1

NEW THERAPIES FOR SLE

DANIEL J WALLACE MD

Clinical Professor of Medicine

Cedars-Sinai Medical Center

David Geffen School of Medicine at UCLA

2

2005 FDA Guidance Document for SLE• The drug is safe

• Clinical indices must be improved (BILAG+ either SLEDAI, SLAM or ECLAM)

• Clinical response index (e.g., RIFLE)

• Quality of life improvement

• ACR/SLICC Damage Index

• Organ specific measures

• Subpart H: surrogate markers or biomarkers

3

SLEDAI (Systemic lupus disease activity index)• Evaluates 24 components and emphasizes organ activity

as opposed to laboratory abnormalities

• 105 possible points---64 of which are central nervous system and 16 are renal

• Anti DNA, C3, Leukopenia, Thrombocytopenia are the only blood determinations and if all abnormal account for only 6 points

• Does not include: hemolytic anemia, pulmonary hypertension, TTP, mesenteric vasculitis, pulmonary hemorrhage

• SLEDAI Flare Index requires a change of 4 points

4

BILAG (British Isles Lupus Assessment Group)

• 8 organ systems with 86 items weighted as 0-4 (not present to new or improved)

• Organ systems: constitutional, musculoskeletal, renal, nervous system, hematologic, cutaneous, cardiopulmonary, eye, gastrointestinal

• Rated A-E (life threatening to not present)

• BLIPS software

• End points as new BILAG A or B

5

Clinical validation of the CLASI• An ACR and dermatology group derived the CLASI (Cutaneous Lupus

Erythematosus Disease Area and Severity Index) (J Inv Derm 2005; 125:889-94) for use in assessing skin scores in clinical trials (analagous to the PASI for psoriasis) fulfills the FDA guidance document’s requirements for validated organ specific measures in following lupus patients

• Index contains weighted anatomic locations, activity (erythema, scale/hypertrophy), damage (dyspigmentation, scarring, atrophy, panniculitis), mucous membranes and alopecia

• First attempt to validate it (abst #1010) in a pilot study of 9 patients at U of Penn given drug interventions was promising but needs much greater experience

6

Newer agents for SLE• Mycophenolate mofetil

• Topical pinecrolimus and tacrolimus

• Tacrolimus

• Leflunomide

• Infliximab and other TNFi

7

Lupus Nephritis• Cost

– Direct medical costs are 4x higher for lupus nephritis pts compared with SLE pts without nephritis ($19,250–$42,174/yr vs $4700–$10,015/yr)

– Extra costs due to hospitalizations and/or dialysis• Response to standard therapy

– 80% respond to IV cyclophosphamide– 35% relapse rate– 10% dialysis

• Poor prognostic factors– AA race does not respond as well to IV cyclophosphamide– Poor initial response– Renal relapse

Houssiau F, 71st ACR, Boston 2007, ACR Clinical Symposium; Clarke A. ibid, #503; Li T, et al. ibid, #1255;Ginzler E, #L13

• Efficacy and safety study to demonstrate superiority of MMF over IVCy in Lupus nephritis (WHO III, IV)

• Induction protocol (370 pts randomized to one of two therapies for 24 wks)• MMF 3 g/d (185 pts)• IV cyclophosphamide 0.5–1.0 g/m2 monthly (185 pts)• All pts received prednisone 60 mg/d with taper

• Response: stable/improved Cr and improved proteinuria

Aspreva lupus management study (ALMS)

8

ALMS: Efficacy and Safety Results

• Conclusions– MMF equal to IVCy for induction– AA and Hispanics may respond better to MMF than

to IVCy– Safety

• MMF: 24 AEs; 12 infections; 9 deaths (7 from infection)• IVCy: 13 AEs; 4 infections; 5 deaths (2 from infection)

Total (%)Caucasian/Asian (%)

AA (%)Hispanic

(%)

MMF 56 56/53 60.4 60.9

IVCy53

(p=NS)

54/64

(p=NS)

38.5

(p=0.033)

38.8

(p=0.011)

