B Cell Therapies

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(No Transcript)
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Advances in B-Cell Biology in the Treatment of
Autoimmune and Inflammatory Diseases
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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-celltargeted therapy
  are changing our understandingof integrated
  immune responses and the pathogenesis of ARDs

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Outline

• B-cell biology in autoimmune disorders
• Overview of B-celltargeting agents
• Recent developments in B-cell targetingin
  rheumatoid arthritis (RA)
• Recent development in B-cell targetingin other
  ARDs

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B-Lineage Cells and Autoimmunity
Mature
Blast
Bone Marrow
Activation
Immature
Plasma cell
T2
T1
Pre B
Pro B
Spleen
MZ
FO
Plasmablast
Memory
GC
DC, dendritic cell FDC, follicular dendritic
cell FO, follicular GC, germinal centerIL,
interleukin LT, lymphotoxin Mf, macrophage MZ,
marginal zone SLE, systemiclupus erythematosus
TNF, tumor necrosis factor. Adapted from Martin
F, Chan AC. Annu Rev Immunol. 200624467-496
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Why Are Some Plasma Cells Short-Lived and
OthersLong-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. 200727384-392.
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Complex Interactions Determine Plasma Cell
Survival

• Adhesion
• CD138
• CD44, 18, 11a
• E-/P-selectin
• Chemokine systems
• CXCR4/CXCL12

• Intracellular survival regulators
• ? Bcl-2, Blimp1, XBP1, Aiolos
• ? BACH2 and Pax5

Bone marrow
GC
B
Competence
Plasmablasts

• Instruction of memory
• B cells by T cells
• CD40/154
• ICOS/ICOS-L
• SAP

Long-lived memory plasma cell

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

• Insoluble survival factors from
• nurse cells
• or stromal cells (within inflamed tissue)

Dörner T, Radbruch A. Immunity.
200727384-392. Tarlinton D et al. Curr Opin
Immunol. 200820162-169.
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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 Peyers 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. 2005174817-826. Silverman GJ.
Arthritis Rheum. 2006542356-2367. Withers DR et
al. Blood. 20071094856-4864. Terstappen LW et
al. Blood. 1990761739-1747.

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Does Extent of Reduction in SynovialB Cells
Explain Clinical Response?
CD22 stainingof synovial tissue
Before Treatment
4 Weeks After Treatment
B-cell depletion
Nondepletion
Vos K et al. Arthritis Rheum. 200756772-778.
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Changes in RA Synovial Patterns After RTX
At 12 weeks clinical nonresponders IgM ACPA and
high synovial CD79a CD20. Level of immediate
posttreatment synovial B-cell depletion is highly
variable, even though high levels of blood-cell
depletion are highly reproducible. At 8 weeks,
there was a significant decrease in Ig
transcripts in patients with ACR50 or greater
responses. Aggregates are only found in 1/3 of
RA biopsies. ACPA, anti-citrullinated
protein/peptide antibodies ACR, American College
of Rheumatology. Kavanaugh A et al. Ann Rheum
Dis. 200766(suppl 2)291 abstract FRI0037
Rosengren S et al.Ann Rheum Dis. 200766(suppl
2)298 abstract FRI0059 Thurlings RM et al.
Ann Rheum Dis. 200766(suppl 2)123 abstract
OP0229 Dass S et al. Ann Rheum Dis.
200766(suppl 2)90 abstract OP0123 Teng Y et
al. Ann Rheum Dis. 200766(suppl 2)299 abstract
FRI0063 Teng Y et al. Ann Rheum Dis.
200766(suppl 2)439 abstract SAT0034 Teng YK
et al. Arthritis Rheum. 2007563909-3918.
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Model of RTX-Induced RA Synovial Changes in
Clinical RespondersBASELINE
CCP, cyclic citrullinated peptide FLS,
fibroblast-likesynoviocyte IFN, interferon
MMP, matrixmetalloproteinase RANKL, receptor
activator ofNF-?B ligand RF, rheumatoid factor.
Silverman GJ, Boyle DL. Immunol Rev.
2008223175-185.
Responsible formarginal erosions and bone loss
Osteoclast
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Model of RTX-Induced RA Synovial Changes in
Clinical Responders4 WEEKS
X
Early synovial B-cell depletion is necessary but
not sufficient! Trends toward ? in plasma cells
in clinical responders (at 6 months)
B cell
X
T cell
Plasma cell
IL-1, IL-6, TNF-a IFN-g
TNF-a IFN-g IL-17 RANKL
RF, anti-CCP antibodies
FLS
Immune complexes Complement fixation Induce Mf
secretion of proinflammatory cytokines
Mf
MMPs Cathepsins
TNF-a IL-1 IL-6
MMPs Cathepsins
TNF-a, IL-1, IL-6
Responsible formarginal erosions and bone loss
Osteoclast
Silverman GJ, Boyle DL. Immunol Rev.
2008223175-185.
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Model of RTX-Induced RA Synovial Changes in
Clinical Responders8 WEEKS
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
X
B cell
X
T cell
Plasma cell
IL-1, IL-6, TNF-a IFN-g
TNF-a IFN-g IL-17 RANKL
RF, anti-CCP antibodies
FLS
Immune complexes Complement fixation Induce Mf
secretion of proinflammatory cytokines
Mf
MMPs Cathepsins
TNF-a IL-1 IL-6
MMPs Cathepsins
TNF-a, IL-1, IL-6
Responsible formarginal erosions and bone loss
Osteoclast
Silverman GJ, Boyle DL. Immunol Rev.
2008223175-185.
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Model of RTX-Induced RA Synovial Changes in
Clinical Responders16 WEEKS
Silverman GJ, Boyle DL. Immunol Rev.
2008223175-185.
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Model of RTX-Induced RA Synovial Changes in
Clinical Responders24 WEEKS
Silverman GJ, Boyle DL. Immunol Rev.
2008223175-185.
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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

