; Abstract OP0253; 9. Aranow C, et al. European League Against Rheumatism Annual Congress; June 13-16, 2018; Amsterdam, Netherlands; Abstract FRI0305; 10. Arriens C, et al. European League Against Rheumatism Annual Congress; Abstract OP0277; 11. Furie R, et al. Lupus Sci Med. 2020;7(suppl 1):A1-A131 A27; 12. Furie R, et al. N Engl J Med. 2020;383(12):1117-1128.

Unmet Needs in SLE Unmet Needs

• Lupus nephritis • Moderate and severe extrarenal disease • Damage prevention – Reduce disease activity – Flare prevention – Spare use of steroids and immunosuppressives

• Minimize comorbidities • Induce remission

Make the patient feel better!

FOCUS ON INVESTIGATIONAL AGENTS FOR SLE

Interferons • Type I

• Type II

– IFN-α, -β, -ω, -ε, -κ – Binds to IFNAR

– IFN-γ – Binds to IFNGR

• Type III – IFN-λ

Can IFN inhibitors reduce SLE clinical activity? IFNAR, interferon alpha/beta receptor; IFNGR, interferon gamma receptor.

Anifrolumab Phase 3 Primary and Key Secondary Efficacy Outcomes TULIP-1

Analysis with amended rules for restricted medications Endpoint Primary outcome: SRI-4 week 52

Placebo (n=184)

Anifrolumab 300 mg (n=180)

Number/Total Number (%)

Difference (95% CI)

Percentage Points

Nominal P Value

79/184 (43%)

84/180 (47%)

3.9 (-6.3 to 14.1)

0.455

• SRI-4 week 52 in IFN gene signature test– high patients

63/151 (42%)

71/148 (48%)

6.4 (-4.8 to 17.7)

0.261

• SRI-4 week 24

79/184 (43%)

83/180 (46%)

3.3 (-6.7 to 13.4)

0.515

• Sustained oral corticosteroid dose reduction to target at week 52

33/102 (32%)

50/103 (49%)

16.7 (3.5 to 29.8)

0.013

• ≥50% Reduction in CLASI activity score from baseline to week 12

14/54 (25%)

25/58 (44%)

18.7 (1.4 to 36.0)

0.034

0.72

0.60

0.83 (0.60 to 1.14)

0.258

Key secondary outcomes

• Annualized flare rate through week 52

CI, confidence interval; Q4W, every 4 weeks. N=457 adult patients with moderate-to-severe SLE on stable treatment were randomized to receive placebo or intravenous anifrolumab 300 mg Q4W for 48 weeks, with a final assessment at week 52. Furie RA, et al. Lancet Rheumatol. 2019;1(4):E208-E219.

Anifrolumab Phase 3 Primary and Key Secondary Efficacy Outcomes TULIP-1

Analysis with amended rules for restricted medications Endpoint Primary outcome: SRI-4 week 52

Placebo (n=184)

Anifrolumab 300 mg (n=180)

Number/Total Number (%)

Difference (95% CI)

Percentage Points

Nominal P Value

79/184 (43%)

84/180 (47%)

3.9 (-6.3 to 14.1)

0.455

• SRI-4 week 52 in IFN gene signature test– high patients

63/151 (42%)

71/148 (48%)

6.4 (-4.8 to 17.7)

0.261

• SRI-4 week 24

79/184 (43%)

83/180 (46%)

3.3 (-6.7 to 13.4)

0.515

• Sustained oral corticosteroid dose reduction to target at week 52

33/102 (32%)

50/103 (49%)

16.7 (3.5 to 29.8)

0.013

• ≥50% Reduction in CLASI activity score from baseline to week 12

14/54 (25%)

25/58 (44%)

18.7 (1.4 to 36.0)

0.034

0.72

0.60

0.83 (0.60 to 1.14)

0.258

Key secondary outcomes

• Annualized flare rate through week 52

N=457 adult patients with moderate-to-severe SLE on stable treatment were randomized to receive placebo or intravenous anifrolumab 300 mg Q4W for 48 weeks, with a final assessment at week 52. Furie RA, et al. Lancet Rheumatol. 2019;1(4):E208-E219.