Ginzler E, et al. 71st ACR, Boston 2007, #L13

9

Targets for New Therapies in SLET cells CTLA4 Ig; modified CD40L mAb

B cells, anti-dsDNA antibodies LJP 394; mAbs to CD20, CD22

antiBLyS, TACI-Ig, BAFF-RFc

Complement anti C5a (approved for PNH)

Cytokines mAbs to IL-10, sIL-6R, IL-6

Promote regulatory cells Expand CD4+CD25+ cells, CD8+CD28- cells

Inhibition of interferon, toll receptors

Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9

T cell regulation of autoantibody production

Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide)

10

How are T-cells activated?• CD80/86:CD28 is one of the best characterized co-stimulatory

pathways– Signal 2

CD80/86:CD28 facilitates T-cell activation, proliferation, survival

and cytokine production

CD28 constitutively expressed on T-cell surface; CD80/86 on APC binds

CD28 on T-cell = signal 2C

D28

ActivatedT-cell

Site of action of abatacept

Antigen

11

Survival of Lupus Mice Treated withCTLA4Ig and Anti-CD40L

Wang et al. J Immunol. 2002;168:2046–2053.

Control

CTLA4Ig/anti-CD40L

CTLA4Ig

Anti-CD40L

Weeks

% A

live

28 38 48 58 68 78 88

100

80

60

40

20

0

12

Phase 2 Trial of Abatacept• Randomized, double-blind, placebo-controlled, phase 2

study• Abatacept compared with Placebo on a background of

oral glucocorticosteroids for subjects with SLE and the prevention of subsequent lupus flares

• Primary objective of this study will be to assess the proportion of subjects with new clinical flare of SLE (BILAG "A" or "B") during the 1 year double-blind treatment period

• Secondary objective of this study will be to assess proportion of subjects with a new clinical flare of SLE (BILAG A or B) within the initial 6 months of the double-blind treatment period and evaluate the proportion of subjects who during the study experienced a BILAG A or B flare

• Expected Total Enrollment is 180

Source: www.clinicaltrials.gov. Accessed January 29, 2007.

13

T-lymphocyte co-stimulatory modulation: Importance of the T-cell subsets

Adapted from Janeway CA Jr, et al. Immunobiology: The Immune System in Health and Disease. 6th e. New York, NY: Garland Science Publishing: 1994. p347

CTLA-Ig Less dependent CTLA-Ig More dependent

Anti-viral / anti-tumor immunity

CD8 T-cells:Peptide + class I

CD4 T-cells:Peptide + class II

Inflammation / Ab production

T T

Dougados M, et al. EULAR 2007, Barcelona, #SP0068

14Dougados M, et al. EULAR 2007, Barcelona, #SP0068

T-lymphocyte costimulatory modulation consequences

• Activation of the co-stimulation– Anti-tumoral effect?– Autoimmune disorders

• Inhibition of the costimulation?– Pro-tumoral effect?– Prevention of autoimmune disorders?

15* in Rilex, June 2005; * in Dillon 2006

Co-stimulation modulator Human diseases

Inhibition

CTLA-4 Ig (abatacept) RA (registration) SLE Juvenile Chronic Arthritis, Multiple sclerosis

LEA29Y (belatacept) Organ transplantation

Anti-CD80/86 Organ transplantation

Anti-CD80 Psoriasis SLE

Anti-BAFF (belimumab) RA SLE

TACI-Ig RA, Lymphoma SLE, Multiple sclerosis

Anti-BAF (AM6, G3) RA SLE

BR3-Fc RA

Anti-α 2 integrine (natalizumab) Multiple sclerosis Crohn's disease

Activation

Anti-CLA-4 (Ipilimumab, ticilimumab)