• Kavanaugh A et al. Ann Rheum Dis. 200766(suppl
  2)291 abstract FRI0037.
• Rosengren S et al. Ann Rheum Dis. 200766(suppl
  2)298 abstract FRI0059.
• 3. Thurlings RM et al. Ann Rheum Dis.
  200867917-925.
• 4. Dass S et al. Ann Rheum Dis. 200766(suppl
  2)90 abstract OP0123.
• 5. Teng YK et al. Arthritis Rheum.
  2007563909-3918.
• 6. Teng Y et al. Ann Rheum Dis. 200766(suppl
  2)439 abstract SAT0034.
• 7. Silverman GJ, Boyle DL. Immunol Rev. 2008
  2231751-85.

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Transcript Analysis of Synovial Biopsies May
Explain How RTX Affects RA Pathogenesis

• Methods
• Knee synovial biopsies at baseline (T0) and 12
  weeks after RTX therapy (T12) from 8 patients
  with RA with incomplete response to anti-TNF
  therapy
• RNA expression analyzed with GeneChip slides
• Results
• 206 genes ? and 330 genes ? between T0 and T12
• Pathway analyses indicated down-regulated genes
  involved in cytokine activity and chemotaxis (eg,
  CCRL2, IL-2BR, CXCL1, CX3CR1)
• Up-regulated genes involved in bone
  mineralization, bone remodeling,and ossification
  (eg, BMP2, TWIST2, P2RX7, CD276)
• Conclusion
• RTX induces specific changes in global gene
  expression in RAsynovial tissue
• RTX may decrease overall inflammatory cytokine
  responses in the affected joint, but also induce
  increases in factors that protect and heal
  periosteal bone

Gutierrez-Roelens I et al. Ann Rheum Dis.
200867(suppl 2)194 abstract THU0182.
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Conventional Immunosuppressive Therapy Can
Deplete Peripheral Plasmablasts and Na?ve B
Cells, but Not Memory B Cells
Plasma cells/blasts
1.2
2.5
6.7
CD27
87.1
72.1
64.0
CD27 memory B cells
11.7
25.4
29.2
CD19
07/21/03
07/28/03
09/09/03
Methylprednisolone Cyclophosphamide

Odendahl M et al. J Immunol. 20001655970-5979.
Figure courtesy of T. Dörner (Berlin, Germany)
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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 2440)
• 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-CCPnegative

