Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases

2

Advances in B-Cell Biology in the Treatment of Autoimmune

and Inflammatory Diseases

3

Learning Objectives

• Discuss recent advances in understanding how B-cell biology affects autoimmune rheumatic diseases (ARDs)

• Review new biologic agents that targetB cells and their mechanisms of action

• Identify how studies of B-cell–targeted therapy are changing our understandingof integrated immune responses and the pathogenesis of ARDs

4

Outline

• B-cell biology in autoimmune disorders

• Overview of B-cell–targeting agents

• Recent developments in B-cell targetingin rheumatoid arthritis (RA)

• Recent development in B-cell targetingin other ARDs

B-Lineage Cells and Autoimmunity

DC, dendritic cell; FDC, follicular dendritic cell; FO, follicular; GC, germinal center;IL, interleukin; LT, lymphotoxin; Mφ, macrophage; MZ, marginal zone; SLE, systemiclupus erythematosus; TNF, tumor necrosis factor.Adapted from Martin F, Chan AC. Annu Rev Immunol. 2006;24:467-496

Plasma cell

Memory

Bone MarrowImmature

Pre BPro B

Plasmablast

Blast

Spleen

T2

MZ

T1

Mature

FO

GC

Auto- antibodies

Graves’ diseaseMyasthenia gravis

Pemphigus vulgarisSLE(RA)

Immune complexes

SLERA

BB

TT

DCDC

Antigen presentationand costimulation

Multiple sclerosisSLERA

TTBB

FDCFDC

DCDC

Lymphoid organogenesis

Multiple sclerosisSjögren’s syndrome

RA

Activation

Inflammatory cytokines

All autoimmunedisorders

TT

B

TNF-TNF- IL-IL-66

MM ? ?

LTLT

5

6

Why Are Some Plasma Cells Short-Lived and Others

Long-Lived? • Plasma cells, which arise after new immune exposures,

are continuously generated in lymphoid tissues, and perhaps in pathologic ectopic lymphoid tissues(eg, rheumatoid synovium)

• There are different life expectancies of Ig-secreting plasmablasts (which can proliferate) and plasma cells(which cannot proliferate)

• Newly generated plasma cells are released into the bloodstream, then migrate to the bone marrow

• As long-term survival requires that they find a “niche,” they must displace “older” plasma cells from their survival niche for long-term survival

Dörner T, Radbruch A. Immunity. 2007;27:384-392.Dörner T, Radbruch A. Immunity. 2007;27:384-392.

7

Bone marrow

Plasmablasts

Long-lived memory plasma cell

B

T

Complex Interactions Determine Plasma

Cell Survival

Instruction of memoryB cells by T cells- CD40/154- ICOS/ICOS-L- SAP

GC

Adhesion- CD138- CD44, 18, 11a- E-/P-selectinChemokine systems- CXCR4/CXCL12

Soluble survival factors- IL-6- IL-21 (?)- TNF, IL5- BAFF/APRILChemokine systems- CXCR4/CXCL12 (?)

Insoluble survival factors from

- nurse cells- or stromal cells

(within inflamed tissue)

Intracellular survival regulators- ↑ Bcl-2, Blimp1, XBP1, Aiolos- ↓ BACH2 and Pax5

Competence

Dörner T, Radbruch A. Immunity. 2007;27:384-392.Tarlinton D et al. Curr Opin Immunol. 2008;20:162-169.

8

Not All CD20+ B Cells Are Susceptible to Depletion

• Deletion is most efficient in blood

• CD20+ precursors and transitional and naïve B cells appear highly susceptible to deletion

• CD20+ B1 cells, MZ B cells, and GC B cells are resistant (GC in GALT Peyer’s patches)

• Most plasma cells are not directly affected by RTX (although in the tonsil a subset may express CD20)

• Effect of RTX on memory B cells and plasmablasts

– Little is known about RTX effects on these cells in lymphoid organs

• IgG-producing plasma cells generally live longer than IgM producers

GALT, gut-associated lymphoid tissue.Gong Q et al. J Immunol. 2005;174:817-826. Silverman GJ. Arthritis Rheum. 2006;54:2356-2367.Withers DR et al. Blood. 2007;109:4856-4864. Terstappen LW et al. Blood. 1990;76:1739-1747.

9

Does Extent of Reduction in SynovialB Cells Explain Clinical Response?

B-cell depletion

Nondepletion

CD22 stainingof synovial tissue

CD22 stainingof synovial tissue Before TreatmentBefore Treatment 4 Weeks After Treatment4 Weeks After Treatment

Vos K et al. Arthritis Rheum. 2007;56:772-778.

11

Responsible formarginal erosions and bone loss

OsteoclastOsteoclast

TNF-, IL-1, IL-6

IL-1, IL-6, TNF-IFN-

T cellT cellPlasma

cellPlasma

cell

MMImmune complexes

Complement fixationInduce M secretion

of proinflammatory cytokines

B cellB cell

RF, anti-CCP antibodiesRF, anti-CCP antibodies

TNF-IL-1IL-6

TNF-IFN-IL-17

RANKL

FLSFLS

MMPsCathepsins

MMPsCathepsins

Model of RTX-Induced RA Synovial Changes in Clinical Responders

BASELINE

CCP, cyclic citrullinated peptide; FLS, fibroblast-likesynoviocyte; IFN, interferon; MMP, matrixmetalloproteinase; RANKL, receptor activator ofNF-κB ligand; RF, rheumatoid factor. Silverman GJ, Boyle DL. Immunol Rev. 2008;223:175-185.

12


4 WEEKS


T cellT cell

MMImmune complexes





TNF-IL-1IL-6

TNF-IFN-IL-17

RANKL

FLSFLS

MMPsCathepsins

Early synovial B-cell depletion is necessary but not sufficient!

Trends toward ↓ in plasma cells in clinical responders (at 6 months)

MMPsCathepsins

TNF-, IL-1, IL-6


B cellB cellXPlasma

cellPlasma

cellX

Silverman GJ, Boyle DL. Immunol Rev. 2008;223:175-185.

13


8 WEEKS


T cellT cell

MMImmune complexes





TNF-IL-1IL-6

TNF-IFN-IL-17

RANKL

FLSFLS

MMPsCathepsins

Early synovial B-cell depletion is necessary but not sufficient!

Trends toward ↓ in plasma cells in clinical responders

Significant ↓ in Ig transcripts in ACR50/70 clinical responders(at 6 months)

Trends toward ↓ in lymphocytic aggregates and T cells

MMPsCathepsins

TNF-, IL-1, IL-6


B cellB cellXPlasma

cellPlasma

cellX


14


16 WEEKS


T cellT cell

MMImmune complexes





TNF-IL-1IL-6

TNF-IFN-IL-17

RANKL

FLSFLS

MMPsCathepsins

Significant synovial B-cell depletion

Significant ↓ in plasma cells

Significant ↓ in T cells and lymphocytic aggregates

Significant ↓ in CD68+ M

All in clinical responders at6 months

MMPsCathepsins

TNF-, IL-1, IL-6


B cellB

cellXPlasma

cellPlasma

cellX

X

?

X


15


T cellT cell

MMImmune complexes





TNF-IL-1IL-6

TNF-IFN-IL-17

RANKL

FLSFLS

MMPsCathepsins

Primary end point is clinical response at 24 weeks

Effects on synovial cytokines/chemokines have not been evaluated at later time points

Direct studies on osteoclasts after RTX are not currently available

MMPsCathepsins

TNF-, IL-1, IL-6


B cellB cellXPlasma

cellPlasma

cellX

?

X

X


24 WEEKS


16

Insights From RA Synovial Biopsy Studies

• There are great variations in the histopathologic changes inducedby RTX

• Based on small open synovial biopsy studies, there may be a sequence of changes in the synovia that leads to clinical response1-6

• B-cell depletion at 4 weeks may predict clinical response; subsequent↓ in plasma cells and Ig transcripts may predict clinical response1,2,5

• RTX-induced depletion of B-lineage cells, with loss of plasma cells and immune complex formation, may induce clinical responses by multiple pathways

• B-Cell Roadblock Hypothesis: As B cells are most susceptible to deletion in the blood, RTX benefits may derive from preventing reseeding of pathogenic B cells to the synovia7

1. Kavanaugh A et al. Ann Rheum Dis. 2007;66(suppl 2):291 [abstract FRI0037]. 2. Rosengren S et al. Ann Rheum Dis. 2007;66(suppl 2):298 [abstract FRI0059]. 3. Thurlings RM et al. Ann Rheum Dis. 2008;67:917-925. 4. Dass S et al. Ann Rheum Dis. 2007;66(suppl 2):90 [abstract OP0123]. 5. Teng YK et al. Arthritis Rheum. 2007;56:3909-3918. 6. Teng Y et al. Ann Rheum Dis. 2007;66(suppl 2):439 [abstract SAT0034].7. Silverman GJ, Boyle DL. Immunol Rev. 2008 223:1751-85.