Anifrolumab Phase 3 Primary and Key Secondary Efficacy Outcomes TULIP-2

Endpoint

Placebo (n=182)

Anifrolumab 300 mg (n=180)

Number/Total Number (%) Primary endpoint: BICLA response at week 52

Difference (95% CI) Percentage Points

Adjusted P Value

57/182 (31.5)

86/180 (47.8)

16.3 (6.3 to 26.3)

0.001

• BICLA response at week 52 in patients with a high type I IFN gene signature

46/151 (30.7)

72/150 (48.0)

17.3 (6.5 to 28.2)

0.002

• Glucocorticoid reduction to target dose, sustained from week 40 to week 52

25/83 (30.2)

45/87 (51.5)

21.2 (6.8 to 35.7)

0.01

• ≥50% Reduction in CLASI activity from baseline to week 12

10/40 (25.0)

24/49 (49.0)

24.0 (4.3 to 43.6)

0.04

• ≥50% Reduction in both swollen and tender joints from baseline to week 52

34/90 (37.5)

30/71 (42.2)

4.7 (-10.6 to 20.0)

0.55

0.64

0.43

0.67 (0.48 to 0.94)

0.08

Key secondary endpoints

• Annualized flare rate through week 52

N=362 adult patients with moderate-to-severe SLE on stable treatment were randomized to receive placebo or intravenous anifrolumab 300 mg Q4W for 48 weeks, with primary endpoint assessment at week 52. Morand EF, et al. N Engl J Med. 2020;382(3):211-221.

Anifrolumab Phase 3 Primary and Key Secondary Efficacy Outcomes TULIP-2

Endpoint

Placebo (n=182)

Anifrolumab 300 mg (n=180)

Number/Total Number (%) Primary endpoint: BICLA response at week 52

Difference (95% CI) Percentage Points

Adjusted P Value

57/182 (31.5)

86/180 (47.8)

16.3 (6.3 to 26.3)

0.001

• BICLA response at week 52 in patients with a high type I IFN gene signature

46/151 (30.7)

72/150 (48.0)

17.3 (6.5 to 28.2)

0.002

• Glucocorticoid reduction to target dose, sustained from week 40 to week 52

25/83 (30.2)

45/87 (51.5)

21.2 (6.8 to 35.7)

0.01

• ≥50% Reduction in CLASI activity from baseline to week 12

10/40 (25.0)

24/49 (49.0)

24.0 (4.3 to 43.6)

0.04

• ≥50% Reduction in both swollen and tender joints from baseline to week 52

34/90 (37.5)

30/71 (42.2)

4.7 (-10.6 to 20.0)

0.55

0.64

0.43

0.67 (0.48 to 0.94)

0.08

Key secondary endpoints

• Annualized flare rate through week 52

Anifrolumab

Differences Between Phase 3 TULIP-1 and TULIP-2 TULIP 1a

TULIP 2

Primary • BICLA

+ +

• SRI Steroid taper

CLASI

Joint scores

Annualized Flare Rate

NS/+

NS, not significant. aPost hoc, with amended medication rules. Furie RA, et al. Lancet Rheumatol. 2019;1(4):E208-E219; Furie R, et al. Lancet Rheumatol. 2020;2(8):E462; Morand EF, et al. N Engl J Med. 2020;382(3):211-221.

Anifrolumab Phase 3 Adverse Events TULIP-2

Adverse events with frequency of >5% in the anifrolumab group Serious adverse event Upper respiratory tract infection Nasopharyngitis Infusion-related reaction Bronchitis Urinary tract infection Herpes zoster Sinusitis Arthralgia Back pain Cough

Placebo (n=182) 31 (17.0) 18 (9.9) 20 (11.0) 14 (7.7) 7 (3.8) 25 (13.7) 2 (1.1) 9 (4.9) 6 (3.3) 3 (1.6) 6 (3.3)