Roll P et al. Arthritis Rheum. 2008581566-1575.
aResponse was defined as improvement in DAS28
1.2. DAS28, Disease Activity Score including a
28-joint count EULAR, European League Against
Rheumatism.
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At Baseline, Higher CD27 Memory B Cell Counts
Correlated WithEarly Relapse in Clinical
Responders After RTX Treatment
CD27 B cells/µL Before Therapy
60.0
memory
CD27
50.0
40.0
30.0
20.0
naive
10.0
P .045
IgD
0.0
Early Relapse
Late Relapse
Memory B cells are either IgD or IgD-
(After Week 40)
(Week 2440)
At Time of B-cell Regeneration, Clinical
Nonresponders Had Higher Levels of IgD CD27
Memory B Cells Lack of Persistent Memory B Cell
Reductions
CD27/IgD B cellsa
2.0
P .019
CD19/CD27 B Cells/ml
0.0
Responder
Nonresponder
(n 12)
(n 5)
aFirst time-point of regeneration
Roll P et al. Arthritis Rheum. 2008581566-1575.
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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. 200729154-163.
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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
  acidassociated 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)

How does epratuzumab work? What are the effects
on the human immune system?
BILAG, British Isles Lupus Assessment Group ACR,
American College of RheumatologyNHL,
non-Hodgkins lymphoma SLEDAI, systemic lupus
erythematosus disease activity index. Dörner T
et al. Arthritis Res Ther. 20068R74.
doi10.1186/ar1942. Jacobi AM et al. Ann Rheum
Dis. 200867450-457.
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Epratuzumab Preferentially Reduced Peripheral
Blood Na?ve B Cells Plasmablasts and CD27
Memory B Cells Are Less Affected
B cells absolute cell number
CD27- naive B cells/ml
CD27 memory B cells/ml
CD27 plasmablasts/ml
Jacobi AM et al. Ann Rheum Dis. 200867450-457.
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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-cellindependent pathway
• CD22-targeted therapy may provide mechanistic
  advantagesin patients with certain autoimmune
  diseases
• More studies are warranted

Jacobi AM et al. Ann Rheum Dis. 200867450-457.
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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-celltargeted therapy are
  providing new therapeutic options as well as
  helping to elucidate previously unknown
  immunologic mechanisms of pathogenesis.

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B-CellDirected Therapyfor RA
RA, rheumatoid arthritis.
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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-celltargeted therapy
  following DMARD and anti-TNF therapy failure
• Describe the safety of long-term and repeated
  courses of B-celltargeted therapy and the
  nuances of fixed or on-demand retreatment
• Summarize the radiographic changes noted
  following B-celltargeted therapy for RA

DMARD, disease-modifying antirheumatic drug TNF,
tumor necrosis factor.
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CD20 A Target on B cells

• 297-AA membrane-associated phosphoprotein (3337
  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

Ofatumumab
Ocrelizumab
TRU-015
CD20
AA, amino acid. Kehrl JH et al. Immunol Today.
199415432-436 Golay J et al. Blood.
2000953900-3908.
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RTX in RA Timeline

• Data from studies featuring RTX in the treatment
  of RA are presentedat the American College of
  Rheumatology (ACR) annual meeting

2002

• The New England Journal of Medicine publishes the
  results of aphase IIa study of RTX in patients
  with moderate to severe RA
• DANCER, a phase IIb study of RTX in RA, meets its
  primary end point

2004

• REFLEX, a phase III clinical study of RTX in RA,
  meets its primary end point

2005

• RTX is approved in combination with MTX to reduce
  signs and symptoms in adult patients with
  moderately to severely active RA who have had an
  inadequate response to one or more TNF-antagonist
  therapies
• The REFLEX trial, a 2-year multicenter,
  randomized, double-blind, placebo-controlled
  phase III study of RTX therapy, is published,
  showing that a single course of RTX with
  concomitant MTX therapy provides significant and
  clinically meaningful improvements in disease
  activity in patients with active, long-standing
  RA who had an inadequate response to 1 or more
  anti-TNF therapies

2006

• Results of an open-label extension analysis
  published patients treated with repeated courses
  of RTX have sustained clinical responses with no
  new adverse events

2007
DANCER, Dose-Ranging Assessment International
Clinical Evaluation of Rituximab in RAMTX,
methotrexate REFLEX, Randomized Evaluation of
Long-Term Efficacy of Rituximab in RARTX,
rituximab TNF, tumor necrosis factor.
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RTX (REFLEX) EULAR Responses Based on RF/Anti-CCP
RF/Anti-CCP(Either or Both)a