18

Conventional Immunosuppressive Therapy Can Deplete Peripheral Plasmablasts and Naϊve B Cells, but Not Memory B Cells

Methylprednisolone Cyclophosphamide

Odendahl M et al. J Immunol. 2000;165:5970-5979. Figure courtesy of T. Dörner (Berlin, Germany)Odendahl M et al. J Immunol. 2000;165:5970-5979. Figure courtesy of T. Dörner (Berlin, Germany)

07/21/03 07/28/03 09/09/03

CD19

CD

27

1.2%

87.1%

11.7%

2.5%

72.1%

25.4%

6.7%

64.0%

29.2%

Plasmacells/blasts

CD27+ memoryB cells

19

Are There Predictive Biomarkers of Response to RTX Treatment in RA?

• Open trial of 17 patients with refractory RA who received a first cycle of rituximab

• 12 patients responded with good EULAR responsesa

– 6 patients with an early relapse (weeks 24–40)– 6 patients with a late relapse (after week 40)

• 5 patients were classified as nonresponders• 1 patient remained in remission after 1 cycle of

treatment• 11/17 patients received a second cycle of rituximab

– 2/11 were RF-negative, 3/11 were anti-CCP–negative

aResponse was defined as improvement in DAS28 ≥1.2.DAS28, Disease Activity Score including a 28-joint count; EULAR, European League Against Rheumatism.

Roll P et al. Arthritis Rheum. 2008;58:1566-1575.

20

At Baseline, Higher CD27+ Memory B Cell Counts Correlated WithEarly Relapse in Clinical Responders After RTX Treatment

CD27+ B cells/µL Before Therapy

Early Relapse Late Relapse

60.0

50.0

40.0

30.0

20.0

10.0

0.0

P = .045

(Week 24–40)(Week 24–40) (After Week 40)(After Week 40)

Roll P et al. Arthritis Rheum. 2008;58:1566-1575.

Memory B cells are either IgD+ or IgD- Memory B cells are either IgD+ or IgD-

At Time of B-cell Regeneration, Clinical Nonresponders Had Higher Levels of IgD+ CD27+ Memory B Cells – Lack of Persistent Memory B Cell Reductions

At Time of B-cell Regeneration, Clinical Nonresponders Had Higher Levels of IgD+ CD27+ Memory B Cells – Lack of Persistent Memory B Cell Reductions

2.0

0.0

Responder Nonresponder

CD27+/IgD+ B cellsa

P = .019

aFirst time-point of regeneration

(n = 12)(n = 12) (n = 5)(n = 5)

CD

19+

/CD

27+

B C

ells

/l

CD

19+

/CD

27+

B C

ells

/l

IgD

CD27

naive

memory

21

Summary• In RA, levels of CD27+ memory B cells increase with disease duration1

• After RTX treatment, at time of B-cell regeneration, clinicalnonresponders had higher levels of IgD+ CD27+ memory B cells

– Lack of lasting memory B cell reductions

• Early relapse after the first RTX cycle was associated with higher CD27+ memory B cell counts prior to therapy and higher IgD+/CD27+ and IgD-/CD27+ B cell counts after first and second treatment cycle, compared with late-relapsing patients

• Yet even for nonresponders after the first cycle, RTX retreatmentcan still be effective

• Clinical response to anti-CD20 treatment may be primarilydependent on the reduction of blood memory B cells, and this may be linked to a reduction of plasmablasts

1. Fekete et al. J Autoimmun. 2007;29:154-163.1. Fekete et al. J Autoimmun. 2007;29:154-163.

22

Epratuzumab: A HumanizedAnti-CD22 Therapeutic Antibody

• CD22 first appears on B cells at the stage of antigen responsiveness

• CD22 acts as a coreceptor with the antigen receptor that can down-regulate antigen responses

• Interacts with inhibitory 2,6-linked sialic acid–associated glycoproteins

• Epratuzumab induces rapid CD22 internalization and phosphorylation

• In clinical trials for ARD and NHL

• Open phase I trial in 12 patients with SLE showed safety and some efficacy based on BILAG scores

– All patients fulfilled ACR criteria

– Majority of patients had low disease activity (median SLEDAI = 2)

BILAG, British Isles Lupus Assessment Group; ACR, American College of Rheumatology;NHL, non-Hodgkin‘s lymphoma; SLEDAI, systemic lupus erythematosus disease activity index. Dörner T et al. Arthritis Res Ther. 2006;8:R74. doi:10.1186/ar1942.Jacobi AM et al. Ann Rheum Dis. 2008;67:450-457.

How does epratuzumab work? What are the effects on the human immune system?

23

Epratuzumab Preferentially Reduced Peripheral Blood Naϊve B Cells; Plasmablasts and CD27+ Memory B

Cells Are Less Affected

Jacobi AM et al. Ann Rheum Dis. 2008;67:450-457.

CD27- naive B cells/lB cells

absolute cell number

CD27+ memory B cells/l CD27++ plasmablasts/l

24

Epratuzumab Modulates the Activation and Proliferation ofB Cells in Patients With SLE

• Epratuzumab was shown to be safe in a phase I open trial

• Surface levels of CD22 were rapidly down-modulated

• Average reduction of 30% of total blood B-cell levels, that lasted for 12 weeks after last infusion

• Reductions primarily in naïve B cells, trend to increase in plasmablasts. No change in memory B cells

• Laboratory studies show epratuzumab causes impaired B-cell proliferative responses to in vitro experimental stimulationof T-cell–independent pathway

• CD22-targeted therapy may provide mechanistic advantagesin patients with certain autoimmune diseases

• More studies are warrantedJacobi AM et al. Ann Rheum Dis. 2008;67:450-457.

25

Conclusions• Studies with RTX have demonstrated an attractive

safety/efficacy profile in RA and encouraged the development of newer agents

• A diversity of additional strategies for targeting B cells, as well as design of biologic agents, are currently under investigation

• Different B-cell subsets, including naïve B cells, plasma cells/blasts, and memory B cells, appear to make different contributions to pathogenesis

• The capacity to inhibit or delete each B-cell subset varies greatly based on the mechanism of action of the therapeutic agent

• Investigations into B-cell–targeted therapy are providing new therapeutic options as well as helping to elucidate previously unknown immunologic mechanisms of pathogenesis.

26

B-Cell–Directed Therapyfor RA

RA, rheumatoid arthritis.

27

Learning Objectives

• State the rationale of B-cell depletion for the management of RA and list at least 3 agents that are being studied in clinical trials

• Summarize the efficacy of B-cell–targeted therapy following DMARD and anti-TNF therapy failure

• Describe the safety of long-term and repeated courses of B-cell–targeted therapy and the nuances of fixed or on-demand retreatment

• Summarize the radiographic changes noted following B-cell–targeted therapy for RA

DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor.

28

CD20: A Target on B cells

• 297-AA membrane-associated phosphoprotein (33–37 kDa)

• Not shed: No known membrane/secreted molecular analogues

• Selective expression: Not expressed on stem cells, pro-B cells, plasma cells, dendritic cells

• Anti-CD20 binding:

– Does not rapidly modulate expression

– Does not cause substantial internalization

• Differences in epitope binding are of unclear clinical significance with regard to safety or efficacy

AA, amino acid.Kehrl JH et al. Immunol Today. 1994;15:432-436; Golay J et al. Blood. 2000;95:3900-3908.

