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Educational SupportThis educational activity is supported by an educational grant from AstraZeneca Pharmaceuticals, LP.

DisclosuresFaculty Planners/Content Creators: Michael Weisman, MD, has served as a consultant for AMPEL BioSolutions, LLC, Ionis Pharmaceuticals, and UCB, Inc. He has done research for DOD/Immunomedics, Inc., Eli Lilly and Company, EMD Serono, Genentech, Human Genome Sciences, and UCB Biosciences.

Mariko L. Ishimori, MD, reports that she has no relevant financial relationships to disclose.

Activity Faculty: Robin Dore, MD, has served as a consultant for Amgen, Abbvie, Celgene, Lilly, Novartis, Radius and Sanofi. She has served on a speakers bureau for Amgen, Abbvie, Celgene, Lilly, Novartis, Pfizer, Radius UCB and Sanofi. She has done research for Amgen, Abbvie, Biogen, Gilead, Lilly and Pfizer.

The independent reviewer and following planners have no relevant conflicts of interest to report:

• Lindsy Forbess, MD

• Ani Mardakhanian, MHA

• Megan Swartz

• Theodore Bruno, MD

• Eve Wilson, PhD

• Heather Tarbox, MPH

• Morghan Long

Disclosure of Potential Conflicts of InterestIt is the policy of Cedars-Sinai Medical Center to ensure balance, independence, objectivity, and scientific rigor in all of its educational activities. Cedars-Sinai Medical Center assesses conflict of interest with its faculty, planners and managers of CME activities. Conflicts of interest that are identified are resolved by reviewing that presenter’s content for fair balance and absence of bias, scientific objectivity of studies utilized in this activity, and patient care recommendations.

While Cedars-Sinai Medical Center endeavors to review faculty content, it remains the obligation of each physician or other healthcare practitioner to determine the applicability or relevance of the information provided from this course in his or her own practice. In accordance with the policy of Cedars-Sinai, faculty are asked to disclose any affiliation or financial interest that may affect the content of their presentations.

Learning Objectives

• Review new scientific insights into the immunopathogenesis of SLE

• Evaluate the mechanisms of action as well as efficacy and safety data pertaining to newer, targeted biologic agents for SLE

• Demonstrate a working understanding of appropriate tests and indices that can objectively quantify SLE disease activity and treatment response

• Evaluate recent data confirming various biomarkers of SLE disease activity, treatment response, and/or prognosis.

Which of the following SLE agents targets the B-cell growth factor BAFF/BLyS?

A. Rituximab

B. Anifrolumab

C. Belimumab

D. Tofacitinib

Rituxim

ab

Anifrolu

mab

Belimum

ab

Tofacit

inib

25% 25%25%25%

Which of the following emerging agents for treatment of SLE met primary endpoints (as specified by the FDA’s US Guidance for Industry) in Phase II or Phase III trials?

A. Abatacept

B. Anifrolumab

C. Rontalizumab

D. Rituximab

Abatace

pt

Anifrolu

mab

Rontaliz

umab

Rituxim

ab

25% 25%25%25%

Which one of the following SLE indices assesses both disease activity AND that there is no significant worsening in any specific organ system?A. SLE Disease Activity Index

(SLEDAI)

B. British Isles Lupus Activity Group (BILAG)

C. Systemic Lupus Activity Measure-Revised (SLAM-R)

D. Systemic Lupus International Collaborative Clinics (SLICC)

SLE D

isease

Act

ivity

Index (

S...

British

Isle

s Lupus A

ctivi

ty G

...

Syste

mic

Lupus A

ctivi

ty M

ea...

Syste

mic

Lupus I

ntern

atio

na...

25% 25%25%25%

Which one of the following biomarkers is currently included in the ACR, SLICC, SLEDAI, SLEDAI 2000, and SELENA-SLEDAI indices?

A. IFN-α

B. TGF-β

C. Complement C4d

D. Anti-dsDNA antibodies

Systemic Lupus Erythematosus (SLE)• Chronic, multisystem, inflammatory

autoimmune disease

• Characterized by flares, spontaneous remission, and relapses

• May affect any part of the body, but often results in damage to:

―Skin*

―Joints*

―Heart

―Kidneys

―Lungs

―Nervous system

*Most commonly affected tissuesWallace DJ. Lupus: The Essential Clinicians Guide. New York, NY: Oxford University Press; 2014.

Epidemiology of SLE

• Prevalence: 20 – 150/100,000

• Incidence: 1 – 10/100,000; increase in recent years, perhaps due to better detection of mild disease

• Higher incidence/prevalence in women of childbearing age

• Occurs more often in some racial/ethnic groups

—African-Americans

—Asians

—Native Americans

—Hispanics

• Associated with significant morbidity and mortality

Squatrito D, et al. Auto Immun Highlights. 2014;5:33-45.

Pathogenesis of SLE

From: Oon S, et al. Clin Transl Immunol. 2016;5:e79.

IFN = interferon; mDC = myeloid-derived dendritic cell; pDC = plasmacytoid dendritic cell; APRIL = A proliferation-inducing ligand; BAFF= B-cell-activating factor (also known as BLγS = B lymphocyte stimulator).

B Cells: Role in SLE Pathogenesis

Edward JCW, Cambridge G. Nat Rev Immunol. 2006;6:394-403.

Type I IFN: Role in SLE Pathogenesis

From: Oon S, et al. Clin Transl Immunol. 2016;5:e79.

IFN Pathway: Role in SLE Pathogenesis

• Serum IFN-α levels are elevated in patients with SLE1

• Increased expression of type I IFN-induced genes (“IFN signature”) are found

in blood and involved tissues in SLE2

• Correlations have been observed between IFN levels and expression of type I

IFN-induced genes and SLE activity1,3

• Other data showing a link between IFN-α and SLE include side effects of IFN

therapy for malignancy and viral hepatitis, resulting in an SLE-like syndrome4

• Inhibition of IFN-α may provide therapeutic benefit in the treatment of SLE

1. Hooks, et al. New Engl J Med. 1979;301:5-8. 2. Crow. Arthritis Rheum. 2003;48:2396-2401. 3. Dall’era, et al. Ann Rheum Dis. 2005;64:1692-1697.4. Ioannou Y, Isenberg DA. Arthritis Rheum. 2000;43:1431-1442.