Tumors

Anti-CD28 (TGN1412) Leukemia Renal cancer

CC-5012 (CD28 activator) Myeloma

CD28 agonist Tumors

Selective co-stimulation modulators in clinical development **

Dougados M, et al. EULAR 2007, Barcelona, #SP0068

16Ng KP, et al. EULAR 2007, Barcelona, #OP0020

Targeted therapeutics: Approaches in SLE

APC T B YCTLA4-Ig CD22

B-cell toleragen

BlySSTACI-IG

CD20

IL-10

Peptide

Antibody

IL-10Apoptoticmaterial

1

2

Cos

timul

ator

y

Fact

ors,

eg

, Bly

S

17

Antigen Independent PhaseAntigen Independent Phase Antigen Dependent PhaseAntigen Dependent Phase

Targets for BLyS/BAFF inhibitors

Targets for Rituximab, Ocrelizumab, Ofatumumab

CD45CD45(AKA (AKA B220)B220)surface surface markermarker

Activated Activated B-cellB-cell

PlasmaPlasmacellcell

SecretedSecretedIgG, IgA, IgG, IgA,

IgE, or IgMIgE, or IgM

Mature Mature B-cellB-cell

Pro-B-cellPro-B-cell Pre-B-cellPre-B-cell Immature Immature B-cellB-cell

Surrogate Surrogate light chainlight chain

DDHHJJHH

IgMIgM IgMIgM IIggDD

AntigenAntigen

IgM, IgD, IgM, IgD, IgA, or IgEIgA, or IgE

CD40L andCD40L andcytokinescytokines

CD40CD40

VVHHDDHHJJHH VVLL JJLL

Adapted from Sell S, et al. Immunology, Immunopathology, and Immunity. 6th ed. Washington, DC: ASM Press; 2001

Potential targets in B-cell lineage

18

Uncontrolled Data of Rituximab in SLE and SS• Two placebo-controlled trials underway in SLE (SS?) (EXPLORER

and LUNAR)• 9 uncontrolled studies presented in lupus and Sjogren’s• New insights from in uncontrolled studies include:

– NK cell levels surge just as B-cell recovery begins– Persistence of B-cells predicts a poorer outcome– Drug may be more effective when used with CTX– In membranous nephritis, rebiopsy shows resorption of immune

depositions– 20% with SLE develop with HACA (3x that reported with RA)– Responses can last up to 1 y. 1/3 don’t require further immune

suppressive Rx– 16 patients with primary Sjogren’s: salivary gland B-cell

morphology returned to baseline after 18 months (ISRs and serum sickness reported in some pts)

– Drug is safe in children with lupus

Ng KP, et al. ACR, Washington DC 2006, #536; Tanaka Y, et al. ibid, #537; Gunnarsson I, et al. ibid, #538; Jónsdóttir T, et al. ibid, #539; Luning Prak ET, et al. ibid, #540; Dass S, et al. ibid, #541; Pers JO, et al. ibid, #1770; Gunnarsson I, et al. ibid, #2097

19Anolik JH, et al. EULAR 2007, Barcelona, #SP0033

B-cell depletion is variable

0.1

1

10

100

0 3 6 9 12

Months

CD

19+

(ly

mp

ho

cyte

s/u

L)

Non-depleters (n=6)

Depleters (n=11)

Recovery to 60% of baseline at 12 monthsFull recovery at 2–3 years in all but 1

201. Genovese M, et al. EULAR 2007, Barcelona, #SAT0008; 2. Manning W, et al. ibid, #SAT0018

Ocrelizumab: Humanized anti-CD20 mAb is effective in RA – 24 Week Phase 1/21

• 237 patients: All RF+; IR to MTX:– Ocrelizumab 10, 50, 200, 500,

1000 mg IV Day 1 and 15 or Pbo

• Dose dependent B-cell depletion and increases in serum BAFF ²

• Most frequent AEs: infusion-associated HA, nausea, chills, pyrexia, dizziness– SAEs and SIEs similar between

active and placebo

• HAHAs Wk 24: 10mg: 19%; 50mg: 10%; 200mg: 0; 500mg: 0; 1000mg: 2.5%

• Conclusions: – No apparent dose response– progressing to phase 2/3

0

20

40

60

80

PlaceboN=41

10mgN=36

50mgN=40

200mgN=40

500mgN=40

1000mgN=40

% r

es

po

nd

ers

ACR20 ACR50 ACR70

0

20

40

60

80

PlaceboN=41

10mgN=36

50mgN=40

200mgN=40

500mgN=40

1000mgN=40

% r

es

po

nd

ers

EULAR Mod/Good DAS Remission

ACR response

EULAR response

21

Synthetic anti-CD 20 – TRU-015: Ongoing Phase II RCT• CD20-directed SMIP (single-