TRU-015

Ofatumumab

CD20

Ocrelizumab

30

29

75

14

44

0

10

20

30

40

50

60

70

80

Placebo RTX Placebo RTX

% P

atie

nts

EU

LAR

Mod

/Goo

dRTX (REFLEX): EULAR Responses

Based on RF/Anti-CCP• While significantly more

patients receiving RTX demonstrated ACR20 and EULAR responses compared with placebo recipients, seronegative patients (for RF and anti-CCP) did not respond as well

Anti-CCP, anti–cyclic citrullinated peptide; EULAR, European League Against Rheumatism;RF, rheumatoid factor.Tak PP et al. Ann Rheum Dis. 2007;66(suppl 2):338 [abstract FRI0192].

aP > .0001 vs placebo, seropositive.bP = .05 vs placebo, seronegative.

RF/Anti-CCP+(Either or Both)a RF/Anti-CCP−b

31

0

10

20

30

40

50

60

70

80

ACR20 ACR50 ACR70 DAS28 ≤ 3.2(Low Disease

Activity)

DAS28 < 2.6(Remission)

Course 1

Course 2

Course 3

Repeated Treatment With RTX Produces Sustained Efficacy in Patients With RA

With an Inadequate Response to DMARDs

DMARD, disease-modifying antirheumatic drug; DAS28, Disease Activity Score including a 28-joint count.Emery P et al. Arthritis Rheum. 2007;56(9 suppl):S151-S152 [abstract 266].

Pat

ient

s (%

)

Week 24 (n = 57)

32

Patient-Reported Outcomes During RTX Treatment of Anti–TNF- Refractory RA in

Addition to ACR Responses

aP < .0001 vs placebo + MTX.MCID, minimum clinically important difference; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; HAQ-DI, Health Assessment Questionnaire Disability Index; PCS, physical component score; MCS, mental component score.Cohen SB, et al. Arthritis Rheum 2006;54:2793-2806. Keystone E et al. Arthritis Rheum. 2008;59:785-793.

0

20

40

60

80

100

FACIT-F HAQ-DI PCS MCS

Placebo + MTX (n = 201)

RTX + MTX (n = 298)

Pa

tien

ts (

%)

Ach

ievi

ng

MC

ID

a aa

0

10

20

30

40

50

60

ACR 20 ACR 50 ACR 70

Placebo

Rituximab

a

a

a

Pa

tien

ts (

%)

33

Repeated Treatment With RTX Produces Sustained Efficacy in Patients With an

Inadequate Response or Intolerance to TNF Inhibitors

0

1020

30

40

5060

70

80

ACR20 ACR50 ACR70 DAS28 ≤ 3.2(Low Disease

Activity)

DAS28 < 2.6(Remission)

Course 1

Course 2

Course 3

Emery P et al. Arthritis Rheum. 2007;56(9 suppl):S151-S152 [abstract 266].

Week 24 (n = 96)

Pat

ient

s (%

)

34

REFLEX: Change in Radiographic Outcomes at Week 56

JSN, joint space narrowing; TGS, total Genant-modified Sharp score.Keystone E et al. Ann Rheum Dis. 2007;66(suppl 2):431-432 [abstract SAT0011].

Mea

n C

hang

e

P = .0046

35

2.75

1.09

2.21

1.190.97

0.85

0

0.5

1

1.5

2

2.5

3Placebo RTX

REFLEX: Change in RadiographicEnd Points at Week 56

The effect of RTX in inhibiting joint damage was consistent for all subgroups examined(baseline: total Sharp score, DAS28, disease duration, CRP, HAQ, SJC, and TJC). The studywas not powered to detect treatment differences within each subgroup; however, numericallysimilar and consistent results were observed for nearly all subgroups analyzed.

CRP, C-reactive protein; SJC, swollen joint count; TJC, tender joint count.1. Cohen S et al. Ann Rheum Dis. 2007;66(suppl 2):428 [abstract SAT0002].2. Keystone E et al. Ann Rheum Dis. 2007;66(suppl 2):431-432 [abstract SAT0012].

Me

an

Ch

an

ge

in

X-r

ay

Sc

ore

Change in Sharp–Genant Total Score atWeek 56 by Anti-CCP Status at Baseline1

(n = 11) (n = 78)Missing

(n = 21) (n = 33)Negative

(n = 85) (n = 129)Positive

Me

an

Ch

an

ge

ACR20 Nonresponders at Week 242

36

REFLEX: RTX Radiographic Findings in RA at 2 years

• X-rays at weeks 0, 24, 56, 104

• Total Genant-modified Sharp score used

– Linear extrapolation used for missing week 104 x-rays (30% of patients)

• Effects on JSN and erosions were similar

• 87% of RTX patients who did not progress in year 1, did not progress in year 2

• The data are confounded by multiple therapeutic changes

Cohen S et al. Ann Rheum Dis. 2008;67(suppl 2):189 [abstract THU0167].

No

T

GS

(%

)T

GS

0.661.14

1.78

2.81

0

1

2

3

4

Year 1 Year 2

RTX(n = 187)

Placebo(n = 281)

6068

4654

0

20

40

60

80

Baseline to1 Year

1 Year to 2 Years

RTX Placebo

37

RTX Fixed Retreatment vs On-Demand Retreatment of RA

• Fixed and on-demand retreatment with RTX showed equal efficacy and safety

• Fixed retreatment was more effective in moderate responders and nonresponders to the first course

• Nonresponders improved significantly only after fixed retreatment

Teng Y et al. Ann Rheum Dis. 2008;67(suppl 2):339 [abstract FRI0167].

Fixed Retreatment

On-Demand Retreatment

0%

10%

20%

30%

40%

50%

60%

70% 64%

53%

28%

18%

4% 6%

ACR 20 ACR 50 ACR 70

Pat

ient

s (%

)

38

N = 300.Finckh A et al. Ann Rheum Dis. 2008;67(suppl 2):127 [abstract OP-0249].

Switching Strategies When an Anti–TNF-α Fails: RTX or Alternate Anti–

TNF-α Overall (%)

• Not effective• ≥AE

6535

Switch to alternate anti-TNF-α (%)

• Adalimumab• Etanercept• Infliximab

562519

Significance

• Overall evolution of DAS 28 more favorable in RTX vs alternate anti–TNF-α

• Concomitant DMARD use• Type of anti–TNF-α agent switch• Type of prior anti–TNF-α failure

–Efficacy–AEs

P = .01

NSNS

(Graph)Signif

NS

IMPROVEMENT

IMPROVEMENT

DA

S 2

8 Δ

Fro

m B

asel

ine

Not Effective AEs

RTX (n = 101)Switch anti–TNF-α agent (n = 199)

Type of Prior Anti–TNF-α Failure

SignificantSignificant Not Not significantsignificant

-1.55

-0.86

-1.03

-0.77

-2

-1.5

-1

-0.5

0

39

Subsequent RTX Treatment Courses: Incidence of Acute Infusion Reactions by

Treatment Course

All-exposure population by treatment course.SIE = serious infusion-associated event.van Vollenhoven RF et al. Arthritis Rheum. 2007;56(9 suppl):S147 [abstract 257].

• SIEs occurred in <1% of patients during course 1 and 2

• No SIEs were observed during course 3 or 4

23117 2

0

20

40

60

80

100

Course 1 (n = 1053) Course 4 (n = 142)

First infusion Second infusion

Pat

ient

s (%

)

40

Design of B-Cell–Targeting Agents

Human

Mouse (red)

Human IgG constant region

Human variable regions

Mouse (red)

Rituximab (CD20) Ocrelizumab (CD20)Ofatumumab (CD20)Belimumab (BAFF)

Epratuzumab (CD22)

TRU-015 (CD20)

Human

Chimeric antibodyChimeric antibody

SMIPSMIP

Decoy receptorsDecoy receptors

(Synthetic) fully human antibody(Synthetic) fully human antibody

Atacicept (BAFF and APRIL)

(TACI-Ig)

BR3-FC (BAFF)

Human (green)

AMG623(BAFF)

Baminercept-alpha(LT-)

Synthetic peptideSynthetic peptide

41

Therapeutic Approachesto B-Cell Depletion

Belimumab (antisoluble BAFF)

Autoreactive B cells

SLERAOther diseases

Atacicept (TACI-Ig)

RTX (anti-CD20)Binds and eliminatesCD20-positive cells

Acts later in B-cell developmentPotently depletes Ig-secreting cells

Neutralizes both BAFF and APRILActs broadly in B-cell developmentPotently depletes Ig-secreting cells

StemCell

MatureB cell

Antibody-producingPlasma cells

TransitionalB cellPro-

B Cell

ImmatureB cellPre-

B Cell

Antigenstimulation

Memory Cell

CD19Epratuzumab (Anti-CD22)Modulates B cell functionWith limited depletion

SLE, systemic lupus erythematosus.