Intracellular IFN Pathway: Role in SLE Pathogenesis

IFNAR =Type 1 IFN receptor; JAK = Janus kinase; TYK = tyrosine kinase; STAT= signal transducer and activators of transcription; IRF9 = interferon regulatory factor 9; ISGF3= interferon-stimulated gene factor 3.Oon S, et al. Clin Transl Immunol. 2016;5:e79.

Cell membrane

New Drugs Are Needed• Only 1 new drug—belimumab—has been FDA-approved for lupus in

over 50 years

• Corticosteroids, methotrexate, azathioprine and cyclophosphamide have been available since 1965

• Most current management options are not specific to SLE and may provide suboptimal control, translating to unacceptably high rates of morbidity and mortality

• Many new agents are in Phase I-III clinical trials, with varied success

Park A. TIME. March 10, 2011. Available at: http://healthland.time.com/2011/03/10/fda-approves-the-first-new-lupus-drug-in-50-years/.Accessed on July 31, 2017.

Currently Available Options

• Corticosteroids*

• Hydroxychloroquine*

• Azathioprine

• Methotrexate

• Cyclophosphamide

• Mycophenolate mofetil

• Cyclosporine

• Tacrolimus

• Rituximab

• Belimumab*

*Only corticosteroids, hydroxychloroquine, and belimumab are FDA-approved for treatment of SLE. Image adapted from Arthritis Research UK. http://www.arthritisresearchuk.org/health-professionals-and-students/reports/topical-reviews/topical-reviews-spring-2013.aspx.

Establish Diagnosis

Determine likely prognosis

Assess severity and organ involvement

• Lifestyle (sun avoidance etc)• Topical agents • Symptomatic agents• Manage co-morbidities

No Major Organ Involvement• Antimalarials• Low-dose steroids• Azathioprine/methotrexate

Major Organ Involvement• Cyclophosphamide (intravenous)• Mycophenolate mofetil• Calcineurin inhibitors (cyclosporine A

or tacrolimus) • Biologics (rituximab or belimumab)

or• Enroll in clinical trial

Multiple Failures in Drug Development

• Since 2005, >25 drugs in Phase II/III trials have failed to meet primary endpoint specified in the FDA’s US Guidance for Industry*

• Many of these agents are clearly effective• Lupus metrics were designed before the era of targeted therapies• Positive results: belimumab and possibly anifrolumab

* SYK = spleen tyrosine kinaseSource: USDHHS: Guidance for Industry Systemic Lupus Erythematosus — Developing Medical Products for Treatment. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072063.pdf. Accessed July 31, 2017

o Abatacept o Edratide o Rituximab

o Abetimus o Epratuzumab o Rontiluzumab

o Anti-IL6 o IDEC-131 o Sifilumumab

o Atacicept o Laquinimod o Sirukumab

o Blisimibob o Prasterone o Tabalibumab

o Corticotropin gel o R333 topical SYK*

Why Have So Many Phase II/III Trials Failed?• Drug did not work or was not safe

• Trial design was flawed

• Choice of primary outcome measure was poor

• Trial was badly implemented —Complex logistics

—“Hassle” factors for study centers that may have discouraged enrollment

—Poor site selection (geographical bias)

• Poor choice of allowed or disallowed concomitant medications

• Artificial mandated use of steroids and tapering that are not used in clinical

practice

• Domains of SLE assessment (SLEDAI, BILAG) may not adequately detect changes

or improvement; composite indices (SRI, BICLA) may amplify SLEDAI/BILAG flaws

SLEDAI = SLE Disease Activity Index; BILAG = British Isles Lupus Assessment Group Index; SRI = SLE Responder Index; BICLA = BILAG-Based Composite Lupus Assessment Isenberg DA, Merrill JT. Expert Rev Clin Immunol. 2016;12:95-98; Looney RJ, et al. Mod Rheumatol. 2010;20:1-10; Wallace, DJ. Lupus. 2016;25:1141-1149.

Target Category or Mechanism Targets

Co-stimulatory blockade CD80/86, CD154

B Cells CD20, CD22, proteosome/plasma cells, anti-BLyS/BAFF, TACI

T Cells CD40L; ICOS, CD4+CD25+ T regulatory cells, CD8+/CD28- T cells

Complement C5a

Cytokines sIL-6R, IL-6, IL-10, IL-12/23, IL-17, IL-18, TNF, anti-IgE

Innate immune systemIFNα and IFNy; TLR7 and/or TLR9; BDCA-2; NA-containing immune complexes

Cell signaling and activation SYK, BTK, JAK/STAT, mTOR, PDE4, calcineurin

ToleragensMHC Class II, peptides derived from nucleosomes, Sm Ag, Igs, 16/6 idioptype, splicosomes

CTLA4 = cytotoxic T-lymphocyte associated protein 4; Ig = immunoglobulin; CD = cluster of differentiation; ICOS = inducible costimulatory molecule; mAb = monoclonal antibody; BlyS = B lymphocyte stimulator; TACI = TACI = transmembrane activator and calcium-modulating cyclophilin ligand interactor; BAFF-RFc = B cell activation factor-rosette-forming cells; IL= interleukin’ sIL=soluble interleukin; TNF = tumor necrosis factor; TLR = Toll-like receptor; NA = nucleic acid; Sm Ag = Smith antigen; BTK = Bruton's tyrosine kinase. JAK = Janus kinase; STAT = signal transducer and activator of transcription; PDE4 = phosphodiesterase-4.

Adapted from Wallace DJ. BMC Med. 2010;8:77.