chain polypeptides), smaller than antibodies

• Mediates ADCC and CDC

• 36 patients w/ active disease despite MTX

• 5 mg/kg IV x1 or 2.5 or 7.5 mg/kg

IV q week x2

• Study ongoing; interim data

• Generally well tolerated

• No infectious or non-infectious SAEs

• B-cell depletion in all cohorts

• B-cell recovery starts at 16 weeks

0

10

20

30

40

50

60

70

80

90

All RF +

% r

esp

on

se

ACR20 ACR50 ACR70

ACR20 at Week 24

Burge DJ, et al. ACR, Washington DC 2006, #463

22

Mechanism of Anti-CD20 (Rituximab) and Anti-CD22 (Epratuzumab) Monoclonal Antibodies

CD22

CD20

B cell

• Antibody-dependent cell-mediated cytotoxicity

• Complement-dependent cytotoxicity

• Apoptosis

• Modest antibody-dependent cell-mediated cytotoxicity

• No complement-dependentcytotoxicity

• Immunomodulatory and antiproliferativeeffect

Anti-CD20 MAbRituximab

Chimeric IgG1κ

Anti-CD22 MAbEpratuzumab

Humanized IgG1

Carnahan et al. Mol Immunol. 2007;44:1331–1341.

23

B-cell–targeted therapies• Anti-CD20 agents:

– Rapidly deplete peripheral B-cells via ADCC and CDC– First dose infusion reactions due to rapid cell death, cytokine

release– Immunogenicity in part related to cell death/debris– Despite fully human or SMIP -single chain polypeptides, smaller

than antibodies; expect immunogenicity

• B-cell growth factors (BLyS/BAFF/APRIL) antagonists– Slower depletion of B-cells – Peripheral and germinal center B-cells undergo apoptosis due to

absence of growth factors– Onset of benefit generally occurs over 3-6 months– Less severe infusion reactions– Less immunogenicity

24

B-cell growth factors

Ligands

Receptors BAFF-R BCMA TACI

BLyS APRIL Heterotrimer

Proteoglycans

Increased B-cell survivalCostimulation of B-cell prolferation

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

Issacs JD, et al. EULAR 2007, Barcelona #SP0069

25

Belimumab (lymphoStat-B)

• Fully-human monoclonal antibody

• Selectively targets and inhibits soluble BLyS– TNF family member that

promotes B-cell differentiation, proliferation, and survival

– Plays critical role in physiologic B-cell development and induces B cells to secrete immunoglobulins

• Inhibition of BLyS can result in autoreactive B-cell apoptosis

26

Systemic Lupus: Belimumab

• Phase 2: 52-week, randomized, double-blind, placebo-controlled trial.

• n=449…but subset analysis using 71.5% of patients defined by ANA>1:80 or dsDNA >30 IU. Moderately ill SLE: baseline mean SELENA SLEDAI= 9.6.

Ginzler E, et al. EULAR 2007, Barcelona, #OP0018

27p<0.01 for the comparison between all active vs placebo from Day 56 through Day 364

Belimumab reduced CD20+ B cells by 61% at Week 76

Furie R, et al. ACR, Washington DC 2006, #535; Wallace D, et al. ibid, #2012; Stohl W, et al. ibid, #1985

28Ginzler E, et al. EULAR 2007, Barcelona, #OP0018

Novel combined endpoint*

>4 point improvement in SELENA SLEDAI score

AND

No new BILAG 1A/2B flares

AND

No worsening in Physician’s Global Assessment (<0.3 point increase)

* Accepted by Regulatory Authorities for Phase 3 Trials

29Ginzler E, et al. EULAR 2007, Barcelona, #OP0018

Combined response rate for belimumab patients significantly higher

46% combined response rate for serologically active patients on belimumab vs 29% for placebo at Week 52