42

Therapeutic Approaches to B-Cell Depletion: Clinical Trial Status

aStatus as of July 17, 2008.

Description Indications

Approved

Rituximab Chimeric anti-CD20 RA

Phase 3a

Ocrelizumab Humanized anti-CD20 antibody based on RTX RA

BelimumabHuman antibody that binds/sequesters BAFF/BLyS, B-cell survival factor

SLE

Phase 2a

Epratuzumab Humanized anti-CD22 antibody SLE

Baminercept Alfa Soluble LTß receptor IgG1 fusion protein RA

TRU-015Anti-CD20 SMIP (small modular immunopharmaceutical)

RA

Ofatumumab Human IgG antibody from humanized transgenic mice RA

43

• Phase I/II dose-escalation RCT with OCR + MTX– 175 patients in whom 1–6

DMARDs failed – ≥8 TJC and SJC plus CRP

≥1 mg/dL or ESR ≥28 mm/h– Single infusion of OCR

(400, 1000, 1500, or2000 mg) or placebo

– No peri-infusionalcorticosteroids

• 1° end point: ACR20 atweek 24

• Complete peripheral B-celldepletion

• Patients with incomplete response require 100 mg IV corticosteroids

Ocrelizumab (OCR): Humanized Anti-CD20 mAb in RA

34

9

3

58

33

19

32

23

14

58

27

13

38

25

00

10

20

30

40

50

60

70

ACR20 ACR50 ACR70

Pat

ient

s (%

)

Placebo

OCR 400

OCR 1000

OCR 1500

OCR 2000

ACR Results at Week 24

ESR, erythrocyte sedimentation rate; IV, intravenous; OCR, ocrelizumab; mAb, monoclonal antibody;RCT, randomized controlled trial.Tak PP et al. Ann Rheum Dis. 2008;67(suppl 2):127 [abstract OP-0250].

45

CD20 – Ofatumumab: HumanAnti-CD20 IgG1 mAb – Phase II Study

Placebo 300 700 1000

AE (%) 57 81 84 83

SAE (%) 4 7 9 11

SIE (%) 4 2 0 4

• Conclusions – No apparent dose response

– No limiting safety signals as yet

aP < .05; bP <.01

15

41

49 46

5

19

26 26

0

9

46

0

10

20

30

40

50

60

Placebo

n = 55

300

n = 58

700

n = 57

1000

n = 54

ACR20 ACR50 ACR70

a

b

Pat

ient

s (%

)

Østergaard M et al. Arthritis Rheum. 2007;56(9 suppl):S793-S794 [abstract 2086].

46

TRU-015 in Patients With RA:Phase II Dose-Ranging Study

• 24-week double-blind RCT in patients with incomplete response to MTX

• 227 patients in United States– ≥6 tender joints and swollen

joints; RF+– Either increased ESR/CRP

or morning stiffness >45 min

• 1 infusion, TRU-015 or placebo– 200, 400, 800, or 1600 mg– Premedicated

• 1 grade 3 AE on infusion day (400-mg group)

• Conclusion: 800 and 1600 mgof TRU-015 IV once statistically superior to placebo at week 24

Burge D et al. Abstract presented at: ACR/ARHP Annual Scientific Meeting; November 6–8, 2007; Boston, Massachusetts; abstract L7.

Pbon = 53

200n = 56

400n = 57

800n = 53

1600n = 57

SAE (%) 2 2 5 2 4

DAS28 −1.2 −1.6 −1.6 −2.1a −2a

ACR20% 33 49 37 65b 61c

ACR50% 9 19 16 26a 13

ACR70% 2 6 6 0 4

∆ HAQ −0.37 −0.5 −0.5 −0.64 −0.7

%↓ CRP 28 38 42 47 48

aP < .05; bP = .003; cP = .008.

48

LTβR-Ig (Baminercept)• Human lymphotoxin- receptor (LT) extracellular domain fused to

human IgG1 Fc receptor acts as a decoy receptor for LT• Effective in murine models of arthritis:

– Blocks induction of arthritis and decreases severity of arthritis in established disease

Lymphotoxin / Pathway is implicated in:• Liver, spleen, and lymph nodes• Gut mucosa and Peyer’s patches

LIGHT Pathway is implicated in:• Mucosal and hepatic inflammation

HVEM, herpes virus entry mediator.Baldassare A et al. Ann Rheum Dis. 2008;67(suppl 2):86 [abstract OP-0122].

Control of LymphoidMicroenvironments

LIGHT

HVEM

T Cells T Cells B cellsB cellsNK cellsNK cells

Activated T cellsActivated T cellsDendritic cellsDendritic cells

LTR

Baminercept alfa

Costimulation of T-cell activity• Affects T-cell responsiveness (proposed) and enhanced survival

LT

B cells, T cells,B cells, T cells,NK cellsNK cells

49

LTβR-Ig (Baminercept) in RA• Placebo dose-finding Phase IIa RCT: 47 pts – IR ≥1 DMARD; +MTX• SC weekly injections x4 and observation to day 77:

– 6 dose cohorts: 0.01, 0.05, 0.1, 0.3, 1 and 3 mg/kg BAM versus PBO

• AEs >5%: PBO 55% and LTβR-Ig 67%– Headache: Placebo 9% and LTβR-Ig 19%– Flu-like symptoms in 25% within 24 h of first injection; ↓ with subsequent injections to 6–9%

• Continued clinical responses after week 4 despite discontinuation of treatment• Phase IIb planned: 5, 50, 200 mg weekly

Sample size:Sample size: 1010 66 66 44 55 66 66mg/kgmg/kg

30

0 0

5040

50

67

0 0 0

25

4033

50

0 0 0

2520 17

33

01020304050607080

PBO BAM 0.01 BAM 0.05 BAM 0.1 BAM 0.3 BAM 1.0 BAM 3.0

Pat

ient

s (%

)

ACR20 ACR50 ACR70

Baldassare A et al. Ann Rheum Dis. 2008;67(suppl 2):86 [abstract OP-0122].

50

Summary

• B-cell–directed therapy has demonstrated clinical and laboratory efficacy in RA

• Multiple other diseases potentially may be treated with B-cell–directed therapy

• Safety issues concerning long-term B-cell depletion are of concern, but data thus far are cautiously reassuring

• New strategies of B-cell targeting may provide more potent therapeutics in the future

51

Assessing Immunocompetence in Patients Treated With

B-cell–Directed Therapies

52

Learning Objectives

• Define immunocompetence and review the impact of B-cell–directed therapies on humoral immunity

• Summarize the safety of B-cell–directed therapies with regard to the following clinical scenarios: repeated use, safety of switching to DMARD or TNF inhibitor after RTX failure, effects on serum immunoglobulins, and serious infection rates

• State clinical considerations for immunizing patients who are candidates for B-cell–directed therapy

DMARD, disease-modifying antirheumatic drug; RTX, rituximab; TNF, tumor necrosis factor.

53

Outline

• Immunocompetence and the effects of B-cell–directed therapies

• Safety of B-cell–directed therapies– Long-term safety of repeated use

– Effects on serum immunoglobulins

– Serious infection rates

– Safety of switching to DMARD or TNF inhibitor after RTX failure

• Immunization and B-cell–directed therapy

• Considerations for immunocompetence of newer B-cell– targeting agents BAFF, APRIL

• Progressive multifocal leukoencephalopathy (PML)in rheumatic diseases

54

Defining Immunocompetence: Promises and Problems With Biologic

Therapies

• Immunocompetence is broadly defined as the capacity of the integrated immune response to defend against infections and malignancies

• An increased rate of infections is the gold standard for detecting compromised immune function, but:

– Clinical trials are generally underpowered for rare events

– Data collected across clinical trials and databasesof such events are not uniform

55

Immunocompetence andB-Cell– Directed Therapy

• Humoral immunity is vital in protecting the host from bacterial infections

• Patients deficient in Ab are prone to polysaccharide encapsulated bacterial infections

• Experience in oncology fails to show that RTX adds risk of SIEs to traditional chemotherapy (except in HIV infections)

RTX spares long-lived plasma cells,which are the primary source of

antimicrobial Abs

Ab, antibody; CCP, cyclic citrullinated peptide; dsDNA, double-stranded DNA; HIV, human immunodeficiencyvirus; RF, rheumatoid factor; SIE, severe infectious event. Looney RJ, et al. Arthritis Rheum. 2008;58:5-14.