Moving Forward: Targets for Therapy in SLE

Abatacept: Costimulatory Blockade• Abatacept (CTLA4-Ig)

—Fully human, soluble recombinant fusion protein made of human CTLA-4 linked to IgG1

—Binds to CD80/86 to prevent costimulatory signal

• FDA-approved for rheumatoid arthritis, but not SLE

• Phase II study in non-renal lupus was unsuccessful1

—Study design issues with high-dose steroids

—Post-hoc analyses showed significantly fewer flares (BILAG A and physician-assessed)

• Phase II study in LN (ACCESS) did not meet primary endpoint2

—Abatacept + cyclophosphamide did not improve LN outcome at 24 or 52 weeks

• Ongoing Phase III trial is evaluating abatacept + MMF + prednisone in class III/IV LN (NCT01714817)

ACCESS = Abatacept and Cyclophosphamide Combination Efficacy and Safety Study; LN = lupus nephritis1. Merrill JT, et al. Arthritis Rheum. 2010;62:3077-3087.2. ACCESS Trial Group. Arthritis Rheumatol. 2014;66:3096-3104.

B Cell Inhibition: Limited Success• Multiple trials targeting B cells cancelled

• B-cell depletion via anti-CD20 (rituximab, obinutuzumab) has not been successful

• Despite open-label trials showing efficacy and safety of rituximab, both major US trials failed

—EXPLORER (78 wk)1

• Patients with moderately-to-severely active extra-renal SLE

• Rituximab in combination with prednisone and AZA, MMF, or MTX

—LUNAR (52 wk)2

• Patients with class III/IV LN

• Rituximab vs placebo with background MMF and corticosteroids

AZA = azathioprine; MMF = Mycophenolate mofetil; MTX = Methotrexate

1. Merrill JT, et al. Arthritis Rheum. 2010 ;62:222-233.2. Rovin BH, et al. Arthritis Rheum. 2012;64:1215-1226.

When Is Rituximab Used?• Central nervous system lupus: usually used after steroids and cyclophosphamide

have failed

• Hematologic SLE: used in the setting of idiopathic thrombocytopenia or hemolytic anemias, where treatment with steroids and IVIG has failed

• Catastrophic antiphospholipid antibody syndrome: used when IV steroids, heparin, and plasma exchange or IVIG have failed

• Refractory inflammatory arthritis

• None of these uses are FDA-approved

IVIG = intravenous immunoglobulin

Mok CC. Int J Rheum Dis. 2015;18:154-63.Beckwith H, Lightstone L. Nephron Clin Pract. 2014;128:250-54.Rodríguez-Pintó I, et al. Ther Adv Musculoskel Dis. 2015; 7:26-30.Bonilla-Abadía F, et al. Autoimm Dis. 2014 (2014), Article ID 731806.

B Cell Growth Factors

Ligands

Receptors BAFF-R BCMA TACI

BLyS APRIL Heterotrimer

Proteoglycans

▪ Increased B-cell survival

▪ Costimulation of B-cell

proliferation

▪ Ig class switch

recombination

▪ Enhanced APC function

▪ Germinal center formation

▪ Regulation of B-cell

tolerance

▪ Sequester APRIL

at cell surface to

improve TACI

and/or BCMA

signalling

▪ Mediate plasma

cell trafficking

BCMA = B-cell maturation antigen; APC = antigen-presenting cell

Isaacs JD. Ann Rheum Dis. 2007;64 (SII):21.

Belimumab

• BLyS/BAFF-specific inhibitor BLyS/BAFF is important for survival of B cells that make autoantibodies

Patients with SLE have higher levels of BLyS/BAFF

• Shown to be effective in two Phase III trials: BLISS-521 and BLISS-762

• Achieved a steroid-sparing effect in BLISS-523

• Modest efficacy in patients who have failed other immunosuppressive agents

• Well tolerated2

1. Navarra SV, et al. Lancet. 2011;377:721-731.2. Furie R, et al. Arthritis Rheum. 2011;63(12):3918-3930.3. Navarra SV, et al. Ann Rheum Dis. 2010;69(Suppl 3):555.

1. Navarra SV, et al. Lancet. 2011;377:721-731.2. Furie R, et al. Arthritis Rheum. 2011;63:3918-3930.

1 2

58%

n=290

44%

n=288

P<0.0006 P<0.05

34%

n=275

43%

n=273

Belimumab 10 mg/kg + standard therapy Placebo + standard therapy

BLISS-52 and BLISS-76: SRI Response Rates at Week 52

Patients Meeting Primary Endpoint at Week 52 in 2 Phase III Trials

Belimumab: Limitations Observed in BLISS Trials

• Not tested in patients with severe disease—patients with serious kidney and brain involvement were excluded1,2

• Patients in both arms were on aggressive immunosuppressive treatments, so the high overall rates of response may have masked benefit1,2

• African American patients, who tend to have severe disease, did not benefit (but open-label trials have since shown efficacy for African Americans and other ethnic groups3,4)

1. Navarra SV, et al. Lancet. 2011;377:721-7312. Furie R, et al. Arthritis Rheum. 2011;63:3918-3930.3. Collins CE, et al. Lupus Sci Med. 2016; 3:e000118.4. Hui-Yuen JS, et al. J Rheumatol. 2015;42:2288-2295.

Belimumab: Which Patients May Benefit Most?

Analysis of pooled data from all BLISS trials suggests that belimumab might be better than standard therapy in patients with:

• Higher disease activity

• Positive anti-dsDNA antibody

• Low complement levels

• Corticosteroid treatment at baseline

Van Vollenhoven RF, et al. Ann Rheumatic Dis. 2012:71:1343-1349.

Possible Cytokine Strategies

• Omalizumab—IgE blocker approved for asthma—Phase I clinical trial in progress

(NCT01716312)

• Tocilizumab—Soluble and membrane-bound IL-6—Phase I clinical trial showed promise

(Illei GG, et al. Arthritis Rheum. 2010;62:542-52)(NCT00046774)

US NIH. ClinicalTrials.gov.