• 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

RF/Anti-CCP-b
aP gt .0001 vs placebo, seropositive. bP .05 vs
placebo, seronegative.
Anti-CCP, anticyclic citrullinated peptide
EULAR, European League Against RheumatismRF,
rheumatoid factor. Tak PP et al. Ann Rheum Dis.
200766(suppl 2)338 abstract FRI0192.
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Repeated Treatment With RTX Produces Sustained
Efficacy in Patients With RA With an Inadequate
Response to DMARDs
Week 24 (n 57)
Patients ()
DMARD, disease-modifying antirheumatic drug
DAS28, Disease Activity Score including a
28-joint count. Emery P et al. Arthritis Rheum.
200756(9 suppl)S151-S152 abstract 266.
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Patient-Reported Outcomes During RTX Treatment of
AntiTNF-a Refractory RA in Addition to ACR
Responses
a
a
a
a
Patients ()
Patients () Achieving MCID
a
a
aP lt .0001 vs placebo MTX. MCID, minimum
clinically important difference FACIT-F,
Functional Assessment of Chronic Illness
TherapyFatigue HAQ-DI, Health Assessment
Questionnaire Disability Index PCS, physical
component score MCS, mental component
score. Cohen SB, et al. Arthritis Rheum
2006542793-2806. Keystone E et al. Arthritis
Rheum. 200859785-793.
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Repeated Treatment With RTX Produces Sustained
Efficacy in Patients With an Inadequate Response
or Intolerance to TNF Inhibitors
Week 24 (n 96)
Patients ()
Emery P et al. Arthritis Rheum. 200756(9
suppl)S151-S152 abstract 266.
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REFLEX Change in Radiographic Outcomes at Week 56
P .0046
Mean Change
JSN, joint space narrowing TGS, total
Genant-modified Sharp score. Keystone E et al.
Ann Rheum Dis. 200766(suppl 2)431-432 abstract
SAT0011.
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REFLEX Change in RadiographicEnd Points at Week
56
Change in SharpGenant Total Score atWeek 56 by
Anti-CCP Status at Baseline1
ACR20 Nonresponders at Week 242
Mean Change
Mean Change in X-ray Score
(n 11) (n 78) Missing
(n 21) (n 33) Negative
(n 85) (n 129) Positive
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. 200766(suppl 2)428 abstract
SAT0002. 2. Keystone E et al. Ann Rheum Dis.
200766(suppl 2)431-432 abstract SAT0012.
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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

4
RTX(n 187)
Placebo(n 281)
2.81
3
TGS
1.78
2
1.14
1
0.66
0
Year 1
Year 2
80
RTX
Placebo
68
60
60
54
46
No ? TGS ()
40
20
0
Baseline to1 Year
1 Year to 2 Years
Cohen S et al. Ann Rheum Dis. 200867(suppl
2)189 abstract THU0167.
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

Patients ()
Teng Y et al. Ann Rheum Dis. 200867(suppl 2)339
abstract FRI0167.
38
Switching Strategies When an AntiTNF-a Fails
RTX or Alternate AntiTNF-a
Type of Prior AntiTNF-a Failure
Not Effective
AEs
0
Not significant
Significant
IMPROVEMENT
-0.5
-0.77
-0.86
-1
DAS 28 ? From Baseline
-1.03
-1.5
-1.55
-2
N 300. Finckh A et al. Ann Rheum Dis.
200867(suppl 2)127 abstract OP-0249.
39
Subsequent RTX Treatment Courses Incidence of
Acute Infusion Reactions by Treatment Course
Patients ()

• SIEs occurred in lt1 of patients during course 1
  and 2
• No SIEs were observed during course 3 or 4