Antimicrobial

Anti-dsDNA

Anti-RBP antibodies(Ro, La, Sm/RNP)

Survive weeks afterRTX Survive months to

years after RTX

Protective vspathogenic antibodies

Protective vspathogenic antibodies

Antimicrobial

Anti-dsDNA

RF and anti-CCPantibodies

Plasmablast(short-lived)

Plasma Cell(long-lived)

Pro-B Pre-B Immature Transitional Naïve Memory

CD20

RTX

56

Immunoglobulin Levels Following RTX Therapy

• Total immunoglobulin (Ig), IgM, IgG

– Every 8–12 weeks after each course

• Always normal IgG & IgM: 761 (72%)

– >1 Ig level <LLN (at any point)

• >1 low IgM: 261 (25%)

• >1 low IgG: 67 (6%)

• Decreases are nonprogressive in most cases

• Patients undergoing repeated courses of RTX have been reported with severely depressed IgM levels, but background therapy has been nonstandardized and has included CTX

CTX, cyclophosphamide; LLN, lower limit of normal.Genovese M et al. Arthritis Rheum. 2007;56(9 suppl):S149-S150 [abstract 261].Popa C et al. Rheumatology (Oxford). 2007;46:626-630.

C1 C2 C3 C4

IgM 10.1 20.4 20.9 31.4

IgG 1.4 3.5 4.0 4.3

SIEs per100 pt-yr

5.4 4.6 6.3 5.4

Percent of Patients IgM/IgG <LLN24 Weeks After RTX

57

Long-Term Safety of RTXWith Repeated Use

• 1053 patients (2438 patient-years) from 3 double-blind trials– 1014 >6 months– 957 >1 year– 701 >2 years– 120 >3 years

• Up to 7 treatments (1000 mg 2 IV, 2 weeks; ≥4 months from last infusion)– 684 ≥2 courses; 400 ≥3 courses; 142 ≥4 courses

• Acute infusion reactions decreased with subsequent courses– 1st infusion: C1, 23%; C4, 11%– 2nd infusion: C1, 7%; C2, 2%

• 702 (67%) had ≥1 infection – URI: 32%; UTI: 11%

• No tuberculosis, opportunistic infections, or viral reactivation

• 36 malignancies in 32 patients (3%): 4 fatal; no lymphomas

C, course; URI, upper respiratory tract infection; UTI, urinary tract infection.van Vollenhoven RH et al. Arthritis Rheum. 2007;56(9 suppl):S147-148 [abstract 257].

58


C1 C2 C3 C4

AEs 4570 1358 339 48

SAEs 222 73 18 3

Infections 954 347 71 11

Infections per 100 pt-yr 83 83 80 88

SIEs 59 19 5 1

SIE per 100 pt-yr 5.1 4.6 5.6 8.0

Safety of Additional Courses of RTX in Patients With Active RA: Open-Label Extension Analysis

AE, adverse event; RA, rheumatoid arthritis; SAE, serious adverse event.Keystone E et al. Arthritis Rheum. 2007;56:3896-3908.

A total of 1,039 patients received >1 course of rituximab. Of these, 570 received 2 courses,

191 received 3 courses, and 40 received 4 courses, for a total of 1,669 patient-years.

59

Serious Infection Rates by Immunoglobulin Levels With

Repeated Use of RTX

All-Exposure Population

(n = 1053)

Patients With Normal IgG

and IgM(n = 761)

Patients with Low IgM at Any Time(n = 261)

Patients With Low IgG at Any Time(n = 67)

Percentage of patients, % 100 72.2 24.7 6.3

Serious infections per 100 pt-yr(95% CI)

5.4 (4.3–6.38)

4.9(3.93–6.06)

6.4(4.74–8.68)

6.8(4.03–11.49)

Genovese M et al. Arthritis Rheum. 2007;56(9 suppl):S149-S150 [abstract 261].

60


Conclusion• A progressive increase in the number of patients who

have ≥1 Ig level below LLN is seen at some point with repeated infusions of RTX

• The rate of infections has been stable

• RTX should be used with caution in patients previously treated with biologics, and long-term studies are needed

• A more complete safety profile of RTX will emerge as more patients are treated, followed up for longer periodsof time, and given more courses of RTX

van Vollenhoven RH et al. Arthritis Rheum. 2007;56(9 suppl):S147-148 [abstract 257].

61

0 2 4 6 8 10

Rate of Serious Infections With Rituximab and Other RA Therapies

Rituxan-exposed patients (n=1053)

Biologic-treated patients (n=9868)(BSR Biologics Register)

Biologic-treated patients (n=928)(German Biologics Register)

DMARD-treated patients (n=1352) (BSR Biologics Register)

DMARD-treated patients (n=601) (German Biologics Register)

Incidence of Serious Infections per 100 Patient-Years

BSR, British Society for Rheumatology.van Vollenhoven RH et al. Arthritis Rheum. 2007;56(9 suppl):S147-148 [abstract 257].Listing J et al. Arthritis Rheum. 2005;52:3403-3412.Dixon WG et al. Arthritis Rheum. 2006;54:2368-2376.

63

Safety of Switching to DMARD or TNF Inhibitor After RTX Failure

All Patients DMARDs Added TNF Inhibitor Added

Before After Before After Before After

Total exposures, pt-yr 143 148 50 42 101 98

SAEs/100 pt-yr (n = 75)

28 (40) 24 (35) NR NR NR NR

SIEs, no. 6 12 1 2 6 9

SIE/100 pt-yr 4 8 2 5 6 9

95% CI 1.9–9.4 4.6–14.9 0.3–14.2 1.2–19 2.9–19.3 4.8–17.7• 153 patients (of 1053) withdrew from RTX extension studies• Entered safety follow-up for up to 48 weeks for SAEs

– Could be treated with DMARD(s) or TNF inhibitor– 107 (70%) treated with TNF inhibitor and 46 (30%) DMARD(s)– Majority had CD19 counts <LLN

• 18 SAEs were infectious – typical clinical course – resolved with treatment• Conclusion: No increased SIEs demonstrated with switching to

DMARD/TNF inhibitor– “Further investigations in larger numbers over time is warranted”

Genovese M et al. Arthritis Rheum. 2007;56(9 suppl):S150 [abstract 262].

64

Can Patients Given Biologics, Including B-Cell–Depleting

Therapy, Be Effectively Immunized?

65

Immunization andImmune Response

• Responses to immunization depend on intact immune response

– T-cell–dependent antigens (peptide)

– T-cell–independent (carbohydrate)

– Response to neoantigens

– Response to recall (booster) antigens

• How do newer targeted immunomodulatory therapies affect immunization responses?

66

Biologics and Immunization

• TNF antagonists may slightly decrease immune response to influenza immunization compared with MTX1

• B-cell depletion in RTX-treated patients with SLE significantly decreased response to pneumococcal vaccine and tetanus immunization in almost all patients, although partial responses were observedon return of peripheral B cells2

• Abatacept decreased response to neoantigens (X174 and KLH) in patients with psoriasis3

KLH, keyhole limpet hemocyanin; MTX, methotrexate; SLE, systemic lupus erythematosus. 1. Kapetanovic MC et al. Rheumatology (Oxford). 2007;46:608-611. 2. Albert DA et al. Arthritis Rheum. 2006;54(9 suppl):S550 [abstract 1323].3. Abrams JR et al. J Clin Invest. 1999;103:1243-1252.

67

Response to Influenza Vaccine in RA Treated With Abatacept

• Previous data suggest that abatacept may blunt response to the T-cell–independent Ag pneumococcus in healthy controls and patients with RA

• Influenza is a T-cell–dependent Ag, with healthy individuals demonstrating seroconversion(4-fold) to 33%–44% of the time

• ARRIVE trial studied abatacept in patients in whom TNF inhibitors failed

• Substudy of 21 patients given influenza vaccine 7 days prior to abatacept in patients receiving long-term therapy

Proportion of Patients Responding* to Different Numbers of Influenza Serotypes –

1 Month Post-immunization

15%

50%

25%

75%

0

10

20

30

40

50

60

70

80

90

0 ≥1 ≥2 3

Number of influenza strains responded

Po

sit

ive

Re

sp

on

de

rs (

%)

• 75% of patients mounted an adequate response to at least 1 strain 1 month post-vaccination; 50% to 2 strains; 15% to all 3

• MTX, consistent with previous studies, blunts response

• Abatacept does not appear to meaningfullyimpair response to influenza

*Positive response defined as post-immunization antibody titer at least 4 times above baseline value.Ag, antigen; ARRIVE, Abatacept Researched in RA Patients With an Inadequate Anti-TNF Response to Validate Effectiveness.Schiff M et al. Arthritis Rheum. 2007;56(9 suppl):S392 [abstract 943].