• BTO63—IL-10

• Ustekinumab—IL-12/23 —Phase 2 clinical trial in progress

(NCT02349061)

• Secukinumab, ixekizumab—IL-17A

Tocilizumab• Humanized mAb; binds soluble and membrane-bound IL-6

• FDA-approved for rheumatoid arthritis

• Rapidly decreases acute-phase reactants1

• Normalizes circulating B cell subsets2

• Phase I trial in patients with mild-to-moderate SLE (N=16)3

—Improvement in disease activity (SELENA-SLEDAI) by week 14

—Reduction in disease markers, eg, complement, anti-dsDNA antibodies

—Main side effect was neutropenia

• Some case reports of tociluzumab-associated drug-induced lupus4,5

• Awaiting further studies, but early reports indicate an important role for IL-6 in SLE pathogenesis; may be a good target for intervention6

1. Snir A, et al. Clin Exp Rheumatol. 2011;29:697-700; 2. Sebba A, et al. Am J Health Syst Pharm. 2008;65:1413-8; Illei GG, et al. Arthritis Rheumatism. 2010;62:542-552; 4. Matsuo Y et al. Rheumatol. 2013; 52:1341-1343; 5. Vermaak E, et al. Rheumatol. 2014; 53 (S1):i60-i61; 6. Tackey E, et al. Lupus. 2004;13:339-43.

Agents Targeting the Innate Immune System: Anti-IFNs

Agent Description/Target

Clinical Trial Findings and Status References

AGS 009(NNC 0152)

mAb to IFN-α Phase I: dose-dependent reduction of IFN-α signatures Tcherepanova I, et al. Ann Rheumatic Dis. 2012;71(S3):536.

Sifalimumab mAb to IFN-α Dose-dependent reduction of IFN signature Promising outcomes in Phase II trial (sifalimumab vs placebo); similar rates of adverse events in both groups except HZ infections (more common with sifalimumab)

Merrill JT, et al. Ann Rheum Dis. 2011;70:1905-13;Khamashta M, et al. Ann Rheum Dis. 2016;0:1-8.

Rontalizumab mAb to IFN-α Safe, but did not meet primary endpoint in Phase II trialBetter response in patients with low IFN signature

Kalunian KC, et al. Ann Rheum Dis. 2016;75:196-202

Anifrolumab IgG1 kappa to IFNAR

Met primary endpoint in Phase II trial; greater effect size in patients with high baseline IFN signature.Phase III studies pending

Furie R, et al. Arthritis Rheum 2017;39:376-86.

IFN-α kinoid vaccine

Induces polyclonal IFN-α neutralizing antibodies

Phase I/II study: decreased expression of IFN- and B-cell associated gene transcriptsIn Phase IIb

Ducreux J, et al. Rheumatol. 2016;55:1901-05

HZ = Herpes zoster

Anifrolumab in Moderate‐to‐Severe SLE

Percent Meeting Primary Endpoint*

34.3

28.8

17.6

0

5

10

15

20

25

30

35

40

45

50

Anifrolumab 300 mg Anifrolumab 1000 mg Placebo

Effect Size for Patients with High IFN Signature

Primary endpoint was the percentage of patients achieving an SRI(4) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than/equal to the dose at week 1 from wk 12 – 24). Furie R, et al. Arthritis Rheumatol. 2017;69:376-386.

36.0

28.2

13.2

0

5

10

15

20

25

30

35

40

45

50

Anifrolumab 300 mg Anifrolumab 1000 mg Placebo

P=.004

P=.063

P=.014

P=.029

Pe

rce

nt

Pe

rce

nt

Targeting the Innate Immune System: Anti-TLR7 and Anti-TLR9• SLE PBMCs have upregulated TLR7 and TLR9 mRNA expression, correlating

with IFN-α expression

• SLE patients may have impaired clearance of apoptotic cells and debris

• RSLV-1321

—Nuclease Fc-fusion protein targeting nucleic acid-containing immune complexes

—Prevents TLR activation

—19-d half-life; favorable safety profile

• BIIB0592

—mAb to BDCA-2, a pDC-specific receptor

—Inhibits production of TLR-induced IFN-I and other inflammatory mediators produced by human pDCs

—Favorable pharmacokinetics/pharmacodynamics and safety profile

1. Burge DJ, et al. Lupus. 2017;26:825-34.2. Martin D, et al. Ann Rheumatic Dis. 2017;76:862.

Pertinent Presumed Pathways in Lupus

JAKsignalingcascade

NFKBsignalingcascadeSYK (& BTK)

signalingcascade

MAPKsignalingcascade

Cytoplasm

Nucleus

Gene Transcription

JAKJAK

STAT

STAT

STATSTAT

ERKJNK

p38

Kinases

Kinases

SYKP13k

BTK

P13k

Secondmessengers

P13Ksignalingcascade

Lipidmessengers

P13kP13K

IKK

NFKB

Cell Activation Inhibition

• Emerging class in SLE –Phase I and II trials

• Targets—JAK: central to cell growth, survival,

development, and differentiation in both adaptive and innate immunity

—BTK: effector molecule for B cell development

—PDE4 enzyme inhibitor

1. Oon S, et al. Clin Transl Immunol. 2016;5:e792. De Souza A, et al. J Drugs Dermatol. 2012;11:1224-1226.

• Agents in Phase I and II development1

—Tofacitinib: mAb to JAK1 and 3—Baricitinib: mAb to JAK1 and 2—Evobrutinib: mAb to BTK inhibitor—Apremilast2

• Oral phosphodiesterase-4 enzyme inhibitor• Open-label study in discoid lupus showed

safety and efficacy

Agents Targeting mTOR

• N-acetylcysteine (NAC):—Reduces mTOR activity in T cells1

—Case reports suggest efficacy in early SLE and LN2,3

• Rapamycin (sirolimus)—Inhibits IL-2 and other cytokines’ receptor-dependent signal transduction

mechanisms via action on mTOR; thereby blocks activation of T and B cells

—Small, open-label study showed efficacy and safety4

—Phase III trial in planning stage

1. Lai ZW, et al. Arthritis Rheum. 2012; 64:2937-2946.2. Li M, et al. Exp Ther Med. 2015;10:689-692.3. Tewthanom K, et al. J Clin Pharm Ther. 2010;35:483-485. 4. Fernandez D, et al. Arthritis Rheum. 2006;54:2983-2988.