56% combined response rate for patients on belimumab at Week 76* p=0.0059 at Week 52, p=0.02 at Week 56

0

10

20

3040

50

60

70

0 28 84 140 224 280 336 392 476 532

Visit day

Res

po

nd

er r

ate

in

sero

log

ical

ly a

ctiv

e p

ts (

%)

PlaceboPlacebo to 10 mg/kg

All active

30

Atacicept inhibits the function of BLys and APRIL• Atacicept is a fusion protein formed between the extracellular

domain of the naturally occurring human TACI receptor and the Fc domain of human IgG1

Atacicept

Extracellular domainof TACI receptor

Fc domain of human IgG

rDNA technology

B-cell

31

Systemic Lupus: Atacicept (TACI-Ig)• 2 Phase I studies of PK and biologic activity

• Appears tolerated and safety is favorable

• Good signs of biologic effects on B-cells whether IV or SC

• Interestingly, measured atacicept-BLys complexes in peripheral blood

• Further development and trials are planned

32

Phase I trials for lupus: Tociluzimab• anti-IL-6R mAb

• Phase I: 16 patients, 6 doses over 12 weeks (3 dosing regimens)

• Safety signals

– Significant decrease in absolute neutrophil count in 60% of patients at highest dose

• Significant decreases noted in IgG and ds DNA Abs

• Significant improvement in SLEDAI and SLAM scores

1. Illei G, et al. ACR, Washington DC 2006, #L20; 2. Dall'Era M, et al. ibid, #L19

33

Mechanism of LJP 394 (Abetimus)• Novel synthetic putative

B-cell toleragen– Four double-stranded

oligodeoxyribonucleotides plus non-immunogenic PEG carrier

– Acts as anti-anti DNA to reduce anti-dsDNAantibodies in SLE patients

– Awaiting results of phase III study with an endpoint of time to nephrotic flare

Alarcon-Segovia et al. Arthritis Rheum. 2003;48:442-453.Furie. Rheum Dis Clin North Am. 2006;32:149-156.

B cell

B-cell receptor

B-cell toleragen

34

Cumulative Renal Flare in Phase 3

Cumulative renal flares by week

0

5

10

15

20

25

30

0 16 32 48 64 80

LJP 394 Placebo

Patients

Week 0

16 32 48 64 88

LJP394

145 111 81 67 50 27

Placebo

153 118 98 82 59 32

35

Tolerance Mechanisms: Edratide (TEVA)

Tsubata et al. Autoimmunity. 2005;38:331-337.

B cell

BCR

Bone Marrow Peripheral lymphoid organs

Reactive to self antigens

B cell

BCR

Self antigen

Deletion

T-cell zoneB cell

BCR

Self antigen

Deletion

Anergy

Receptorediting

B cell

BCR

Self antigen

Deletion

B cellBCR

Follicle

36

IFNgIL-10BlySTNFaIL-1

IL-12

Innate Immune Responses in SLE

• Toll-like receptors 7 and 9 in immature DC activated by complexes of self protein + RNA (TLR7) and DNA (TLR9)

• These complexes are normally rapidly cleared, but accumulate in SLE• Clearance defects in mice or humans → SLE • Activation of TLR7/9 induces immature DC secretion of IFN-α

immature DC induce T and B cell responses against the RNA and DNA and associated proteins

Activated B cell

Activated T cell

B cell

T cell

Mature DC

Activated mono/macrophage

Immature DC

INCREASED IFN

BacteriaViruses

SLE DNA/IC

CpG DNAssRNAdsRNA

Immune complexes in

SLE bind TLR7 and 9

37

Induction of type I Interferon pathway through Toll-like receptors

TLR3 TLR4 TLR7/8 TLR9

Inflammatory CytokinesType I Interferon

Inflammatory Cytokines Inflammatory CytokinesType I Interferon

PotentialEndogenousLigands:

dsRNA

∞RNA-containingImmune Complexes

FibronectinProducts

CpG DNA-containingImmune Complexes

ExogenousLigands: LPS ssRNA Demethylated

CpG DNA

dsRNA-containingImmune Complexes

TRAM TIRAPTrf

Trf MyD88

MyD88 MyD88

38

Toll-like Receptors in RA and SLE

• In RA – increased TLRs 3, 4, 7 on

dendritic cells (DC)1

– increased viral ds-RNA in joints compared with OA2

• In mouse models arthritis– TLR 2 deficiency decreased

susceptibility to arthritis,– TLR4 deficiency decreased

severity, erosions – Abs to TLR 4 prevented

arthritis1

• DS-RNA arthritogenic when injected into mouse joint, mediated by type 1 IFN from DC2

• CpG DNA sequences, common in bacterial DNA bind TLR 7 and 9 in DCs and B cells.

• Lupus immune complexes bind TLR 7 and Fcγ on DC, releasing cytokine and IFN3

• Antimalarials block the activation TLR 7 and 9

• IFN increase SLE flares and increased in SLE serum

• IFN signaling molecule Stat1 upregulated in SLE4

Genentech, Coley and MEDI-545 clinical trials

1. Radstake TR, et al. EULAR 2007, Barcelona, #SP0136; 2. Magnusson M, et al. ibid, #SP0112; 3. Richez C, et al. EULAR 2007, Barcelona #OP0179; 4. Karonitsch TM, et al. ibid, #OP0178; 5. Means TK, et al. J Clin Infect 2005;115:407

RA SLE

39

Hydroxychloroquine, “Antimalarials” are TLR Antagonists

1. Hydroxychloroquine and other “antimalarials” have been used in treating SLE and RA for decades, but MOA was unknown

2. Recent discovery: these antimalarials are TLR7/8/9 antagonists at clinically relevant doses

3. New approach to treatment – develop improved TLR antagonistsa. Small moleculeb. Orally available

40

CPG 52364 showed dose-dependent inhibition of TLR9-mediated IP-10 induction in mice

Female adult BALB/c mice (n=5/gp) received different doses of CPG 52364 or chloroquine by IP injection. At 1 h post dose, animals received 100µg CpG-DNA ODN subcutaneously. Plasma was collected at 3 h post agonist injection and used for IP-10 assay by ELISA. Value are presented as percent mean TLR9 agonist activity.

  

Female adult BALB/c mice (n=5/gp) received different doses of CPG 52364 or chloroquine by IP injection. At 1 h post dose, animals received 100µg CpG-DNA ODN subcutaneously. Plasma was collected at 3 h post agonist injection and used for IP-10 assay by ELISA. Value are presented as percent mean TLR9 agonist activity.

  

41

Hydroxychloroquine (HCQ) and Toll Receptors• TLRs 7, 8 and 9 are activated

inappropriately by endogenous RNA and DNA in SLE. This is inhibited by HCQ, which was thought to work primarily by diminishing antigen presentation

• Mice were treated with HCQ for 5 days. TLR9 activation was strongly inhibited (and to a lesser extent TLR 7). Ag presentation was incompletely blocked.

• The TLR mechanism is more important than antigen presentation inhibition and TLR antagonists represent a novel approach for SLE therapeutics

Weeratna R, et al. 71st ACR, Boston 2007. #1310

42

SLE is a Disease of TLR-Driven Amplification of Autoimmunity

Dendritic CellsTLR7+ / 8+ / 9+

B cellsTLR9+ / TLR7

Inducible

Cytokine/Chemokine InducedActivation/Maturation

And Damage

Apoptotic debrisSelf-antigen

Autoimmune Complex-DrivenTLR Cellular Activation

TLR signal

Anti-self responseCytokine/chemokine

TissueDamage

End OrganFailure

T-cell NK cell

Inflammation

CPG 52364TLR7/8/9 Antagonist

XX

Complexuptake

XX

CPG 52364 (Coley) is a TLR 7,8,9 antagonist in a Phase I trial with similar actions to hydroxychloroquine

Akira S, et al. Nat Imunol 2001;2:675; Lipford G, et al. 71st ACR, Boston 2007. #1596

43

Interferons and Systemic Lupus Erythematosus

• Type I interferons (IFNs) may play a critical role in the pathogenesis of systemic lupus erythematosus (SLE) – Serum IFN-α levels are elevated in patients with SLE1

– Increased expression of type I IFN-induced genes in blood and involved tissues in SLE2

– Correlation between IFN levels and expression of type I IFN-induced genes and SLE activity1,3

– Development of SLE in patients undergoing IFN-α treatment4

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

1 Hooks JJ, et al. New Engl J Med. 1979;301:5-8; 2 Crow M. Arthritis Rheum. 2003;48:2396-2401; 3 Dall’era MC, et al. Ann Rheum Dis. 2005;64:1692-1697; 4 Ioannou Y, Isenberg DA. Arthritis Rheum. 2000;43:1431-1442.

44

MEDI-545 (Medimmune/AstraZeneca)• Fully human anti–IFN-α IgG1k

monoclonal antibody

• Inhibits IFN-a signaling through IFN-α receptor (IFNAR)

• Double-blind, placebo-controlled phase I trial of single escalating dose, intravenous MEDI-545 (0.3–30 mg/kg) in patients ≥18 years old with SLE – 2:1 randomization, 84-day

follow-up

• There was no safety signal observed

• Effects of MEDI-545 on neutralization of type I IFN gene signature in blood and skin and on disease activity were explored

Wallace D, et al. 71st ACR, Boston 2007. #1315

IFN-a

IFNAR1IFNAR2

PPSTAT2PP

IRF-9

STAT2PP

STAT1PP IRF-9

Tyk2Tyk2Tyk2Tyk2

STAT1

P

Jak1Jak1Jak1Jak1

45

MEDI-545 Reduces Type I IFN Gene Signature, Type I IFN–Induced Proteins in Skin, and Improves Disease Activity

Day 14

Skin, day 0–28

5/1729%

1/333%

MEDI-545Placebo0

20

30

40

Pts

, N

10

>3 point increase in SLEDAI score<3 point increase in SLEDAI score

P=0.0136

Wallace D, et al. 71st ACR, Boston 2007. #1315

Type I IFN–induced proteins in skin

Change in proteinChange in transcript

20%97%

75%99%

87%99%

HERC5 ISG15 IP10

Improvement in disease activity

Day 0

Day 14

46

MEDI-545 Can Normalize Type I IFN Gene Signature in Blood: Heat Map of Gene Expression

Day Neutralization

Wallace D, et al. 71st ACR, Boston 2007. #1315

Calculation based on top 25 type I IFN–inducible genes upregulated in whole blood of one patient treated with 30 mg/kg MEDI-545 (day 0, 1, 4, 7, 14)

47

Th1/Th2 Paradigm

T-bet

Naïve T-cell

IL-5

IL-10

IL-13

IL-4

IL-6

Helminth protection (allergy, atopy, SLE)

IL-4

STAT6

GATA3

CMAT

IL-12

IL-18

Th1 cell

IFN-LT-IL-2IL-22

Cell-mediated immunity

Intracellular pathogens

AutoimmunityIL-12RIL-18R

Th2 cell

Schulze-Koops H, et al. EULAR, 2006, Amsterdam, #SP0130. Zhu J, et al. Cell Res 2006;16:3

(-)

(+)

(-)

(+)

48

FoxP3

T cell subsets: Th17 and Treg cells• Th17 cells are abundant in gut, maintain mucosal homeostasis

• Upregulated in inflammatory diseases including MS, RA, IBD

• IL-23 important for the maintenance of the Th17 phenotype

Treg cell

Self Ag + TGF

IL-10

TGFPROTECTION

IL-17

IL-22

INFLAMMATIONSelf Ag + TGF + IL-6

IL-23 (survival)

IL-23R

CTLA-4

TGF

AITR, GITRNaïve T-cell

RORt

Th17 cell

Betelli, et al. Nature 2006;441:235; Ivanov, et al. Cell 2006;26:1121; Tesmer L, et al. 70th ACR, Washington DC, 2006. #297

49

T-regs in autoimmune disease• CD4+CD25+ regulatory cells prevent the activation of autoreactive T-

cells• T-cells from lupus prone mice are relatively resistant to the

suppressive effect of CD4+CD25+ • Work at the NIH (Lipsky et al) suggests CD4+CD25+ upregulation is a

potential therapeutic avenue in lupus management • Active as opposed to inactive SLE is associated with less

CD4+CD25+ activity (poster and picture represented on the slide

Bonelli M, et al. EULAR 2007, Barcelona #FRI0080

50

Vitamin D and IL-10: An importantpotential link in SLE• IL-10 is a complex cytokine whose levels are

elevated in SLE and has both pro- and anti-inflammatory effects

• Vitamin D levels are decreased in SLE

• Vitamin D independently promotes IL-10 secretion

• Activated B cells produce Vitamin D which down regulates the immune response

• Efforts to produce a Mab to IL-10 are potentially problematic

1. Radbruch, et al. EULAR 2007, Barcelona; 2. Kamen DL, et al. Autoimmune Rev 2006;5: 114–7

51

Vitamin D May Play a Role in SLE

• 25-OH vitamin D inhibits Th1 cell proliferation, cytokine production, autoantibody production and APC activation in SLE patients; may be clinically relevant

• 124 Toronto women with SLE who underwent DEXA scanning had significantly lower levels of 25-OH vitamin D levels compared with other DEXA patients; this finding did not correlate with bone density.

• Among 274 Israeli lupus patients, 38% had low vitamin D levels and higher SLEDAI and ECLAM scores. Hydroxychloroquine-treated patients had higher vitamin D levels, corticosteroids had no impact

71%

38%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Insufficient Deficient

Insufficient: <30ng/ml of 25-0H vitamin DDeficiency: <15ng/ml of 25-0H vitamin D

Amital H, et al. 71st ACR, Boston 2007. #535; Toloza S, et al. ibid. #1117; Cantorna et al. Exp Biol Med, 2004

52

IL-18 and SLE• A member of the TNF

superfamily which supports the expansion of Th1 and NK cells

• Mouse models of SLE overexpress IL-18

• Increased levels in SLE sera and renal tissue which correlates with TNF levels and disease activity

• Administration of infliximab decreases expression of IL-18. Targeted therapies against IL-18 are in development

Aringer M, et al. EULAR 2007, Barcelona, #OP0177

TN, IL-18 and SLE activity

Ser

um

TN

F (

pg

/ml)

0

200

100

300

0 4 8 12SIS

t=0.76, p<0.0001

Ser

um

IL-1

8 (p

g/m

l)

0

200

100

300

0 4 8 12SIS

t=0.38, p<0.02

53

Microparticles and lupus• 200-700 nm in size surrounded by phospholipid bilayers

• Released by cell death to the surface; taken up by macrophages and induce apoptosis and T cell proliferation

• 40 SLE pts and matched controls— increased levels that correlated with SLEDAI scores

• Also increased in Sjogren’s, vasculitis, antiphospholipid syndrome in other studies

Huber L, et al. EULAR 2007, Barcelona #OP0180

54

Targets for New Therapies in SLET cells CTLA4 Ig; modified CD40L mAb

B cells, anti-dsDNA antibodies LJP 394; mAbs to CD20, CD22

antiBLyS, TACI-Ig, BAFF-RFc

Complement anti C5a (approved for PNH)

Cytokines mAbs to IL-10, sIL-6R, IL-6

Promote regulatory cells Expand CD4+CD25+ cells, CD8+CD28- cells

Inhibition of interferon, toll receptors

Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9

T cell regulation of autoantibody production

Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide)

55

New therapies for APS• Biologics: LJP 1082

• Oral heparins

• Rituximab

• Glycoprotein IIb/IIIa specific antagonists

• Tissue factor expression inhibitors

• P38 MAPK inhibitors

• Thromboxane A2 inhibitors

• Anti C5a