68

RTX and Vaccination

• Following RTX administration,post-vaccination protection ratesare decreased in response to

– Pneumococcal vaccine1

– Tetanus toxoid1

– Trivalent influenza vaccine2,3

1. Albert DA et al. Arthritis Rheum. 2006;54(9 suppl):S550 [abstract 1323].2. Gelinck L et al. Ann Rheum Dis. 2007;66(suppl 2):160 [abstract THU0116]. 3. Oren S et al. Ann Rheum Dis. 2007;66(suppl 2):363 [abstract FRI0275].

69

Immunization Responses With RTX in Patients With RA

• 4 patients treated with RTX (1000 mg 2)

– Immunization with trivalent influenza A/B at 84 days during B-cell depletion

• 19 patients receiving TNF antagonists

• 20 healthy controls

• Evaluation of preimmunization and postimmunization titers to antigens

Gelinck LB et al. Ann Rheum Dis. 2007;66:1402-1403.

70

RTX Impairs Ability to Respond to Influenza Vaccine in Patients With RA

Response Defined as GMT > 40 units

RA-RTX

N = 4

RA-TNF

N = 19

HC

N = 20

A/H3N2 (%) 50 84 100

A/H1N1 (%) 23 84 88

Influenza B (%) 24 84 96

GMT, geometric mean titers; HC, healthy controls.Gelinck LB et al. Ann Rheum Dis. 2007;66:1402-1403.

A/H3N2 A/H3N2 A/H1N1A/H1N1 Influenza B Influenza B

Pre

-vac

cin

atio

nP

re-v

acci

nat

ion

HCRA - TNFRA - RTX

HCRA - TNFRA - RTX

VaccinationVaccination

44

88

1616

3232

6464

128128

256256

512512

10241024

PrePre PostPost


11

88

1616

3232

6464

128128

256256

51251210241024

PrePre PostPost

44

22


11

88

1616

3232

6464

128128

256256

51251210241024

PrePre PostPost

44

22

Po

st-v

acci

nat

ion

Po

st-v

acci

nat

ion

GM

TG

MT

71

Immunization: Summary• Consider immunization responses when treating patients with RA and

when introducing new targeted therapies

• Live attenuated virus vaccines should be avoided in all patients receiving immunosuppressants (based on absence of data)

• Some immunomodulatory therapies may significantly attenuate the efficacy of other immunizations

• Timing of immunizations may be clinically important

• Evaluating larger numbers of patients treated with these agents alone and in combination with other DMARDS and concomitantly evaluating appropriate controls using standardized definitions of response are very important in guiding clinical care

• Appropriate immunization should be performed prior toinitiation of RTX therapy


.


.

74

PML in Rheumatic Diseases• PML is a neurologic disease caused by infection with the JC polyomavirus that

occurs in susceptible patient populations

• Recently reported in 0.1% of patients receiving natalizumab, a promising drug for multiple sclerosis (also in clinical trials for RA and Crohn’s disease)

• Mechanism of action is unknown

• 70-year-old woman with SLE and HA previously treated with CTX, AZA, and long-term GC; developed vertigo and ataxia after 4 infusions of RTX– MRI had multiple brain lesions and biopsy showed PML

– The patient died 1 year later

• 45-year-old woman with SLE since 1982, previously treated with CTX, IV methylprednisolone, and daily GC. CD4 count was low (<200). The patient received 3 courses of RTX with daily GC in 2003–2006– In April 2006, she developed neurologic symptoms and signs and had multiple

brain lesions by MRI, and was found to have JC virus in the CSF

– The patient died in July 2006

AZA, azathioprine; CSF, cerebrospinal fluid; GC, glucocorticoids; HA, hemolytic anemia; MRI, magnetic resonance imaging.US Food and Drug Administration. FDA Alert: rituximab (marketed as Rituxan). December 2006. Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/rituximab.pdf. Accessed December 18, 2007.

75

PML and RTX

• PML has not been diagnosed in any patient to date in clinical trials

• Systematic reviews of PML and of rheumatic disease and PML have suggested that patients with SLE may have a unique susceptibility to PML1

• Rheumatologists should familiarize themselves with PML and consider it in the differential diagnosis of immunosuppressed patients with unexplained neurologic disease

1. Calabrese LH et al. Arthritis Rheum. 2007;56:2116-2128.

76

Immunocompetence and Biologic Therapies:

Promises and Problems• Efforts to improve our assessment of

compromised immune responses in patients with rheumatic disease treated with biologics include:

– Uniform assessment of infections (bacterial, opportunistic, and viral) across trials and databases

– Uniform assessment of vaccine response from early clinical trials

– Detailed assessment of in vitro immunity, including cellular humoral and innate responses

77

The Use of B-cell–Directed Therapies in SLE,

Vasculitis, and Other Autoimmune Diseases

SLE, systemic lupus erythematosus.

78

Learning Objectives• Describe the rationale of B-cell depletion for the

management of SLE, vasculitis, and other autoimmune diseases

• Summarize recent clinical trial data on the use of rituximab, belimumab, and epratuzumab in the treatment of SLE

• Summarize recent clinical trial data on the use of B-cell targeting in the treatment of Sjögren’s syndrome

• Summarize recent clinical trial data on theuse of B-cell targeting in other vasculitides

79

B-Cell–Depletion Therapyin SLE

• B lymphocytes may play a central role in the pathogenesis of SLE

– As precursors of antibody-secreting cells, B cells are the source of pathogenic autoantibodies

– B cells are not merely the passive producers of immunoglobulins, but also play a central role in autoimmunity

• B-cell depletion has recently emerged as a promising therapeutic approach to the treatment of autoimmune diseases, including SLE

80

CTX, cyclophosphamide; dsDNA, double-stranded DNA; IV, intravenous; RTX, rituximab. 1. Edwards JC et al. N Engl J Med. 2004;350:2572-2581.2. Ng KP et al. Ann Rheum Dis. 2007;66(suppl 2):56-57 [abstract OP0020].3. Ng KP et al. Ann Rheum Dis. 2006;65:942-945.

RTX B-Cell–Depletion Therapy in Patients With SLE: Long-Term

Follow-Up and Predictors of Response• Observations of nonrandomized clinical experience (since June 2000)

in 41 patients with refractory SLE at University College, London1-3

– Mean duration of follow-up 37 months (2 patients lost to follow-up)

– Patients must have failed to respond to CTX or methotrexate

– RTX 1 g IV 2 (14 days apart) + CTX

• RTX therapy showed efficacy – Mean duration of B-cell depletion was 4 months (range 2–15)

– Serum immunoglobulins decreased but not below lower limit of normal

– Anti-dsDNA antibody levels significantly reduced 6 months after B-cell–depletion therapy

– Protein/creatinine ratio fell (but change did not reach statistical significance)

• 13 patients re-treated

81

• 11 (55%) of 20 patients who flared did so 6–12 months after treatment

• Predictors of lack of response – Patients with anti-ENA antibodies (anti-Sm or anti-La) were

more likely to flare

– Lower serum C3 at baseline was associated with shorter timeto flare following B-cell–depletion therapy

• 2 (5%) of 39 patients in the cohort have died (varicella pneumonitis and SLE pancarditis)

• AEs: single cases of hematuria, self-limiting neutropenia, pneumococcal sepsis/pneumonia, serum sickness–like reaction, active pancreatitis, seizure

RTX B-Cell–Depletion Therapy in Patients With SLE: Long-Term

Follow-Up and Predictors of Response

AE, adverse event; ENA, extractable nuclear antigen.1. Ng KP et al. Ann Rheum Dis. 2007;66(suppl 2):56-57 [abstract OP0020].2. Ng KP et al. Ann Rheum Dis. 2006;65:942-945.