Anifrolumab, 300 mg (n=180) Number (%) 15 (8.3) 39 (21.7) 28 (15.6) 25 (13.9) 22 (12.2) 20 (11.1) 13 (7.2) 12 (6.7) 10 (5.6) 10 (5.6) 10 (5.6)

A pooled analysis (N=925) found anifrolumab was associated with increased incidence of herpes zoster and respiratory tract infections and lower reported rate of SLE worsening as SAEs.2 SAE, serious adverse event. N=362 adult patients with moderate-to-severe SLE on stable treatment were randomized to receive placebo or intravenous anifrolumab 300 mg Q4W for 48 weeks, with primary endpoint assessment at week 52. 1. Morand EF, et al. N Engl J Med. 2020;382(3):211-221; 2. Tummala R, et al. Lupus Sci Med. 2021;8(1):e000464.

Targeting JAK1/JAK2

Baricitinib Phase 2 Primary and Key Secondary Endpoints • Baricitinib: 3 dosage groups (placebo, baricitinib 2 mg, baricitinib 4 mg) – Enrollment: N=314 – Extrarenal study; 24-week endpoint

• SLEDAI-2K clinical score ≥4 • Active SLEDAI-2K arthritis and/or rash Placebo Outcomea (n=105)

SLEDAI-2K resolution of arthritis or rash CLASI activity score 28-Tender joint count reduction 28-Swollen joint count reduction SRI

53% -2.8 -5.6 -4.6 48%

Baricitinib 2 mg QD (n=105) 58% -1.7b -6.5 -4.1 51%

Phase 3 studies are underway. QD, once daily. aNo significant changes in DNA Ab or C3. bP<0.05. Wallace DJ, et al. Lancet. 2018;392(10143):222-231.

Baricitinib 4 mg QD (n=104) 67%b -2.3 -6.9b -4.8 64%b

FOCUS ON NEWLY APPROVED AND INVESTIGATIONAL AGENTS FOR LN

Belimumab

Rationale in LN • Post hoc analysis of phase 3 belimumab trials demonstrated improvement in renal parameters1 • Increased serum BAFF levels and heightened intrarenal BAFF production • Neutralizing BAFF and downregulating autoreactive B-cell function in kidneys represent a compelling therapeutic approach to LN2-4

Belimumab was FDA approved in December 2020 for treatment of adult patients with active LN who are receiving standard therapy.5 1. Dooley MA, et al. Lupus. 2013;22(1):63-72; 2. Kang S, et al. J Immunol. 2017;198(7):2602-2611; 3. Schwarting A, et al. Lupus. 2018;27(2):243-256; 4. Sun CY et al. Int J Rheumatol. 2013; 2013:954292; 5. See Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/daf/; Accessed April 20, 2021.

Phase 3 Belimumab After 104 Weeks in LN • 448 participants with active class III, IV, or V LN • 1:1 randomization to intravenous belimumab vs placebo on background of MMF or ELNT cyclophosphamideazathioprine (all with corticosteroids) • No unexpected safety signal

Primary endpoint

Endpoint

Result, %

Primary efficacy renal response at week 104

Belimumab: 43a

CRR at week 104 Major secondary endpoints

Ordinal renal response without urinary sediment at week 104

Placebo: 32 Belimumab: 30a Placebo: 20

Primary efficacy renal response at week 52

Belimumab: 47a

Time to renal-related event or death

Belimumab: NAb

CRR PRR No response

Placebo: 35 Placebo: NA Belimumab: 30a Placebo: 20 Belimumab: 18 Placebo: 17 Belimumab: 52

Placebo: 63 Belimumab, n=223; placebo, n=223. aP<0.05; bP=0.001. CRR, complete renal response; ELNT, Euro-Lupus Nephritis Trial; HR, hazard ratio; NA, not applicable; OR, odds ratio; PRR, partial renal response. Furie R, et al. N Engl J Med. 2020;383(12):1117-1128.