All-exposure population by treatment course. SIE
serious infusion-associated event. van
Vollenhoven RF et al. Arthritis Rheum. 200756(9
suppl)S147 abstract 257.
40
Design of B-CellTargeting Agents
Chimeric antibody
(Synthetic) fully human antibody
Human variable regions
Human IgG constant region
Human
Ocrelizumab (CD20) Ofatumumab (CD20) Belimumab
(BAFF) Epratuzumab (CD22)
Rituximab (CD20)
SMIP
Synthetic peptide
Decoy receptors
Human
Human (green)
Atacicept (BAFF and APRIL) (TACI-Ig)
TRU-015 (CD20)
BR3-FC (BAFF)
Baminercept-alpha (LT-?)
AMG623 (BAFF)
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Therapeutic Approachesto B-Cell Depletion
Memory Cell
Immature B cell
Mature B cell
Transitional B cell
Antigenstimulation
Antibody-producing Plasma cells
Pro- B Cell
Stem Cell
Pre- B Cell
Epratuzumab (Anti-CD22)
CD19
Modulates B cell function With limited depletion
CD22
CD20
SLE
Autoreactive B cells
RA
RTX (anti-CD20) Binds and eliminatesCD20-positive
cells
Other diseases
Belimumab (antisoluble BAFF)
Acts later in B-cell development Potently
depletes Ig-secreting cells
Atacicept (TACI-Ig)
Neutralizes both BAFF and APRIL Acts broadly in
B-cell development Potently depletes Ig-secreting
cells
SLE, systemic lupus erythematosus.
42
Therapeutic Approaches to B-Cell Depletion
Clinical Trial Status
aStatus as of July 17, 2008.
43
Ocrelizumab (OCR) Humanized Anti-CD20 mAb in RA

• Phase I/II dose-escalation RCT with OCR MTX
• 175 patients in whom 16DMARDs failed
• 8 TJC and SJC plus CRP1 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

ACR Results at Week 24
70
Placebo
58
58
60
OCR 400
OCR 1000
50
OCR 1500
38
40
34
OCR 2000
33
Patients ()
32
27
30
25
23
19
20
14
13
9
10
3
0
0
ACR20
ACR50
ACR70
ESR, erythrocyte sedimentation rate IV,
intravenous OCR, ocrelizumab mAb, monoclonal
antibodyRCT, randomized controlled trial. Tak
PP et al. Ann Rheum Dis. 200867(suppl 2)127
abstract OP-0250.
44
CD20 OfatumumabHuman Anti-CD20 IgG1 mAb

• Phase II trial in 225 DMARD/TNF incomplete
  responders
• Ofatumumab IV day 1/15 or placebo premedication
  100 mg corticosteroid antihistamines
  acetaminophen
• Primary end point ACR20 week 24
• No significant change in IgA, IgM, or IgG all
  patients were human anti-human antibodynegative
  at 24 weeks
• 51 of all AEs occurred on infusion days
• Majority were mild
• Common Terminology Criteria (CTC) grade 3
• None in placebo group
• 1 serious AE (SAE) in 700 group
• 3 SAEs in 1000 group
• No CTC grade 4 or 5 events

Østergaard M et al. Arthritis Rheum. 200756(9
suppl)S793-S794 abstract 2086.
45
CD20 Ofatumumab HumanAnti-CD20 IgG1 mAb
Phase II Study
ACR20
ACR50
ACR70
60
49
50
46
41
40
Patients ()
b
30
26
26
a
19
20
15

• Conclusions
• No apparent dose response
• No limiting safety signals as yet

9
10
6
5
4
0
0
Placebo
300
700
1000
n 55
n 58
n 57
n 54
aP lt .05 bP lt.01
Østergaard M et al. Arthritis Rheum. 200756(9
suppl)S793-S794 abstract 2086.
46
TRU-015 in Patients With RAPhase 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/CRPor morning stiffness gt45
  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

aP lt .05 bP .003 cP .008.
Burge D et al. Abstract presented at ACR/ARHP
Annual Scientific Meeting November 68, 2007
Boston, Massachusetts abstract L7.
47
Repeated Administration of TRU-015 in Patients
With RA
AEs gt10

• SMIP protein against CD20
• Dose-dependent B-cell depletion
• Retreatment in 36/54 patients from phase I/IIa
  RCT
• IV infusion 5 or 15 mg/kg 1
• INF every 6 months if B-cell recovery
• Up to 6 courses given
• 4 AEs on day of infusion
• 3 mild (facial flushing, facial erythema,
  pruritus)
• 1 moderate (Bakers cyst)
• Conclusions Retreatment after B-cell recovery
  well tolerated

R1, first retreatment R2, second retreatment
URI, upperrespiratory tract infection. Burge D
et al. Ann Rheum Dis. 200867(suppl 2)128
abstract OP-0252.
48
LTßR-Ig (Baminercept)

• Human lymphotoxin-b receptor (LTb) extracellular
  domain fused to human IgG1 Fc receptor acts as a
  decoy receptor for LTb
• Effective in murine models of arthritis
• Blocks induction of arthritis and decreases
  severity of arthritis in established disease

B cells, T cells,NK cells
Activated T cells Dendritic cells

• Lymphotoxin a/b Pathway is
• implicated in
• Liver, spleen, and lymph nodes
• Gut mucosa and Peyers patches

• LIGHT Pathway is implicated in
• Mucosal and hepatic inflammation

LT??
LIGHT
Baminercept alfa
HVEM
LT?R
T Cells B cells NK cells
Control of Lymphoid Microenvironments

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

HVEM, herpes virus entry mediator. Baldassare A
et al. Ann Rheum Dis. 200867(suppl 2)86
abstract OP-0122.
49
LTßR-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 gt5 PBO 55 and LTßR-Ig 67
• Headache Placebo 9 and LTßR-Ig 19
• Flu-like symptoms in 25 within 24 h of first
  injection ? with subsequent injections to 69
• Continued clinical responses after week 4 despite
  discontinuation of treatment
• Phase IIb planned 5, 50, 200 mg weekly

Baldassare A et al. Ann Rheum Dis. 200867(suppl
2)86 abstract OP-0122.
50
Summary

• B-celldirected therapy has demonstrated clinical
  and laboratory efficacy in RA
• Multiple other diseases potentially may be
  treated with B-celldirected 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
WithB-cellDirected Therapies
52
Learning Objectives

• Define immunocompetence and review the impact of
  B-celldirected therapies on humoral immunity
• Summarize the safety of B-celldirected 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-celldirected
  therapy

DMARD, disease-modifying antirheumatic drug RTX,
rituximab TNF, tumor necrosis factor.
53
Outline

• Immunocompetence and the effects of
  B-celldirected therapies
• Safety of B-celldirected 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-celldirected 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)

Pro-B
Pre-B
Immature
Transitional
Naïve
Memory
CD20 RTX
Plasmablast (short-lived)
Plasma Cell (long-lived)
Protective vspathogenic antibodies
Protective vspathogenic antibodies
Antimicrobial Anti-dsDNA Anti-RBP antibodies(Ro,
La, Sm/RNP)
Antimicrobial Anti-dsDNA RF and
anti-CCPantibodies
Survive weeks after RTX
Survive months toyears after RTX
RTX spares long-lived plasma cells,which are the
primary source ofantimicrobial 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. 2008585-14.
56
Immunoglobulin Levels Following RTX Therapy
Percent of Patients IgM/IgG ltLLN 24 Weeks After
RTX

• Total immunoglobulin (Ig), IgM, IgG
• Every 812 weeks after each course
• Always normal IgG IgM 761 (72)
• gt1 Ig level ltLLN (at any point)
• gt1 low IgM 261 (25)
• gt1 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.
200756(9 suppl)S149-S150 abstract 261.Popa C
et al. Rheumatology (Oxford). 200746626-630.
57
Long-Term Safety of RTXWith Repeated Use

• 1053 patients (2438 patient-years) from 3
  double-blind trials
• 1014 gt6 months
• 957 gt1 year
• 701 gt2 years
• 120 gt3 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. 200756(9
suppl)S147-148 abstract 257.
58
Long-Term Safety of RTXWith Repeated Use
Safety of Additional Courses of RTX in Patients
With Active RA Open-Label Extension Analysis
A total of 1,039 patients received gt1 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.
AE, adverse event RA, rheumatoid arthritis SAE,
serious adverse event. Keystone E et al.
Arthritis Rheum. 2007563896-3908.
59
Serious Infection Rates by Immunoglobulin Levels
With Repeated Use of RTX
Genovese M et al. Arthritis Rheum. 200756(9
suppl)S149-S150 abstract 261.
60
Long-Term Safety of RTXWith Repeated Use

• 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.
200756(9 suppl)S147-148 abstract 257.
61
Rate of Serious Infections With Rituximab and
Other RA Therapies
Incidence of Serious Infections per 100
Patient-Years
Rituxan-exposed patients (n1053) Biologic-treate
d patients (n9868)(BSR Biologics
Register) Biologic-treated patients
(n928)(German Biologics Register) DMARD-treated
patients (n1352) (BSR Biologics
Register) DMARD-treated patients (n601) (German
Biologics Register)
BSR, British Society for Rheumatology. van
Vollenhoven RH et al. Arthritis Rheum. 200756(9
suppl)S147-148 abstract 257. Listing J et al.
Arthritis Rheum. 2005523403-3412. Dixon WG et
al. Arthritis Rheum. 2006542368-2376.
62
Serious Infection Rates During Treatment With
DMARDS or Anti-TNF Agents Following RTX Therapy
All-exposure population. Genovese M et al.
Arthritis Rheum. 200756(9 suppl)S150 abstract
262.
63
Safety of Switching to DMARD or TNF Inhibitor
After RTX Failure

• 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 ltLLN
• 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. 200756(9
suppl)S150 abstract 262.
64
Can Patients Given Biologics, Including
B-CellDepleting Therapy, Be Effectively
Immunized?
65
Immunization andImmune Response

• Responses to immunization depend on intact immune
  response
• T-celldependent antigens (peptide)
• T-cellindependent (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
  (fX174 and KLH) in patients with psoriasis3

• KLH, keyhole limpet hemocyanin MTX,
  methotrexate SLE, systemic lupus erythematosus.
• Kapetanovic MC et al. Rheumatology (Oxford).
  200746608-611.
• Albert DA et al. Arthritis Rheum. 200654(9
  suppl)S550 abstract 1323.
• Abrams JR et al. J Clin Invest.
  19991031243-1252.

67
Response to Influenza Vaccine in RA Treated With
Abatacept
Proportion of Patients Responding to Different
Numbers of Influenza Serotypes 1 Month
Post-immunization

• Previous data suggest that abatacept may blunt
  response to the T-cellindependent Ag
  pneumococcus in healthy controls and patients
  with RA
• Influenza is a T-celldependent Ag, with healthy
  individuals demonstrating seroconversion(4-fold)
  to 3344 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

• 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. 200756(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. 200654(9
suppl)S550 abstract 1323.2. Gelinck L et al.
Ann Rheum Dis. 200766(suppl 2)160 abstract
THU0116. 3. Oren S et al. Ann Rheum Dis.
200766(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.
2007661402-1403.
70
RTX Impairs Ability to Respond to Influenza
Vaccine in Patients With RA
A/H3N2
A/H1N1
Influenza B
HC RA - TNF RA - RTX
1024
1024
1024
512
512
512
256
256
256
128
128
128
64
64
Pre-vaccination
Post-vaccination
GMT
64
32
32
16
16
32
8
8
16
4
4
8
2
2
4
1
1
Pre
Post
Pre
Post
Pre
Post
Vaccination
Vaccination
Vaccination
GMT, geometric mean titers HC, healthy
controls. Gelinck LB et al. Ann Rheum Dis.
2007661402-1403.
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

Gelinck LB et al. Ann Rheum Dis.
2007661402-1403. .
72
Considerations for Immunocompetence of Newer
B-CellTargeting Agents BAFF, APRIL
73
Considerations for Immunocompetence of
NewerB-CellTargeting Agents Baminercept
(LTßR-Ig)

• LTß-Ig is a fusion protein binding to LTa1ß2 and
  LIGHT (members of the TNF family) on T, B, and NK
  cells
• Blocks interaction with antigen-presenting and
  stromal cells
• The LT pathway regulates organization of the
  lymphoid microarchitecture and lymphoid
  trafficking
• LTß-deficient mice have absent secondary lymphoid
  tissue and profound immunodeficiency
• Partially deficient LTß mice are susceptible to a
  wide variety of pathogens Listeria,
  Mycobacterium tuberculosis, viruses, and
  parasites1,2

1. Xu G et al. J Immunol. 20071795358-5366. 2.
Lin X et al. Int Immunol. 200315955-963.
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
  Crohns 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 (lt200). The patient
  received 3 courses of RTX with daily GC in
  20032006
• 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/rituxi
mab.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.
2007562116-2128.
76
Immunocompetence and Biologic TherapiesPromises
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-cellDirected 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 Sjögrens
  syndrome
• Summarize recent clinical trial data on theuse
  of B-cell targeting in other vasculitides

79
B-CellDepletion 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
RTX B-CellDepletion Therapy in Patients With
SLE Long-TermFollow-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 215)
• Serum immunoglobulins decreased but not below
  lower limit of normal
• Anti-dsDNA antibody levels significantly reduced
  6 months after B-celldepletion therapy
• Protein/creatinine ratio fell (but change did not
  reach statistical significance)
• 13 patients re-treated

CTX, cyclophosphamide dsDNA, double-stranded
DNA IV, intravenous RTX, rituximab. 1. Edwards
JC et al. N Engl J Med. 20043502572-2581. 2. Ng
KP et al. Ann Rheum Dis. 200766(suppl 2)56-57
abstract OP0020. 3. Ng KP et al. Ann Rheum Dis.
200665942-945.
81
RTX B-CellDepletion Therapy in Patients With
SLE Long-TermFollow-Up and Predictors of
Response

• 11 (55) of 20 patients who flared did so 612
  months after treatment
• Predictors of lack of response
• Patients with anti-ENA antibodies (anti-Sm or
  anti-La) weremore likely to flare
• Lower serum C3 at baseline was associated with
  shorter timeto flare following B-celldepletion
  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
  sicknesslike reaction, active pancreatitis,
  seizure

AE, adverse event ENA, extractable nuclear
antigen. 1. Ng KP et al. Ann Rheum Dis.
200766(suppl 2)56-57 abstract OP0020. 2. Ng
KP et al. Ann Rheum Dis. 200665942-945.
82
2-Year Extended Follow-Up ofOpen-Label Phase
I/II Trial of RTX for Active, Refractory SLE

• RTX (500 mg IV weekly ? 4 in 5 patients and 1000
  mg IV ? 2 on days 0 and 14 in 10) was
  administered to patients with active, refractory
  SLE (mean BILAG score 12.5, range 817)
• Peripheral B cells rapidly decreased by day 14 in
  all patients and remained low until 6 months
  post-treatment, except for 1 patient whose
  peripheral B cells remained low for 2 years
• No significant change in Ig levels
• ? autoantibody levels and ? complement levels in
  a majority of patients
• RTX resulted in sustained improvement of disease
  activity in 5 of 14 patients at2 years
• Mean BILAG scores improved from 12.5 to 4.6
• Mean background corticosteroid dose decreased
  from 25.2 to 7.7 mg
• 6 patients required repeated courses of RTX for
  persistent disease activity
• Severe AEs occurred in 7 patients, all with
  antiphospholipid antibodies (DVT 2, multiple
  infarctions 2, pulmonary infarction, MI,
  cerebral hemorrhage,transverse myelitis)
• 2 patients died (cerebral hemorrhage and
  catastrophic APS)

APS, antiphospholipid syndrome BILAG, British
Isles Lupus Assessment Group DVT, deep
venousthrombosis Ig, immunoglobulin MI,
myocardial infarction. Tanaka Y et al. Ann Rheum
Dis. 200867(suppl 2)54 abstract OP-0020.
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.
200756(9 suppl)S458 abstract 1124. 2.
Lindholm C et al. Ann Rheum Dis. 200867(suppl
2)344 abstract FRI0184. 3. Sangle SR et al.
Arthritis Rheum. 200756(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 12 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. 200867(suppl
2)54 abstract OP-0021. 2. Guzman RA et al. Ann
Rheum Dis. 200867(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 lt10 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 ongoing

AUC, 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?methoddetailid11247http//clinica
ltrials.gov/ct2/show/NCT00137969
http//clinicaltrials.gov/ct2/show/NCT00282347
86
RTX B-CellDepletion 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

PML, progressive multifocal leukoencephalopathy. 1
. Ng KP et al. Ann Rheum Dis. 200766(suppl
2)56-57 abstract OP0020 2. Ng KP et al. Ann
Rheum Dis.200665942-945. 3. Tanaka Y et al.
Ann Rheum Dis. 200867(suppl 2)54 abstract
OP-0020 4. Amoura Z et al. Arthritis Rheum.
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87
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,Physicians Global
Assessment and QOL (SF-36 PCS), and decreased
BILAG 1A or 2B flares
88
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 fromgt7.5 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