83

SLE: Case Series of RTX (anti-CD20) Treatment of Patients With SLE Refractory

to Conventional Therapy• Among 22 patients, RTX treatment1:

– Resolved anemia, thrombocytopenia, and/or cryoglobulinemia in all 18 patients with severe hematologic manifestations

– Decreased daily proteinuria by ≥50% at 6 months in 4 (66%) of 6 patients with lupus nephritis

• Among 19 patients, RTX treatment2:

– Improved thrombocytopenia in 7 (64%) of 11 patients within 3 months, resolved anemia in 3 (75%) of 4 patients, and improved cutaneous manifestations of lupus in 4 of 4 patients

– Decreased levels of antiplatelet and anti-RBC antibodies, but not of anti-dsDNA antibodies

• Among 16 patients, RTX treatment3:

– Improved disease activity ( BILAG score) in 9 (56%) of 16 patients

– Did not prevent progression to stage 5 CKD in 5 patients with severe proliferative, crescentic lupus nephritis

• Although some manifestations of refractory SLE may improve, some forms of lupus nephritis may progress despite RTX therapy

CKD, chronic kidney disease; RBC, red blood cell.1. Amoura Z et al. Arthritis Rheum. 2007;56(9 suppl):S458 [abstract 1124].2. Lindholm C et al. Ann Rheum Dis. 2008;67(suppl 2):344 [abstract FRI0184].3. Sangle SR et al. Arthritis Rheum. 2007;56(9 suppl):S215 [abstract: 441].

84

RTX + IV CTX Induction for Patients With Lupus Nephritis

• RTX + IV CTX may serve as an alternative induction regimen for patients with severe lupus nephritis1

– 18 patients with biopsy-proven lupus nephritis (10 proliferative GN, 7 membranous GN, 1 unknown)

– RTX 375 mg/m2 IV weekly 4 + IV CTX (at weeks 1 and 4)

– After 6 months, 17 (94%) of 18 patients had clinical improvement; 1 had early relapse• Histologic examination showed significant improvement in most patients at 6 months

– At 2 years (n = 17), 15 (88%) of 17 patients had persistent clinical improvement; 2 had relapsed

• MMF may serve as a maintenance regimen for patients with severe lupus nephritis, following RTX + IV CTX induction regimen2

– 35 patients with SLE and biopsy-confirmed active nephritis (ISN/RPS class IV [70%] or V [30%]), refractory to standard treatment

• Treated with RTX 750 mg IV + methylprednisolone 500 mg IV + CTX IV on days 1 and 15

• Followed by maintenance MMF 1–2 g/d for 2 years

– At end of 2 years, significant improvement in C3, C4, anti-dsDNA antibodies, and proteinuria in all patients; serum creatinine remained stable

– No SAE; 6 patients had mild viral infections

• No comparison with induction regimens using methylprednisolone+ CTX alone or RTX alone

ISN, International Society of Nephrology; MMF, mycophenolate mofetil; RPS, Renal Pathology Society; SAE, serious adverse event.1. Jónsdóttir T et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0021].2. Guzman RA et al. Ann Rheum Dis. 2008;67(suppl 2):219 [abstract THU0260].

85

EXPLORER: Efficacy and Safety of RTX in Patients With Moderate to

Severe SLE • Phase II/III randomized, double-blind, placebo-controlled study to

evaluate efficacy and safety of RTX in patients (n = 257) with moderate to severe SLE receiving background prednisone therapy

• Primary end point: Proportion of patients who achieved either a major clinical response or partial clinical response measured by the BILAG index at 52 weeks

• Secondary end points: Time-adjusted AUC of BILAG disease activity, improvement in BILAG disease activity, time to flare, QOL, and proportion taking <10 mg prednisone daily

• Study did not meet its primary end point or any of its six secondary endpoints

• Reasons for failure unclear

• Clinical trial in lupus nephritis ongoingAUC, area under the curve; EXPLORER, A Study to Evaluate the Efficacy and Safety of Rituximab inPatients With Moderate to Severe Systemic Lupus Erythematosus; QOL, quality of life.http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11247;http://clinicaltrials.gov/ct2/show/NCT00137969; http://clinicaltrials.gov/ct2/show/NCT00282347

86

PML, progressive multifocal leukoencephalopathy.1. Ng KP et al. Ann Rheum Dis. 2007;66(suppl 2):56-57 [abstract OP0020]; 2. Ng KP et al. Ann Rheum Dis.2006;65:942-945. 3. Tanaka Y et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0020]; 4. Amoura Z et al. Arthritis Rheum. 2007;56(9 suppl):S458 [abstract 1124]; 5. Lindholm C, et al. Ann Rheum Dis 2008;67(suppl 2):344; 6. Sangle SR et al. Arthritis Rheum. 2007;56(9 suppl):S215 [abstract: 441]; 7. Jónsdóttir T et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0021]; 8. Guzman RA, et al. Ann Rheum Dis. 2008;67(suppl 2):219 [abstract THU0260]; 9. http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11247; 10. Calabrese LH et al. Arthritis Rheum. 2007;56:2116-2128.

RTX B-Cell–Depletion Therapy in Patients With SLE: Summary

• Observations of nonrandomized clinical experience in patients with refractory SLE at 7 institutions suggests therapeutic efficacy of RTX when used in addition to standard (anchor) therapy1-8

– Serum immunoglobulin and anti-dsDNA antibody levels decreased for at least 6 months after treatment1,2

– Presence of anti-Sm or anti-La antibodies or low C3 at baseline may identify patients who will flare after treatment1,2

• However, a prospective randomized, double-blind, placebo-controlled study of RTX in patients with moderate to severe SLE receiving background prednisone therapy failed to demonstrate efficacy9

• 23 (64%) of 36 reported cases of PML in patients with rheumatic diseases have occurred in patients with SLE, most of whom had not received RTX10

87

RCT, randomized controlled trial; SELENA, Safety of Estrogens in Lupus Erythematosus National Assessment;SLEDAI, SLE Disease Activity Index; SF-36 PCS, physical component score of theSF-36 health survey.1. Ginzler E et al. Ann Rheum Dis. 2007;66(suppl 2):56 [abstract OP0018].2. Furie R et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0017].

Phase II RCT of Belimumab in SLE: Combined Response Rate Is Significantly Higher for Belimumab-Treated Patients

• 1, 4, and 10 mg/kg belimumab dosed on days 0, 14, 28, and then every week through week 52

• Changes in immunosuppressants, glucocorticoids permitted

• 46% combined response rate for patients with serologically active disease receiving belimumab versus 29% for placebo at week 521

• No dose response observed2

• 56% combined response rate for patients receiving belimumab at week 762

In subjects with serologically active disease, significant improvements in SLE disease activity shown by SELENA-SLEDAI,Physician’s Global Assessment and QOL (SF-36 PCS), and decreased BILAG 1A or 2B flares

88

1. Petri M et al. Arthritis Rheum. 2007;56(9 suppl):S527 [abstract 1316].2. Furie R et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0017]. 3. Ginzler E et al. Ann Rheum Dis. 2008;67(suppl 2):217 [abstract THU0253]. 4. Merrill JT et al. Ann Rheum Dis 2008;67 (suppl 2):217 [abstract THU0254].

B-Cell Depletion With Belimumab in Patients With SLE

• Efficacy1-3

– Although the primary study end point (a reduction in the SELENA-SLEDAI score) was not achieved, there were indications of efficacy over 3 years:

• Combined response rate of 46% at week 52 (n = 235); increased to 65% withbelimumab treatment continued to week 160 (n = 170)

• Rate of SLE flares decreased progressively with belimumab treatment to 7% after 3 years

• Belimumab treatment allowed reduction of prednisone dose to 7.5 mg/d from>7.5 mg/d at baseline in up to 44% of patients after 1 year and in up to 62% ofpatients by 3 years

• Sustained response to belimumab is independent of type of autoantibody presentat baseline

• Safety4

– Belimumab is well tolerated in combination with antimalarials and immunosuppressive drugs

– Similar incidence rates of AEs, SAEs, serious infections, and malignancies between belimumab- and placebo-treated patients during the first year of treatment

– Incidence rate of AEs did not increase over time, during more than 3 years of belimumab exposure

89

• Biomarkers

– Changes correlated with clinical improvement observed over 2.5 years of belimumab treatment: in C3 and C4 levels

in anti-dsDNA antibody levels

in IgG, IgM, and IgE levels (more in subjects with elevated levels at baseline)

• Reversion of anti-Sm and anti-RNP serologic findings from positive to negative in some belimumab-treated subjects

Stohl W et al. Arthritis Rheum. 2007;56(9 suppl):S210 [abstract 426].