OR or HR (95% CI) 1.6 (1.0-2.3) 1.7 (1.1-2.7) 1.6 (1.1-2.4) 0.5 (0.3-0.8) NA NA NA

Voclosporin in LN

AURORA Phase 3 Results1 Endpoint Primary

Secondary

Metric

Voclosporin, %

Placebo, %

Renal response at 52 weeks

40.8a

22.5

Renal response at 24 weeks

32.4b

19.7

PRR at 24 weeks

70.4a

50.0

PRR at 52 weeks

69.8a

51.7

Time to UPCR ≤0.5

HR=2.02a

–

Time to 50% reduction in UPCR

HR=2.05a

–

Voclosporin was FDA approved in 2021 for the treatment of adult patients with active LN. No unexpected safety signals and overall incidence of SAEs were similar in both groups.1,2 BID, twice daily; eGFR, estimated glomerular filtration rate; UPCR, urine protein/creatinine ratio. 357 patients randomly assigned 1:1 to voclosporin (23.7 mg BID) or placebo in combination with MMF, 1 g BID, and rapidly rapidly tapered renal response. The primary endpoint was renal response (RR) at 52 weeks, defined as UPCR of ≤0.5 mg/mg, eGFR ≥60 mL/min, or no confirmed decrease from baseline in eGFR of >20%, steroid taper, and no administration of rescue medications. aP<0.001; bP=0.002. 1. Teng YKO, et al. Lupus Sci & Med. 2020;7(Suppl 1):A1-A131; Abstract 011; 2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213716s000lbl.pdf; 1/2021.

Phase 2 Obinutuzumab in LN Nobility Trial

CRR Placebo Obinutuzumab

P=0.026

Overall Renal Response (ORR or PRR) Placebo Obinutuzumab

54%

41% 29%

23%

Week 104

CRR required all of:

P=0.005

• UPCR <0.5 • Serum creatinine ≤ULN • Serum creatinine ≤115% of baseline value • <10 RBC/HPF without RBC casts

Week 104

ORR required all of:

• UPCR <1 (<3 if baseline UPCR ≥3) • UPCR ≤50% of baseline • Serum creatinine ≤115% of baseline • RBC ≤50% above baseline or <10 RBC/HPF

Phase 3 studies are currently underway2 HPF, high-power field; ORR, overall renal response rate; RBC, red blood cells; ULN, upper limit of normal. N=125 patients with active Class III/IV LN were randomized to receive obinutuzumab or placebo infusions in combination with MMF and corticosteroids. 1. Furie R, et al. ACR Convergence 2020; Virtual. November 7, 2020; Abstract 0988; https://acrabstracts.org/abstract/two-year-results-from-a-randomized-controlled-study-of-obinutuzumab-forproliferative-lupus-nephritis/. Accessed April 14, 2021; 2. https://clinicaltrials.gov/ct2/home.

Week 76 Renal Responses, by B-Cell Depletion Status

Phase 2 Obinutuzumab in LN: Nobility

CRR

mCRR

Placebo (n=62) Obinutuzumab detectable B cells (n=20) Obinutuzumab sustained depletion (n=32)

72%

37%

CRR required all of: • • • •

UPCR <0.5 Serum creatinine ≤ULN Serum creatinine ≤15% of baseline value <10 RBC/HPF without RBC casts

Modified CRR Modified CRR required: • UPCR <0.5 • Serum creatinine ≤ULN

vs placebo; bP<0.05 vs placebo. Eleven patients in the obinutuzumab group with insufficient data to determine depletion status were excluded. mCRR, modified complete renal response. Furie R, et al. Lupus Sci Med. 2020;7(suppl 1):A1-A131 A27.

aP<0.2

66% a

45% 29%

18%

CRR

50%

35%

Overall Renal Response (CRR or PRR)

ORR PRR required all of:

• UPCR ≥50% reduction to <1 (to <3 if baseline ≥3) • Serum creatinine ≤15% of baseline value • RBC ≤50% above baseline or <10 RBC/HPF

PATIENT GOALS AND TREATMENT SUCCESS

Degree of Disease Activity Leads to More Damage… Damage Begets More Damage

Patients With Increased Damage, % 1 Year 5 Years

Baseline SLEDAI-2K score Prednisone SDI score Urowitz MB, et al. J Rheumatol. 2021;48(1):67-73.

6-7

5.1

23.1

8-9

6.6

25.4

≥10

6.8

36.8

<7.5 mg/d

3.5

21.8

≥7.5 mg/d

7.8

36.9

4.6

29.0

7.4

34.3

13.6

43.7

…And Damage Increases Mortality Risk Publication

Hazard Ratio (95% CI)

Mok et al. 2005 Fernandez et al. 2007 Cardoso et al. 2008 Urowitz et al. 2008 Chambers et al. 2009 Johnsen et al. 2011 Gafter-Gvili et al. 2013 Telles et al. 2013 Bruce et al. 2015 Joo et al. 2016 Pooled studies (P=0.027, I2=52.1%) Pooled studies without Mok et al (P=0.087, I2=42.0%)

3.65 (1.52-8.76) 1.20 (1.00-1.44) 1.35 (1.16-1.57) 1.24 (1.14-1.35) 1.40 (1.14-1.72) 1.48 (1.37-1.60) 1.28 (1.08-1.50) 1.40 (1.08-1.82) 1.46 (1.18-1.81) 1.20 (1.00-1.40) 1.34 (1.24-1.44) 1.33 (1.25-1.42) 0.1

Weight From RandomEffects Analysis, % 0.69 9.47 11.56 17.41 8.18 18.06 10.63 5.88 7.77 10.36

Meta-analysis suggested a 34% increased risk of death for each 1-point increase in SDI score.1 Murimi-Worstell IB, et al. BMJ Open. 2020;10(5):e031850.

Treat-to-Target in SLE

Recommendations From an International Task Force Research Agenda for Some of the 11 Recommendations Recommendation 1 • Development of definition(s) of remission in SLE • Further studies linking specific disease activity states to long-term outcomes • Definition of a minimal acceptable disease activity

van Vollenhoven RF, et al. Ann Rheum Dis. 2014;73(6):958-967.

Both Active Disease and Glucocorticoids Predict Damage in SLE Disease activity Steroids Damage Early mortality

T2T endpoints need to address: • Disease activity • Medications

T2T, treat to target. Conti C, et al. Lupus. 2016;25(7);719-726.

Treat-to-Target Concept in SLE Active disease Low disease activity Remission on treatment Remission off treatment

Rate of damage accrued Morand EF. Nat Rev Rheumatol. 2016;12(12):696-698.

No damage accrued

Treat-to-Target Concept in SLE No threatening disease activity No toxic therapy “Come back in 3 months”

Active disease Low disease activity Remission on treatment Remission off treatment

Can this be quantified?

Rate of damage accrued Morand EF. Nat Rev Rheumatol. 2016;12(12):696-698.

No damage accrued

Validated Definition of Lupus Low Disease Activity State (LLDAS) SLEDAI-2K ≤4, with no activity in major organ systems (renal, CNS, cardiopulmonary, vasculitis, fever) No new features of SLE disease activity compared with the previous assessment (measured with SLEDAI-2K) PGA (scale 0-3) ≤1 Current prednisolone (or equivalent) dose ≤7.5 mg daily Standard maintenance doses of immunosuppressive drugs and approved biologic agents CNS, central nervous system; PGA, physician global assessment. Golder V, et al. Lancet Rheumatol. 2019;1(2):e95-e102

1.2

LLDAS Is Attainable and Offers “Dose-Dependent” Protection From Damage Accrual

Rate Ratio

1.0

1 0.8a

0.8

0.63b

0.6

0.47b

0.4

0.39b

0.2 0.0

0%-25%

25%-50%

50%-75%

Proportion of Observation in LLDAS, %

>75%

“50:50 rule”—50% reduction in damage accrual, with 50% of time in LLDAS. aP<0.002. bP<0.0001.

N=1356 patients in the Hopkins Lupus Cohort were followed quarterly for almost 20 years. Petri M, et al. Arthritis Rheumatol. 2018;70(11):1790-1795.

Cumulative Probability (Without Flare)

1.00 0.75 0.50 0.25 0

Outcome Flare

In LLDAS <50% of follow-up In LLDAS ≥50% of follow-up

P<0.0001 0

0.5

1.0

1.5

2.0

2.5

Years of Observation

3.0

95% CI

P Value

0.41

0.35-0.48

<0.0001

1.00 0.75 0.50

Outcome Damage

In LLDAS <50% of follow-up In LLDAS ≥50% of follow-up

0.25

3.5

Time-dependent proportional hazards model Percentage of time (<50% vs ≥50%) HR

Cumulative Probability (Without Damage)

Prospective Validation– Exposure-Dependent Effect of LLDAS

P<0.0001 0

0.5

1.0

1.5

2.0

2.5

Years of Observation

3.0

Time-dependent proportional hazards model Percentage of time (<50% vs ≥50%) HR

95% CI

P Value

0.54

0.42-0.70

<0.0001

Yet even ≥20% of observed time in LLDAS is associated with significantly improved outcomes. Golder V, et al. Lancet Rheumatol. 2019;1(2):e95-e102.

3.5

LLDAS in Clinical Trials

Phase 3 Trials With Belimumab BLISS-52 57.6a

60 50

Placebo Belimumab 10 mg/kg

43.6

40 30 20 5.8

10 0

aP<0.0001; bP<0.05.

12.5b

SRI-4

LLDAS

Patients Achieving Response at Week 52, %

BLISS-76 43.2b

45 40 35

Placebo Belimumab 10 mg/kg

33.5

30 25 20

14.4b

7.8

10 5 0

SRI-4

LLDAS

Adults with active SLE who were on a stable treatment regimen for ≥30 days, which could include prednisone alone or combination with antimalarial, NSAID, or immunosuppressive agents, were randomized to either intravenous belimumab or placebo every 2 weeks for 3 doses, followed by dosing Q4W. Oon S, et al. Ann Rheum Dis. 2019;78(5):629-633.

Increased LLDAS in Anifrolumab Phase 2b (post hoc) Patients Who Attained LLDAS, % (95% CI)

Placebo Anifrolumab 300 mg

Week 52 Landmark 39.4

Placebo

Anifrolumab 300 mg

–

3.41

Nominal P value

–

<0.001

40 30

16.7

20 10 0

Placebo

Anifrolumab 300 mg

Post-hoc analysis of the phase 2b MUSE trial where patients with active SLE were randomized to receive placebo (n=102) or intravenous anifrolumab 300 mg (n=99) Q4W plus standard of care for 48 weeks. Morand EF, et al. Ann Rheum Dis. 2018;77(5):706-713.

What About Remission? Remission (DORIS) vs LLDAS

LLDAS

“Clinical remission on treatment”

Serologic Activity Allowed

≤4

≤1



Remission 1

Remission 6 Remission 7

≤7.5



Remission 3 Remission 5

Antimalarials ± Prednisolone Immunosuppressants Dose (mg) Allowed

Remission 2 Remission 4

Complete remission

SLEDAI

PGA (0-3)

0 (clinical)

≤5 <0.5 0 

Remission 8 DORIS, definition of remission in SLE. van Vollenhoven R, et al. Ann Rheum Dis. 2017;76(6):960-977; Golder V, et al. Lancet Rheumatol. 2019;1(2):e95-e103-110.

≤5

        

When a Patient Is “Doing Well” on Treatment • Taper corticosteroids • Attend to quality-of-life concerns • Attend to comorbid conditions

In Summary • Research into the pathogenic mechanisms in SLE have led to development of the first targeted therapy in SLE – Belimumab, an anti–B-lymphocyte stimulator mAb, is FDA approved to treat patients aged ≥5 years with active, autoantibody-positive SLE who are receiving standard therapy

• Other targeted therapies for use in SLE such as calcineurin inhibitors and JAK inhibitors, and B-cell targeted therapies are in mid- to late-stage clinical trials • Elucidating the role of IFN signaling in SLE has led to the development of agents that target various aspects of the IFN pathway • Belimumab and voclosporin are recently FDA-approved agents for LN • Achieving low disease activity, potentially by employing a treat-to-target approach, can reduce organ damage in SLE

The future is bright for our patients with SLE.