CM EMmTORC

1mTORC

2

NAC and Rapamycin Control T Cell Lineage Specification in SLE via mTOR

Perl A. Nature Rev. 2016;12:169-182.

Toleragens• Synthetic peptides created to mimic and

interfere with immune response to specific antigens

• Hoped for result is induction of tolerance to specific antigens

• Challenges—Exact autoantigens in SLE are not known—Disease is heterogeneous in its presentation

and manifestations—Some autoantigens may be more important

in early vs late disease

1. Zimmer R et al. Ann Rheum Dis. 2013;72:1830-1835. 2. Urowitz M et al, Lupus Sci Med. 2015;2:e000104.

• Rigerimod (P140): MOA not well understood but tolerogenic/ immunomodulatory effects lead to inhibition of T cell reactivity with MHC-presented self-peptides

—Phase IIb trial showed that the agent was well tolerated; primary outcome measure was met1

—Phase III trials underway

• Edratide: mAb to ssDNA 16/6 idiotype—Phase II trial showed favorable safety

profile; secondary, but not primary endpoints met.2

—Phase III trial to start in 2017

Umbilical Cord Mesenchymal Stem Cell Transplantation in Severe and Refractory SLE

Sun L, et al. Arthritis Rheum. 2010 Aug;62(8):2467-75.

What Would an Ideal Agent Do?

• Prevent flares and progression of SLE

• Treat lupus nephritis, and other SLE manifestations

• Lead to and/or maintain remission

• Reduce use of steroids

• Reduce risk of infection

• Reduce risk of cancer and heart disease, better disease control

• Protect fertility

• Simplify monitoring

• Be cost effective

Future Outlook• While there is no known “cure,” ongoing advances in SLE research

offer hope

• Many new, potential treatments are being developed and tested

• Increased awareness among patients and physicians will help diagnose SLE sooner, allowing effective treatment to begin earlier

• Treating SLE can be challenging, but with focused, specialized medical care, many people lead fulfilling lives

Measurement of Disease Activity in SLE

• Challenges with assessing disease activity:―Complex and diverse features of SLE

―Fluctuating disease level

―Variation in organ and non-organ manifestations among patients and within the same patient over time

―No true gold standard

―Administrative burden and time-intensive nature of training and data collection

―Availability of multiple instruments

Despite these challenges, why should we quantify disease activity in SLE?

Disease Activity Predicts Organ Damage and Death

SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index.Lopez R, et al. Rheumatology. 2012;51:491-498.

.

• Increased disease activity is associated with significantly increased risk of organ damage and death

• A 1-point increase in adjusted BILAG score was associated with:– 8% increase in the risk of any new

organ damage– 11% increase in risk of CV,

pulmonary, or musculoskeletal damage

– 15% increase in mortality

Time to SDI Δ ≥1 by Disease Activity Level* (N=350)

Pe

rce

nt

Surv

ival

Length of Follow-up (years)

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 20

Low

High

Pe

rce

nt

Surv

ival

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 20

*Low disease activity=BILAG score 0 to <2.59; high disease activity=BILAG score ≥6.84

Rahman P, et al. Lupus. 2001;10:93-96.

• Initial SDI assessment was performed ≥6 months after study enrollment

• Early organ damage was defined as initial SDI ≥1

• 25% of patients with early damage died within 10 years vs 7.3% with no early damage (P=0.0002)

Early Organ Damage Is Associated With Reduced 10-Year Survival Rate

a

Survival Probability in Patients With and Without Early Organ Damage (N=263)

Surv

ival

Pro

bab

ility

Disease Duration (years)

1.0

0.9

0.8

0.7

0.6

2 4 6 8

Initial SDI=0, n=190

Initial SDI >0, n=73

0 10

Toloza SMA, et al. Arthritis Rheum. 2004;50:3947-3957.

LUMINA Sub-analysis: Organ Damage Appears Faster With Higher Disease Activity

• Assessed factors associated with time to initial organ damage in SLE patients with disease duration >6 months and no previous damage (SDI = 0)

• Organ damage occurred in 34% of patients during the follow-up period from time = 0 to time of SDI > 0 (median = 24 mo; range = 5-112 months)

• Higher level of disease activity at time = 0 predicted shorter time to initial organ damage

—Mean baseline SLAM was 9 ± 6 for those with damage vs 7 ± 6 for those without damage

LUMINA = LUpus in MInorities: NAture Versus Nurture; SLAM = Systemic Lupus Activity Measure; SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index

Clinical Measures to Evaluate SLE ActivityDomain/Outcomes Measure(s) Notes

Disease Activity SLEDAI (SLEDAI, SLEDAI-2K, Mex-SLEDAI, SELENA-SLEDAI)

First developed in 1985, widely used

SRI-50 In use since 2010 to assess 50% improvement

BILAG index Widely used since 1993 in different versions

SLAM (SLAM, SLAM-R, SLAQ) Widely used since 1989 but now rarely used

Flare indices: SELENA-SLEDAI Flare Index, BILAG (new A or B)

In use since 2010

SLICC-ACR Damage Index In use since 1996, physician-completed

Others: ECLAM, LAI, SIS, RIFLE Rarely used

Damage LDIQ Patient-completed

Renal biopsy, end stage renal disease Measures of renal damage

SLEDAI = SLE Disease Activity Index; Mex-SLEDAI = Mexican SLEDAI; SELENA = Safety of Estrogen in Lupus National Assessment; SRI = SLE Response Index; BILAG = British Isles Lupus Assessment Group; SLAM = Systemic Lupus Activity Measure; SLAM-R = SLAM (revised); SLAQ = Systemic Lupus Activity Questionnaire; ECLAM = European Consensus Lupus Activity Measure; LAI = Lupus Activity Index; SIS = NIH Systemic Lupus Index Score; RIFLE = Response Index For Lupus Erythematosus; SLICC = Systemic Lupus International Collaborative Clinics; LDIQ = Lupus Organ Damage Instrument.

van Vollenhoven RF, et al. Ann Rheumatic Dis. 2014;73:958-967.

Systemic Lupus Erythematosus Activity Index (SLEDAI)

Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index

van Vollenhoven RF, et al. 2014;73:958-967.

BILAG: No Significant Worsening in Any Specific Organ System• Included in the SRI to ensure no

significant worsening in any specific organ system over the previous month by tracking flares and flare severity

• 86 items reflecting disease activity within 8 organ systems; each organ receives a letter score

BILAG SCORE DESCRIPTION

BILAG-A Requires disease-modifying treatment (prednisone >20 mg/day or immunosuppressant)

BILAG-B Mild, reversible problems requiring symptomatic therapy (antimalarials, NSAIDs, prednisone <20 mg/day)

BILAG-C Stable, mild disease

BILAG-D No activity in previously affected system

BILAG-E System never involved

Lam GKW, et al. Clin Exp Rheumatol. 2005;23(suppl 39):S120-S132.

Why Do We Need a New Instrument? • SLEDAI: 30-years-old; reflects bias of the importance of lab tests; weighted for

rare serious events (CNS Lupus); ignores other significant manifestations (ILD, pulmonary HTN); validated for clinical activity, but a poor measure of change in activity

• BILAG: Impractical, insensitive, time consuming, never validated in a US population, reflects disease state rather than activity

• Damage indices: Cannot distinguish between damage due to SLE drugs used to treat SLE

• QOL instruments:

• Value increasingly recognized

• Reflect impact of the disease on the patient

• Need further validation in the clinic

Health-related Quality of Life (QOL) Measures

• SF-36: Generic questionnaire (not SLE-specific)

• LupusQoL, SLE Symptom Checklist, SLEQoL, L-QoL: SLE-specific questionnaires

• Patient-reported outcomes• SLE-specific: Lupus Impact Tracker, Lupus Foundation of America Patient-

Reported Outcome

• Not SLE-specific: Patient-Reported Outcomes Measurement Information System (PROMIS)

SRI

SRI responders had to meet all 3 criteria

Composite Index in Clinical Trials: SRI Response Rate at Week 52

≥4-point reduction in SELENA-SLEDAI score2

SELENA-SLEDAI1

No new BILAG A or

2 new BILAG B organ domain scores1,3

BILAG3

No worseningin PGA

(<0.3-point increase)1,4,5

PGA

1. Petri M, et al. N Engl J Med. 2005;353:2550-2558; 2. BENLYSTA [package insert]. Rockville, MD: Human Genome Sciences, Inc.; 2012; 3. Hay EM, et al. Q J Med. 1993;86:447-458; 4. Navarra SV, et al. Lancet. 2011;377:721-731; 5. Furie R, et al. Arthritis Rheum. 2011;63:3918-3930.

ACR Guidelines for Monitoring Activity of Lupus Nephritis1

Recommended Monitoring of Lupus Nephritis*

BP UA Protein:CR Serum CR C3/C4 Levels Anti-DNA

Active nephritis at onset of treatment

1 1 1 1 2† 3

Previous active nephritis, none currently

3 3 3 3 3 6

Pregnant with active GN at onset of treatment

1 1 1 1 1 1

Pregnant with previous nephritis, none currently

1 1 3 3 3 3

No prior or current nephritis 3 6 6 6 6 6

*Values are the monthly intervals suggested as the minimum frequency at which the indicated laboratory tests should be measured in the SLE scenarios shown in the left-hand column. †Opinion of the authors based on a study published after the Task Force Panel had voted.2

GN = glomerulonephritis; BP = blood pressure; UA = urinalysis; CR = creatinine1. Hahn BH, et al. Arthrit Care Res. 2012;64:797-808.2. Grootscholten C, et al. Kidney Int. 2006;70:732-742.

Challenges to Managing and Quantifying SLE—Some Thoughts

• Episodic disease: we treat aggressively when disease is active, back off when quiet

• Unlike RA, we cannot treat to SLE target because we don’t have a target—no instrument definition of remission or low disease activity

• Most instruments combine all SLE features for use in clinical trials, but may not reflect what is going on for individual patient

• We treat organ-threatening manifestations aggressively – best data here

• Holy Grail: an instrument (or biomarker, or PRO, etc.) that can predict a flare and help prevent damage

RA = rheumatoid arthritis; PRO = patient-reported outcome

Definition of a Biomarker• A characteristic that is objectively measured and evaluated as an indicator of

normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention

—Prognostic: predict or describe damage to tissues/organs—Diagnostic: confirm the presence or subtype of disease—Predictive: predict future disease in the pre-clinical phase—Pharmacodynamic: guide therapeutic choices and response to therapy—Surrogate: substitute for a clinical endpoint

• Explorations for new candidate biomarkers to date have targeted immune molecules or used comprehensive screening approaches

—Genomics—Transcriptomics—Proteomics—Metabolomics

• IRIDESCENT: literature scanning of comprehensive and targeted studies related to SLE

Biomarkers Definitions Working Group. Clin Pharmacol Ther. 2001;69:89-95.Arriens C, et al. Rheumatol. 2017;56:i32-i45.

Traditional SLE Biomarkers: ANA and Anti-dsDNA

• Included in ACR, SLICC, SLEDAI, SLEDAI 2000, SELENA-SLEDAI

• ANA—95-98% of SLE patients are positive—Low specificity (60%) for SLE

• Anti-dsDNA—Predictive of disease flares—Altered with immunosuppressive therapies—Correlates with improvement in proteinuria in LN—Measured longitudinally in routine clinical practice—Not unique to SLE

• A wide range of promising biomarkers have been identified in recent years, but few are currently practical

B Cell Growth Factors

BCMA = B-cell maturation antigen; APC = antigen-presenting cellIsaacs, et al. 2007 EULAR, Barcelona. Abstract SP0069.

Ligands

Receptors BAFF-R BCMA TACI

BLyS APRIL Heterotrimer

Proteoglycans

• Increased B-cell survival• Costimulation of B-cell proliferation• Ig class switch recombination• Enhanced APC function• Germinal center formation• Regulation of B-cell tolerance

• Sequester APRIL at cell surface to improve TACI and/or BCMA signalling

• Mediate plasma cell trafficking

BLyS/BAFF

• Elevated mRNA and protein levels in SLE vs control serum

• Elevated BLyS levels correlate with anti-dsDNA antibody levels, but change in serum BlyS does not correlate with change in disease activity

• BLyS levels may be related to future disease development

• Not associated with specific organ involvement, but patients with renal SLE may have higher levels than those with non-renal SLE

• Low BLyS at baseline in LN patients predicts good response

Liu C-C, et al. Ther Adv Musculoskel Dis. 2013;5:210-233.Eldin NSS, et al. Microbiol Res Rev. 2013;1:1-11.Parodis I, et al. Lupus Science & Medicine. 2015;2:e000061.

Emerging Cytokine Biomarkers

• TNF-

• TGF-

• IL-1

• IL-12

• IL-23

• IL-6

• IL-17

• IL-21

Arriens C, et al. Rheumatol. 2017;56:i32-i45

TGF = transforming growth factor; IL = interleukin

• IL-6

• IL-17

• IL-21

IL-6 in SLE• Systemic presence in SLE:

—Increased systemic IL-6 in active SLE—Increased IL-6 production by T and B cells—Increased expression of IL-6R by B cells in active SLE—Blocking IL-6 decreases spontaneous Ig and anti-dsDNA production ex vivo

• Effects on the kidney:—IL-6 increases mesangial cell proliferation—Increased IL-6 expression is found in kidneys of patients with LN—Increased urinary IL-6 levels are found during active LN

• Anti-IL-6 studies in SLE suggest role in pathogenesis and targeted therapy—Decrease in acute phase reactants—Decrease in anti-dsDNA antibodies

Illei GG, et al. Arthritis Rheum. 2010; 62:542-552.

IL-17 in SLE

• Secreted by TH17 cells, which are upregulated in SLE, RA, MS, IBD

• Activation of fibroblasts → expression of genes involved in inflammation

• Activation of epithelial and endothelial cells → expression of cytokines and adhesion molecules

• Activation of macrophages → cytokine production

• Dendritic cells → enhanced maturation

Iwakura Y, et al. J Clin Invest. 2006;116:1218-1222; Park H et al. Nat Immunol. 2005;6:1133-1141. Pietrzak AT et al. Clin Chim Acta. 2008;394:7-21. Miossec P. Arthritis Rheum. 2007;56:2111-2115.

IL-21 in SLE

• IL-21 drives extensive plasma cell differentiation and immunoglobulin production from stimulated murine and human naïve and memory cells

• Levels of IL-21 are markedly elevated in mouse models and SLE patients

• SLE is associated with polymorphisms in IL-21 and IL-21R genes

• Blocking IL-21 is effective therapy in MRLlpr/lpr mice

• Deletion of the IL-21R gene prevents lupus in BXSB-Yaa mice

McPhee CG, et al. J Immunol. 2013;191:4581-4588. Webb R, et al. Arthritis Rheum. 2009; 60:2402-2407; Herber D, et al. J Immunol. 2007;178:3822-3830. Bubier JA, et al. Ann N Y Acad Sci. 2007;1110:590-601.

Limitations of Cytokine Measurement

• Cytokine production can be affected by:—Age

—Sex: Women develop autoimmune disease more often

—Timing of measurement: Some cytokines have differential expression through the day

—Sample handling

—Other factors, eg, diet, exercise, stress

IFN and IFN-inducible Chemokines• Type 1 IFNs

• IFN signature

• IFN-inducible chemokines—levels may correlate with disease activity,

particularly lupus nephritis:

—MCP-1 (CCL2)

—RANTES (CCL5)

—MIP-3B (CCL19)

—IP-10 (CXCL10)

—SIGLEC-1

—CXCL1

—CXCL16

Liu C-C, et al. Ther Adv Musculoskel Dis. 2013; 5:210-233.

IFN-α

• Increased levels of IFN-α have been reported with patients with severe SLE manifestations and activation of inflammatory cytokines.1

• Increased IFN-α has been reported with flares, with some studies showing correlation with SLEDAI, anti-dsDNA antibody levels, and IL-10 levels.2

1. Becker-Merok A, et al. Lupus 2013;22:155-63; 2. Bengtsson AA, et al. Lupus 2000;9:664-671.

Candidate Biomarker: IFN Signature

• Type I IFN is an important endogenous mediator of inflammation and immunity, but measurement of IFN in serum can be difficult as levels may be low

• IFN dysregulation is seen in gene expression profiles, including genes regulating type I IFN pathways and IFN-inducible genes (IFN signature)

• Changes in IFN signatures are associated with disease activity, autoantibody formation, and organ complications

• SLE patients often have elevated IFN scores;* further, higher IFN scores are associated with a more severe disease course

*Determined based on expression of IFN-inducible genesStypińska B, et al. Int J Mol Sci. 2015;16:24194-24inter218. Baechler EC, et al. Proc Natl Acad Sci. 2003;100:2610-2615.

Genetic Factors

• Hereditary components predispose to SLE

• 10-12% of SLE patients have an affected first-degree relative

• Higher incidence of SLE concordance is seen in monozygotic twins (25%) than in fraternal twins (1-2%)

• Deviation from 100% concordance in monozygotic twins indicates that other factors contribute to disease development

• Many different gene products contribute to SLE susceptibility

• Polygenic and pleiomorphic nature of SLE makes identification of genetic susceptibility challenging

Buckman KJ, et al. Arch Int Med. 1978;138:1674-1676. Pistiner M, et al. Sem Arthritis Rheum. 1991;21:55-64. Deapen D, et al. Arthritis Rheum. 1992;35:311. Cooper GS, et al. Arthritis Rheum. 1998 Oct;41(10):1714-1724.

Epigenetics and Rheumatic Diseases

Genome

Inherited

Phenotype

Development Differentiation Dietary components

Pollution

Epigenetic changes

Infections Smoking Ageing

Acquired

Inherited

Adapted from Huber LC, et al. Arthritis Rheum. 2007;56:3523-3531.

Emerging Epigenetic Markers

• Epigenetics: Heritable modifications regulating gene expression without altering gene sequence

• Epigenetic changes are heritable, but may be influenced by environment, which may contribute to incomplete concordance in monozygotic twins

• Mechanisms include:—Hypo/hypermethylation in T cells

—Histone 4 modification

—Micro-RNA under/overexpression

Liu C-C, et al. Ther Adv Musculoskel Dis. 2013; 5:210-233.

—Micro-RNA under/overexpression

MicroRNA

• Short, non-coding RNAs which regulate post-transcriptional gene expression

• Bind to sequences in mRNA and regulate gene expression

• A single miRNA may regulate thousands of mRNAs

• A single mRNA may be targeted by multiple miRNAs

• miRNAs are critical for development of the immune system regulation of adaptive and innate immune responses

• miRNAs are promising novel biomarkers for SLE

Bartel D, et al. Cell. 2004;116:281-97. Baltimore D, et al. Nat Immunol. 2008;9:839-45. Liu C, et al. Ther Adv Musculoskel Dis. 2016;5:210-33.

miRNA as Biomarkers in SLE

MicroRNA Cell Type Alteration Consequence

miR-146a PBMCs Underexpression Type I IFN overproduction

miR-21 CD4 T cells Overexpression

Downregulation of DNMT1 (indirect)

and decreased DNA methylation

miR-148a CD4 T cells Overexpression

Downregulation of DNMT1 (direct) and

decreased DNA methylation

miR125a PBMCs Underexpression

Increased KLF expression and

RANTES overproduction

miR-126 CD4 T cells Overexpression

Downregulation if DNMT1 and

decreased DNA methylation

DNMT1 =DNA (cytosine-5) methyltransferase 1; KLF = Krüppel-like transcription factor; RANTES: regulated on activation, normal T cell expressed and secreted protein.Tang Y, et al. Arthritis Rheum 2009;60:1065-75. Pan W, et al. J Immunol. 2010;184:6773-81. Zhao X, et al. Arthritis Rheum 2010;62:3425-3435.

Lupus Nephritis: Traditional Biomarkers

• Serum creatinine levels

• Serum C3/C4 levels

•Anti-dsDNA levels

•Urine protein levels

•Urine sediments

•Kidney biopsy

Lupus Nephritis: Emerging Biomarkers

Serum, peripheral blood, and kidney• Anti-nucleosome antibodies (serum)

• Anti-C1q antibodies (serum)

• Complement C4d (kidney biopsy)

• Complement C4d (erythrocyte-bound;

peripheral blood)

Liu C-C, et al. Ther Adv Musculoskel Dis. 2013;5:210-233.

Urinary proteins• Monocyte chemoattractant protein-1

(MCP-1)• Neutrophil gelatinase-associated lipocalin

(NGAL)• Tumor necrosis factor-like weak inducer

of apoptosis (TWEAK)• Transferrin (TF)• α1-acid glycoprotein (AGP; AAG)• Ceruloplasmin (CP)• Lipocalin-type prostaglandin D-synthetase

(L-PGDS)• Hepcidin• Tumor growth factor β (TGFβ)

Challenges in Identifying SLE Biomarkers

• Differing patient populations in various studies can result in conflicting results

• Varying organ manifestations

• Treatment history may affect expression

• State of disease (early vs late)

• Racial/ethnic make up of population under study, particularly with genetic biomarkers

• Choice of controls

• Variations in activity and outcome measures

Illei G, et al. Arthritis Rheum. 2004;50:1709-1720.

Summary• Quantifying disease activity in SLE is critical to improving patient

outcomes

• New/improved instruments/indices are needed for clinical use

• Combining currently available biomarkers, physical exam, and patient history may allow for better assessment of disease activity

• Continuing technological developments (“omics”) will fuel identification of novel biomarkers

• Biomarker assessment may someday inform therapeutic regimens

• Clinical utility of novel biomarkers outside of the research environment remains a work in progress

Arriens C, et al. Rheumatol. 2017;56:i32-i45

Which of the following SLE agents targets the B-cell growth factor BAFF/BLyS?

A. Rituximab

B. Anifrolumab

C. Belimumab

D. Tofacitinib

Rituxim

ab

Anifrolu

mab

Belimum

ab

Tofacit

inib

25% 25%25%25%

Which of the following emerging agents for treatment of SLE met primary endpoints (as specified by the FDA’s US Guidance for Industry) in Phase II or Phase III trials?

A. Abatacept

B. Anifrolumab

C. Rontalizumab

D. Rituximab

Abatace

pt

Anifrolu

mab

Rontaliz

umab

Rituxim

ab

25% 25%25%25%

Which one of the following SLE indices assesses both disease activity AND that there is no significant worsening in any specific organ system?A. SLE Disease Activity Index

(SLEDAI)

B. British Isles Lupus Activity Group (BILAG)

C. Systemic Lupus Activity Measure-Revised (SLAM-R)

D. Systemic Lupus International Collaborative Clinics (SLICC)

SLE D

isease

Act

ivity

Index (

S...

British

Isle

s Lupus A

ctivi

ty G

...

Syste

mic

Lupus A

ctivi

ty M

ea...

Syste

mic

Lupus I

ntern

atio

na...

25% 25%25%25%

Which one of the following biomarkers is currently included in the ACR, SLICC, SLEDAI, SLEDAI 2000, and SELENA-SLEDAI indices?

A. IFN-α

B. TGF-β

C. Complement C4d

D. Anti-dsDNA antibodies

This activity is supported by an educational grant from

AstraZeneca Pharmaceuticals, LP