B-Cell Depletion With Belimumab in Patients With SLE

90Petri M et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0016].

B-Cell Depletion With Epratuzumab in SLE: RCTs

• 90 patients with SLE and moderate to severe flares randomized in 2 phase II RCTs, each of which was terminated prematurely because of interruptions in medication supply

• Up to 4 treatment cycles over a 48-week period

– Placebo

– Epratuzumab 360 mg/m2

– Epratuzumab 720 mg/m2

• Primary end point: Reduction of all BILAG A to B, BILAG B to C, no worsening in other systems, no addition or increase in immunosuppressives/antimalarials or corticosteroids above tapering levels

91

HAHA, human antihuman antibody; ITT, intention to treat.1. Petri M et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0016].2. Wallace D et al. Ann Rheum Dis. 2008;67(suppl 2):212 [abstract THU0238].

B-Cell Depletion With Epratuzumab in Patients With SLE

• Patients in both epratuzumab groups had greater reductions in total BILAG scoresfrom weeks 4 through 48, compared with placebo1

• Physician and patient globalassessment scores were alsosignificantly improved in theepratuzumab-treated groups1

• Overall efficacy was most consistentin the epratuzumab 360-mg/m2 group1

• Epratuzumab-treated patients used less corticosteroid than placebo-treated patients over 24 weeks2

• AE incidence was similar among epratuzumab- and placebo-treated patients2

• Low incidence of immunogenicity (HAHA)2

0

5

10

15

20

25

30

35

40

45

50

BILAG Response (ITT)

% o

f P

atie

nts

Placebo (n = 30)

Epratuzumab 360 mg/m2 (n = 34)

Epratuzumab 720 mg/m2 (n = 10)

92

B-Cell–Depletion Therapy in Patients With SLE: Summary

• To date, no B-cell–directed therapy is approved for the treatment of SLE

• Most clinical trials of both B-cell depletion and anti-BAFF therapy, thus far, have been of either inadequate design (open-label and uncontrolled) or flawed by interruptions in medication supply, making it difficult to determine the functionality of these therapies in this setting

• Safety signals in controlled clinical trials to date are modest, but caution clearly is indicated until better safety and efficacy data are available

93

B-Cell Targeting in Sjögren’s Syndrome (SS)

• Epithelial inflammatory disease driven by cellular and humoral factors

• No evidence of effective remittive therapy

• Strong evidence of

– B-cell hyperactivity

– Polyclonal B-cell activation

– Hypergammaglobulinemia

– Multiple autoantibodies:SSA/SSB, antifodrin, others

– Elevated levels of BAFF

Micrograph courtesy of Leonard Calabrese, DO

Ramos-Casals M et al. Ann Rheum Dis. 2005;64:347-354.

95

1. St. Clair EW et al. Arthritis Rheum. 2007;56: (suppl 9):S449-450 [abstract 1102].2. Levesque MC et al. Arthritis Rheum. 2007;56: (suppl 9):S445-S446 [abstract 1091].

RTX for Primary SS • Open trial in 12 patients with SS and 1 or more severe disease

manifestations (fatigue, parotid enlargement, neuropathy, interstitial pulmonary disease [IPD], purpura) treated with 1 g RTX, 100 mg methylprednisolone 2

• 10/10 fatigue; 3 parotid, 4 neuropathy, 1 IPD, 1 purpura

• Significant decrease in physician and patient global assessment, fatigue, and joint pain; no significant change for sicca assessments; no serum sickness or SAE related to drug

• All patients became B-lymphopenic; reconstitution was similar to that seen in studies of RTX in RA and SLE, with transitional and plasmablastic phenotype and a paucity of memory (CD27) B cells

• Larger placebo-controlled trials are needed

96

EU, European Union; USA, United States of America; VAS, visual analog scale.Dass S et al. Arthritis Rheum 2007;56:(suppl):S446-S447 [abstract 1094].

Safety and Efficacy of RTX in SS: First Randomized Placebo-

Controlled Trial• Primary SS causes significant symptoms but has

no effective therapy

• Subjects: Primary SS by EU-USA criteria, antibodies to Ro and La, and fatigue >50% on VAS

• Treatment: RTX 1 g 2 with prednisone (tapering 60→30→0 over 14 days) or placebo

• Primary end point: ≥20% improvement in fatigue

97Dass S et al. Arthritis Rheum. 2007;56:(9 suppl):S446 [abstract 1094].

Safety and Efficacy of RTX in SS: Results of the First

Double-blind Randomized Placebo-Controlled Trial

• 18 available for analysis

– Failure to reach primary end point for fatigue (VAS)

– VAS fatigue improved 48% RTX vs 20% placebo (NS); 8/9 versus 5/9 achieved ≥20% improvement in fatigue VAS (NS); significant improvement in SF-36

– RTX patients had significant reductions in rheumatoid factor (RF) but not Ro, La, or IgG

– 3 SAEs with 1 serum sickness

• Marked variability of clinical responses

98

ANCA, antineutrophil cytoplasmic antibody.1. Ruddy S et al, eds. Kelley’s Textbook of Rheumatology. 6th ed. Philadelphia, Pa: W.B. Saunders; 2001. 2. Vassilopoulos D et al. AIDS. 2005;19(suppl 3):S123-S127.

Vasculitis and B-Cell Targeting: Rationale

• Sansonno D et al. Blood. 2003;101:3818-3826.

• Zaja F et al. Blood. 2003;101:3827-3834.

• Multiple case reports and small series: Lamprecht Pet al. Ann Rheum Dis. 2003;62:1230-1233; Cai FZ.J Rheumatol. 2006;33:1197-1198; Basse G et al. Transplantation. 2005;80:1560-1564; Quartuccio Let al. Rheumatology (Oxford). 2006;45:842-846.

• Kay J et al. N Engl J Med. 2005;353:1605-1613.

Cryoglobulinemia-Mediated Vasculitis ANCA-Associated Vasculitis

• Keogh KA et al. Am J Respir Crit Care Med. 2006;173:180-187.

• Smith KG et al. Arthritis Rheum. 2006;54:2970-2982.

• Golbin JM et al. Arthritis Rheum. 2006;54(9 suppl):S527[abstract 1265].

• Aries PM et al. Ann Rheum Dis. 2006;65:853-858; Flossmann Oet al. Ann Rheum Dis. 2006;65:841-844.

• Golbin JM et al. Clin Exp Rheumatol. 2007;25(1 suppl 44):S74-S76.

• Brihaye B et al. Clin Exp Rheumatol. 2007;25(1 suppl 44):S23-S27.

99

WG, Wegener’s granulomatosis.1. Golbin JM et al. Arthritis Rheum. 2006;54(suppl 9):S527 [abstract 1265].2. Molloy E et al. Arthritis Rheum. 2007;56(suppl 9):S769 [abstract 2020].

Repeated B-Cell Depletionin ANCA-Associated Vasculitis

• 2006: Golbin et al suggested repeated treatment with RTX and profound B-cell depletion are well tolerated in relapsing WG; B-cell depletion appears effective for maintaining remission and relapse was not seen in the absence of B cells or ANCA

• 2007: Molloy et al retrospectively reported 4 patients with refractory ANCA disease each responding initially to RTX therapy; all patients eventually relapsed despite ongoing B-cell depletion

• Until controlled studies are completed, the decision to use RTX therapy in ANCA-associated disease should be based on assessment of risk/benefit to the individual patient.

101

RTX in ANCA-Associated Vasculitis: Summary to Date

• In ANCA-associated vasculitis, most but not all preliminary (noncontrolled) studies of B-cell depletion suggest that this strategy is a safe and effective mechanism-based approach for remission induction and maintenance

• Repeated courses are equally effective and thus far associated with few infectious complications

• Limited trials in cryoglobulinemia with and without HCV infection have demonstrated efficacy and reasonable safety of anti-CD20 based therapy

• A large controlled trial of RTX for ANCA-associated vasculitis (RAVE) is fully recruited and analysis is pending (www.clinicaltrials.gov)

HCV, hepatitis C virus.

Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases

Documents

Transcript of Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases