Efficacy and safety of MabThera

1
Efficacy and safety of MabThera (rituximab) in
rheumatoid arthritis (RA)
2
Contents

• The role of B cells in the pathophysiology of RA
• MabThera (rituximab) the first selective B cell
  therapy for RA
• The DANCER study
• The REFLEX study
• Efficacy of repeated courses of MabThera in RA
• Safety and tolerability of MabThera in RA
• Conclusions

3
The role of B cells in the pathophysiology of RA
4
B cells key players in RA pathophysiology

• For the past 20 years, RA has been considered a
  T cell-mediated disease
• Recently, the important role of B cells in the
  pathophysiology of RA has been revealed
• This new discovery has led to a breakthrough in
  the management of RA

(Dörner Burmester, 2003)
5
B cells key players in RA pathophysiology
(contd)

• There is an abundance of B cells in the synovium
  of RA-affected joints
• These lymphocytes can be organised into lymphoid
  structures
• Three critical roles of B cells in RA
  pathogenesis
• Antigen presentation and T cell activation
• Autoantibody production
• Cytokine production

(Panayi Hainsworth, 2005 Silverman Carson,
2003)
6
Role of B cells in RA (1) antigen
presentationleading to T cell activation

• B cells are highly efficient antigen-presenting
  cells (APCs)
• Antigen presentation leads to T cell activation
• Activated T cells produce cytokines that activate
  macrophages to produce pro-inflammatory
  cytokines
• Results in inflammation and joint destruction

(Lanzavecchia, 1990 Lund et al, 2005 ONeill
et al, 2005 Roosnek Lanzavecchia, 1991
Silverman Carson, 2003)
7
Role of B cells in RA(2) autoantibody production

• Autoreactive B cells produce autoantibodies,
  including RF
• Formation of RF immune complexes in the synovium
  leads to production of pro-inflammatory
  cytokines through
• Complement activation
• Macrophage activation

(Abrahams et al, 2000 Silverman Carson, 2003
Sutton et al, 2000)
8
Role of B cells in RA (3) cytokine production

• Activated B cells produce cytokines (e.g. TNF-a,
  interleukin IL-6, lymphotoxin) which are known
  to promote inflammation and joint damage in RA
• Lymphotoxin promotes the formation of new
  lymphoid structures in the synovium, thus helping
  to perpetuate autoimmune reactions

(Duddy et al, 2004 Lund et al, 2005)
9
B cell development
Stem cell
(Roitt et al, 2002 Silverman Weisman, 2003)
10
B cell development
(Roitt et al, 2002 Silverman Weisman, 2003)
11
B cell function
B cell death
Short-lived plasma cell (secretes IgM)
Long-lived plasma cell
Antigen, APCs and T cells
Memory B cell
Activated B cell
Naïve B cell
Germinal centre B cell
Antigen
Affinity maturation of B cell receptor
(Ahmed et al, 2002 Roitt et al, 2002 Silverman
Weisman, 2003)
12
Steps in the maturation of B cellsCD20 only
expressed in a subset of B cells
(Roitt et al, 2002 Sell Max, 2001 Silverman
Weisman, 2003)
13
MabThera (rituximab) the first selective B
cell therapy for RA
14
Rituximab a novel biological agent for RA

• Rituximab is a novel genetically engineered
  anti-CD20 therapeutic monoclonal antibody that
  selectively targets CD20-positive B cells

(Shaw et al, 2003 Silverman Weisman, 2003)
15
The structure of rituximab
The variable region is from the anti-CD20
murine antibody fragment IDEC-2B8
Rituximab compriseshuman IgG and ?-constant
regions
(Rybak et al, 1992 Shaw et al, 2003 Silverman
Weisman, 2003)
16
CD20 an ideal B cell target

• CD20 is a 297-amino acid phosphoprotein (3337
  kDa) found on the surface of B cells
• CD20 is highly expressed on B cells but is not
  expressed on stem, dendritic or plasma cells
• No known natural ligands for CD20

(Golay et al, 2000 Johnson Glennie, 2003
Silverman Weisman, 2003)
17
Rituximab selectively targets CD20-positive B
cells

• Murine-derived region binds to the B cell-surface
  CD20 antigen
• Human-derived region activates cellular
  mechanisms to initiate B cell depletion

(Rybak et al, 1992 Shaw et al, 2003 Silverman
Weisman, 2003)
18
Rituximab selectively targets CD20-positive B
cells (contd)

• B cell depletion occurs via three proposed
  mechanisms
• Complement-dependent cytotoxicity (CDC)
• Antibody-dependent cellular cytotoxicity (ADCC)
• Apoptosis

19
Rituximab mode of action(1) selective B cell
depletion by CDC

• Through binding to CD20, rituximab interacts with
  C1q (a protein of the complement system)
• This triggers the activation of the complement
  system
• Ultimately, this leads to B cell lysis via
  formation of pores in the membrane

(Cartron et al, 2004 Reff et al, 1994 Shaw et
al, 2003)
20
Rituximab mode of action (2) selective B cell
depletion by ADCC

• Attraction and binding of effector cells (e.g.
  macrophages, natural killer cells and cytotoxic T
  cells)
• Release of granules containing perforins and
  other mediators by effector cells
• Lysis of the B cell

(Cartron et al, 2004 Clynes et al, 2000)
21
Rituximab mode of action (3) selective B cell
depletion by apoptosis

• When rituximab binds to CD20, it causes a signal
  to be sent into the B cell, which induces death
  by apoptosis

(Cartron et al, 2004 Shan et al, 1998)
22
Rituximab in RA proof of concept study

• RF-positive RA patients who failed 15
  disease-modifying antirheumatic drugs (DMARDs)

(Edwards et al, 2004)
23
Phase IIa study design and treatment groups
MTX (10 mg/week)
RANDOMISE
Rituximab (1000 mg x 2)
MTX IRs
Single course of two infusions
Rituximab (1000 mg x 2)
CTX (750 mg x 2)
Rituximab (1000 mg x 2)
MTX (10 mg/week)
Week 48(exploratory analysis)
Week 24(primary analysis)
17-day glucocorticoid regimen in all arms
IRs inadequate responders
(Edwards et al, 2004)
24
Significant and sustained ACR response after
only 2 infusions
24 weeks
48 weeks











plt0.05, Fishers exact test comparing the MTX
group with each rituximab group. ACR American
College of Rheumatology
(Edwards et al, 2004)
25
Global development of rituximab in RA

(WA17042/IDEC 102-20) Phase III Patients with
active RA who had failed prior treatment with TNF
inhibitor therapies

(WA17043/U2644g) Phase IIb Patients with active
RA despite prior treatment with DMARDs
26
The DANCER studyEfficacy and safety data from
the Dose-ranging Assessment iNternational
Clinical Evaluation of Rituximab in RA (DANCER)
study
(Emery et al, 2006)
27
DANCER study objectives

• Phase IIb study to
• Determine the appropriate treatment regimenof
  rituximab with MTX in patients with RA
• Dose
• Concomitant use of glucocorticoids

(Edwards et al, 2004 Emery et al, 2006)
28
DANCER study design
All groups received doses 2 weeks apart
no glucocorticoids
Primary endpoint patients () with an ACR20 at
Week 24
i.v. premedication onlya
Rituximab 1000 mg x 2 (n192)
i.v. premedication plus oralb
no glucocorticoids
Randomised(n465)
Rituximab 500 mg x 2 (n124)
i.v. premedication onlya
i.v. premedication plus oralb
no glucocorticoids
Follow-upto 2 years
Placebo(n149)
i.v. premedication onlya
i.v. premedication plus oralb
24 weeks
Baseline
All arms received weekly MTX 1025 mg (oral or
parenteral) aMethylprednisolone 100 mg i.v. on
Days 1 and 15 bmethylprednisolone 100 mg i.v.on
Days 1 and 15 plus oral prednisone 60 mg/day on
Days 27 and 30 mg/day on Days 814
(Emery et al, 2006)
29
DANCER study randomisation
Primary ITT population (n367)RF-positive only
(Emery et al, 2006)
30
DANCER study population

• Key inclusion criteria
• RA patients who failed 15 DMARDs (other than
  MTX), including biological response modifiers
• Swollen joint count (SJC) and tender joint count
  (TJC) ?8 at screening and baseline
• Elevated erythrocyte sedimentation rate (ESR 28
  mm/h) or C-reactive protein (CRP 1.5 mg/dL)
• Primary endpoint
• ACR20 at Week 24 in RF-positive patients

(Emery et al, 2006)
31
DANCER study demographics
Characteristics Placebo(n149) Rituximab500 mg x 2 (n124) Rituximab1000 mg x 2 (n192)
Female () 80 83 80
Male () 20 17 20
Age (mean, years) 51 51 51
MTX dose (mg/week) 15.6 16.0 14.9
Previous DMARDs (mean, n) 2.2 2.5 2.5
Prior TNF inhibitor therapy () 26 33 28
Patients receiving concomitant glucocorticoids () 63 53 64
Patients receiving NSAIDs or COX-2 () 82 82 78
NSAIDs non-steroidal anti-inflammatory drugs
(Emery et al, 2006 Roche, data on file)
32
DANCER study baseline characteristics
Characteristics Placebo(n149) Rituximab500 mg x 2 (n124) Rituximab1000 mg x 2 (n192)
Disease duration (years) 9.3 11.1 10.8
SJC (mean, number) 21 22 22
TJC (mean, number) 35 33 32
RF (mean, IU/L) 437 421 437
CRP (mean, mg/dL) 3.3 3.2 3.0
ESR (mean, mm/h) 40 45 41
DAS28 (mean, score) 6.8 6.8 6.7
RF-positive patients, intention-to-treat (ITT)
population (n367) DAS28 disease activity
score based on 28 different joint counts
(Emery et al, 2006)
33
Rapid and sustained B cell depletion over 24
weeks
300
200
Mean CD19-positive B cells (x 103/µL)
Lower limit of normal
100
0
12
1
15
4
8
16
20
24
Days
Weeks
Glucocorticoid groups combined within each
rituximab group. Glucocorticoids did not
influence B cell levels in any rituximab group
(Emery et al, 2006)
34
DANCER study ACR response at 24 weeks after the
first course
Patients ()
RF-positive patients, ITT population (n367)
(Emery et al, 2006)
35
DANCER study change in DAS at 24 weeksafter
the first course
plt0.0001vs placebo
Mean change in DAS28


RF-positive, ITT population (n367)
(Emery et al, 2006)
36
DANCER studyEULAR response at 24 weeks after
the first course

plt0.0001 vs placebo

Patients ()

RF-positive patients, ITT population (n367)
(Emery et al, 2006)
37
DANCER study doseresponse relationship for
high-hurdle endpoints at 24 weeks
Good EULAR response
DAS remission
DAS low disease
ACRn
ACR70




Patients/change ()
P 0.029 P lt 0.0001
(Emery et al, 2006 Roche, data on file)
38
DANCER study glucocorticoids do not
contribute significantly towards long-term
efficacy
Probability of achieving an ACR20 response
depends onrituximab treatment (plt0.001) but not
on glucocorticoids
Variable DF Wald ?2 p-value
Rituximab 2 23.94 lt0.0001
Glucocorticoids 2 3.59 0.166
DF degree of freedom
(Emery et al, 2006 Roche, data on file)
39
DANCER study lasting improvement in physical
function over 24 weeks
Weeks
0
RF-positive patients, ITT population (n367)
-0.1
Minimum clinically important difference (MCID)
Mean change in HAQ-DI
-0.3
-0.5
(Emery et al, 2006 Roche, data on file)
40
DANCER study Lasting improvement in fatigue
over 24 weeks
Weeks
24
0
4
8
12
16
20
0
-10
Change in Functional Assessment for Chronic
Illness Therapy Fatigue(FACIT-F) score ()
-20
-30
(Emery et al, 2006 Roche, data on file)
41
DANCER study efficacy summary

• After only 2 infusions administered 2 weeks
  apart, rituximab, in combination with MTX,
  significantly improves signs and symptoms of RA,
  physical function and fatigue at 24 weeks
  compared with MTX alone
• A doseresponse relationship is apparent in
  extreme endpoints
• Glucocorticoid administration has no effect on
  the long term efficacy of rituximab

(Emery et al, 2006 Fleischmann et al, 2005)
42
The REFLEX studyA Randomised Evaluation oF
Long-term Efficacy of rituXimab in RA (REFLEX)
(Cohen et al, 2006)
43
REFLEX study design
Screen/TNF
Randomisation
Treatment period
Randomization
and/or DMARD




t
Long-term follow-up
Rituximab MTX(Group A) n 308
MTX ?3 months
Potential for subsequent courses of rituximab in
patients with ?20 reduction in SJC and TJC from
Week 24
Placebo MTX (Group B) n 209
Screen
Wk 24
Wks 4, 8,12, 16, 20
Wk2
Day1
Wk 56
Rescue (Week 16)
Group A Standard of care
Group B Rituximab MTX
(Cohen et al, 2006)
44
REFLEX study key entry criteria

• RA patients with inadequate response to treatment
  with TNF inhibitor therapy due to intolerance or
  lack of efficacy
• SJC and TJC both ?8 (based on 6668 joint counts)
• Elevated acute-phase reactant. Either
• CRP ?1.5 mg/dL, or
• ESR ?28 mm/h
• Radiographic evidence of at least one joint with
  definite erosion attributable to RA

(Cohen et al, 2006)
45
REFLEX study efficacy endpoints

• Primary endpoint (24 week)
• ACR20 response
• Secondary endpoints (24 weeks)
• ACR50/70 response
• DAS28 score
• EULAR response
• ACR core set

(Cohen et al, 2006)
46
REFLEX studybaseline disease characteristics
Characteristic Placebo(n209) Rituximab(n308)
Age (years) 52.8 52.2
Disease duration (years) 11.7 12.1
SJC (n) 22.9 23.4
TJC (n) 33.0 33.9
Proportion RF-positive () 79 79
CRP (mg/dL) 3.8 3.7
ESR (mm/h) 48.4 48.0
DAS28 (score) 6.8 6.9
HAQ (score) 1.9 1.9
Total Genant-modified Sharp score 47.9 48.3
All variables are mean values except proportion
RF-positive
(Cohen et al, 2006)
47
REFLEX studybaseline RA treatment history
Treatment Placebo(n209) Rituximab(n308)
Previous DMARDsa (mean, n) 2.4 2.6
Baseline weekly MTX dose (mean, mg) 16.7 16.4
Baseline glucocorticoid use () 61 65
Inadequate efficacy of TNF inhibitors () 90 92
Previous TNF inhibitors (mean, n) 1.5 1.5
1 previous TNF inhibitor () 60 60
2 previous TNF inhibitors () 31 31
3 previous TNF inhibitors () 9 9
aExcluding MTX and TNF inhibitors
(Cohen et al, 2006)
48
REFLEX study patient disposition
Disposition, n () Placebo (n209) Rituximab (n308)
Withdrawn 97 (46) 54 (18)
Reason for withdrawal
Adverse event 1 (lt0) 8 (3)
Insufficient therapeutic response 83 (40) 36 (12)
Refused treatment 5 (2) 5 (2)
Failure to return 3 (1) 4 (1)
Other 5 (2) 1 (lt1)
Completed 24 weeks 112 (54) 254 (82)
(Cohen et al, 2006 Roche, data on file)
49
REFLEX study selective peripheral B cell
depletion over 24 weeks
Last observation carried forward for missing
values
(Cohen et al, 2006)
50
REFLEX studyACR responses at 24 weeks after
the first course
plt0.0001
plt0.0001
Patients ()
plt0.0001
(Cohen et al, 2006)
51
REFLEX studyLasting ACR20 response over 24 weeks
A statistically significant ACR20 response from
Week 8
60
50
plt0.0001
40
30
Patients ()
20
10
0
0
4
8
12
16
20
24
Weeks
Placebo (n201)
Rituximab 1000 mg x 2 (n298)
(Cohen et al, 2006)
52
REFLEX study significant improvements across
the ACR core set at 24 weeks
Mean change from baseline Mean change from baseline Mean change from baseline
Core set parameter Placebo(n201) Rituximab(n298) p-value
SJC (n) -2.6 -10.4 lt0.0001
TJC (n) -2.7 -14.4 lt0.0001
Pt global assessment (mm) -5.3 -26.0 0.0048
Ph global assessment (mm) -6.2 -29.5 lt0.0001
HAQ-DI -0.1 -0.4 lt0.0001
Pain (mm) -2.5 -23.4 0.0045
CRP (mg/dL) 0.0 -2.1 lt0.0001
ESR (mm/h) -4.1 -18.5 lt0.0001
ITT population, analysis of covariance (ANCOVA)
calculation Pt patient Ph physician
(Cohen et al, 2006)
53
REFLEX studyLasting change in DAS28 over 24
weeks
Weeks
p0.0001
Mean change in DAS28





(Cohen et al, 2006)
54
REFLEX studyEULAR responses at 24 weeks
(Cohen et al, 2006)
55
REFLEX study change in fatigue (FACIT-F) at 24
weeks after the first course
(Cohen et al, 2006)
56
REFLEX studychanges in SF-36 categories at 24
weeks after the first course
Improvement defined as a gt6.33 change from
baseline in mental health score and a gt5.42
change from baseline in physical health score
(Roche, data on file)
57
REFLEX study week 24 efficacy results in
sub-populations

• RF status
• Number of prior TNF inhibitors
• Reason for TNF inhibitor failure

58
REFLEX study ACR responses at 24 weeks in
RF-positive versus RF negative patients (ITT)
RF-positive (ITT) RF-negative (ITT)
plt0.0001
54
plt0.0009
41
plt0.0001
29
NS
19
plt0.0001
17
p0.045
13
12
9
6
5
2
0
(Cohen et al, in press Roche, data on file)
59
REFLEX study Efficacy is optimized when used
early in the biological treatment algorithm
Evaluable patients placebo (n121), rituximab
(n179) placebo (n80), rituximab (n119)
(Kremer et al, 2006)
60
REFLEX study ACR20 at 24 weeksby TNF inhibitor
IR category
Patients ()
n180
n273
n42
n56
IR inadequate response
(Roche, data on file)
61
REFLEX study results at 48 weeks
Long term follow-up
(patients and investigators blinded)
Week 24 Primary endpoint
Rituximab 1000 mg x 2 MTX (n308)
Week 48 completers, n ()
114 ( 37)
Placebo MTX (n209)
24 (11)
Week 16
8 TJC and 8 SJC eligibility for receiving
repeat course
Rescue treatment with rituximab 1000 mg x 2 MTX
(Cohen et al, 2006)
62
REFLEX study results at 48 weeks sustained
response after the first course
Completing Week 48 Placebo MTX (n24)
(11) Rituximab MTX (n114) (37)
Patients ()
Observed data
(Cohen et al, 2006)
63
REFLEX study response is optimal at 24 weeks
Non-responder imputation
(Cohen et al, 2006)
64

• Radiological assessment at 56 weeks

65
REFLEX study patient disposition after 24 weeks
Phase III REFLEX n463
Rituximab 1 g x 2 MTX n277
Double-blind treatment
n128
n67
n83
Placebo MTX n186
Open-label treatment rituximab 1 g x 2 MTX
Rescue treatment with rituximab 1 g x 2 MTX,
n83
n22
Repeat treatment extension n217
Numbers represent patients with radiographic
data available at 56 weeks
(Roche, data on file)
66
REFLEX study radiological assessment methods

• Radiographs were scored by two independent
  assessors (blinded to treatment, sequence and the
  relative timing of the assessments) using the
  Sharp method as modified by Genant
• This method allows quantitative analysis of two
  different aspects of joint damage
• Joint erosions (representing direct invasion of
  cartilage and bone by proliferating synovial
  pannus)
• Joint space narrowing (representing destruction
  of surface cartilage)

67
REFLEX study patient disposition over 56 weeks
No. of patients No. of patients
Placebo (n186) Rituximab (n277)
Completed 56 weeks 141 (76) 202 (73)
Withdrew 46 (25) 75 (27)
Withdrew and received treatment with TNF inhibitor 12 (6.5) 29 (10.5)
Patients with radiographic data available at 56
weeks
(Roche, data on file)
68
REFLEX study patient treatment
Placebo (n186) Rituximab (n277)
Completed 56 weeks (placebo only) 36 (19) NA
1 course of rituximab 118 (63) 149 (54)
2 courses of rituximab 31 (17) 110 (40)
3 courses of rituximab 1 (lt1) 18 (6)
(Roche, data on file)
69
REFLEX study significant inhibition of
radiological progression at 56 weeks
p0.0043
p0.0106
Mean change from baseline
p0.0007
Patients with initial and at least 1 follow up
with linear extrapolation as required
(Keystone et al, 2006)
70
REFLEX study patients with no radiographic
changes at 56 weeks
p0.0445
Placebo (n184)
Rituximab 1000 x 2 (n273)
70
p0.0904
61
60
53
52
46
50
40
Patients ()
30
20
10
0
No change in erosion score
No change in total Genant-modified Sharp score
Missing values were imputed using linear
extrapolation from baseline and Week 24
radiographs
(Keystone et al, 2006)
71
REFLEX study summary

• In patients with long-standing disease who had an
  inadequate response or intolerance to TNF
  inhibitor therapies, a first course of 2
  infusions of rituximab administered 2 weeks apart
  provided
• First signs of treatment response from 4 to 8
  weeks
• Statistically significant and clinically
  meaningful improvement in the signs and symptoms
  of RA as measured by ACR response and DAS28 at 24
  weeks

(Cohen et al, 2006)
72
REFLEX study summary (contd)

• Sustained clinical response through to Week 48
  only in a subset of patients, while the majority
  required a repeat treatment course between 24 and
  48 weeks
• Rituximab significantly inhibits radiographic
  progression in RA patients with an inadequate
  response or intolerance to 1 or more TNF
  inhibitor
• A unique finding in this patient population

(Cohen et al, 2006)
73

• Efficacy of repeated courses of rituximab in RA

74
Repeat treatment courses with rituximab
Course Patients (n)
1 1039
2 570
3 191
4 40
(van Vollenhoven et al, 2006)
75
Subset analysis for efficacy
Patients receiving 2 or more courses of
rituximab (1 g x 2) MTX with an IR to TNF
inhibitors
1 or more courses of rituximab
2 or more courses of rituximab
No. patients who have reached 24 weeks
follow-up post second course
279
158
1039
570
146 patients who had initially received
rituximab (0.5 g x 2) MTX or rituximab
monotherapy were excluded from the efficacy
analyses
99
145
Patients receiving 2 or more courses of rituximab
(1 g x 2) MTX with an IR to DMARDs
(Emery et al, 2006 Keystone et al, 2006)
76
Eligibility criteria for repeated treatment

• Initial criteria
• Completed ?24 weeks in their initial study
• 50 improvement in both SJC and TJC
• Evidence of returning peripheral B cells
• Exhibited returning clinical symptoms of RA
• These initial criteria were then amended
• Patients had shown a defined improvement
  following a single course of rituximab given
  within the initial study
• ?20 reduction in both SJC and TJC (at the same
  time) during any visit from Week 16 onwards
• SJC 8 (66 joint count) and TJC 8 (68 joint
  count)
• Additional treatment courses were administered at
  the treating physicians discretion

(Emery et al, 2006 Keystone et al, 2006)
77
Consistent time interval between treatment courses
Time to subsequent treatment course
43.0
36.7
30.9
30.1
Median duration (weeks)
(van Vollenhoven et al, 2006)
78

• Efficacy of repeated courses of rituximab in
  patients with an inadequate response or
  intolerance to TNF inhibitor therapy

79
Efficacy is maintained or further improved with
repeat treatment courses
Prior TNF inhibitor population
Versus original baseline
(Keystone et al, 2006)
80
Quality of life is maintained or further improved
with repeat treatment courses
Prior TNF inhibitor exposure population Mean
change in mental and physical components of the
SF-36 at 24 weeks
Versus original baseline
(Tak et al, 2006)
81

• Efficacy of repeated courses of rituximab in
  patients with an inadequate response to DMARD
  therapy

82
Efficacy is maintained or further improved with
repeat treatment courses
DMARD IR population
Versus original baseline
(Emery et al, 2006)

83
Efficacy is maintained or further improved with
repeat treatment courses

DAS low disease
DAS remission
Patients ()
Patients ()
Time (weeks)
Time (weeks)
Versus original baseline (DMARD-IR population)
(Roche, data on file)
84
Long-term efficacy of rituximab in RA
conclusions

• A second course of rituximab not only maintains
  but further improves response
• These findings are consistent across different
  patient populations
• Most patients received a second treatment course
  2448 weeks after their first treatment course

(Emery et al, 2006 Tak et al, 2006 Keystone et
al, 2006 van Vollenhoven et al, 2006)
85
Safety and tolerability of rituximab in RA
86
Safety and tolerability of rituximab in RA

• First course during placebo-controlled study
  periods
• Repeated courses
• Events of interest

87
Duration of rituximab exposure (as of October
2005)
Duration of observation Patients (n)
Total (any duration) 1039
gt6 months 987
gt1 year 839
gt2 years 139
gt3 years 89
Total exposure 1669 patient-years
(Roche, data on file van Vollenhoven et al, 2006)
88
Adverse events (AEs) during double-blind study
periods (24 weeks)
Placebo MTX (n398) Rituximab MTX (n540)
AEs () 80 85
Serious AEs () 7 7
AEs leading to withdrawal () lt1 3
(Roche, data on file pooled safety analysis)
89
Most frequent AEs during double-blind study
periods (24 weeks)
Pooled Phase II Study Population Pooled Phase II Study Population Phase III Study Population Phase III Study Population
MTX Placebo N 189 n () Rituximab MTX N 232 n () MTX Placebo N 209 n () Rituximab MTX N 308 n ()
Hypertension 10(5) 22(9) 11(5) 21(7)
Nausea 14(7) 19(8) 5(2) 22(7)
Rash 6 (3) 18 (8) 9 (4) 17 (6)
Pyrexia 1(lt1) 12 (5) 7 (3) 15 (5)
Pruritis 1 (lt1) 14 (6) 4 (2) 12 (4)
Urticaria 0 2 (lt1) 3 (1) 10 (3)
Rhinitis 2 (1) 6 (3) 4 (2) 8 (3)
Throat irritation 0 5 (2) 0 6 (2)
Hot Flush 4 (2) 2 (lt1) 0 6 (2)
Hypotension 11 (6) 10 (4) 1 (lt1) 5 (2)
Chills 3 (2) 13 (6) 6 (3) 3 (lt1)
Adverse Reactions Occurring in at least 1 of
Rheumatoid Arthritis Patients and More Frequently
in Patients receiving MabThera during blinded
Phase II and III Clinical Studies
(SmPC MabThera July 2006)
90
Most frequent AEs during double-blind study
periods (24 weeks) (contd)
Pooled Phase II Study Population Pooled Phase II Study Population Phase III Study Population Phase III Study Population
MTX Placebo N 189 n () Rituximab MTX N 232 n () MTX Placebo N 209 n () Rituximab MTX N 308 n ()
Urinary tract Infections 8 (4) 14 (6) 17 (8) 15 (5)
Upper Respiratory Tract 28 (15) 31 (13) 26 (12) 48 (16)
Lower Respiratory Tract Infection/Pneumonia 10 (5) 9 (4) 5 (2) 8 (3)
Asthenia 0 3 (1) 1 (lt1) 6 (2)
Dyspepsia 3 (2) 9 (4) 0 7 (2)
Abdominal Pain Upper 3 (2) 7 (3) 1 (lt1) 4 (1)
Hypercholesterolemia 1 (lt1) 3 (1) 0 6 (2)
Arthralgia/musculoskeletal pain 8 (4) 18 (7) 6 (3) 17 (7)
Muscle Spasms 0 1 (lt1) 2 (1) 7 (2)
Osteoarthritis 1 (lt1) 4 (2) 0 6 (2)
Paraesthesia 2 (1) 4 (2) 1 (lt1) 8 (3)
Migraine 0 4 (2) 2 (1) 5 (2)
Adverse Reactions Occurring in at least 1 of
Rheumatoid Arthritis Patients and More Frequently
in Patients receiving MabThera during blinded
Phase II and III Clinical Studies
(SmPC MabThera July 2006)
91
Second and subsequent treatment courses are
better tolerated
(van Vollenhoven et al, 2006)
92
Second and subsequent treatment courses are
better tolerated
Course 1
Course 2
Course 3
n2239
n113
n101
n1618
n465
n551
of adverse events
No prioranti-TNF
Prioranti-TNF
No prioranti-TNF
No prioranti-TNF
Prioranti-TNF
Prioranti-TNF
Number of events reported for each course for
which a severity assessment was determined by the
investigator
(Roche, data on file)
93
Events of specific interest

• Ig counts
• Infections
• Protective immunity
• Infusion reactions
• Malignancies
• Human anti-chimeric antibody (HACA)
• Subsequent exposure to biological DMARDs

(Roche, data on file van Vollenhoven et al, 2006)
94
Similar B cell response across treatment courses
Weeks
(Roche, data on file)
95
Mean (SD) serum Ig levels tend to decrease but
remain within the normal range over 24 weeks
(REFLEX Study)
SD standard deviation
(Roche, data on file)
96
Proportion of patients with Ig concentrations
ltLLN at Week 24 by treatment course
Course 1 (n1039) Course 2 (n570) Course 3 (n191)
Total Ig ltLLN 0.1 0.7 -
IgG ltLLN 1.4 4.3 5.9
IgM ltLLN 10.3 18.5 23.5
All exposure population
(Roche, data on file)
97
Rate of serious infections before and after low
IgM detection
Prior to total IgM ltLLN (n207) After total IgM ltLLN (n207)
Total patient years 156.62 219.61
Number of serious infections 8 13
Serious infections per 100 patient-years (95 CI) 5.1 (2.6, 10.2) 5.9 (3.4, 10.2)
All exposure population
Serious and/or those requiring i.v. antibiotics
(van Vollenhoven et al, 2006)
98
Infections occurring during 24-week
placebo-controlled periods
Placebo MTX, n () (n398) Rituximab MTX, n () (n540)
All infections, n () 135 (34) 210 (39)
Serious infections, n () 5 (1) 10 (2)
The type and duration of infections were similar
between the rituximab and placebo groups
(Rituxan prescribing information)
99
Rates of infections and serious infections remain
unchanged with repeat treatment courses
Course 1 (n1039) Course 2 (n570) Course 3 (n191)
Patient years 1154.1 417.5 87.8
Infections, n 954 347 71
Infections/100 pt-yr (95 CI) 82.66 (77.58, 88.08) 83.11 (75.81, 92.34) 80.86 (64.09, 102.04)
Serious infections, n 59 19 5
Serious infections/100 pt-yr (95 CI) 5.11 (3.96, 6.60) 4.55 (2.90, 7.14) 5.69 (2.37, 13.68)
All exposure population
(van Vollenhoven et al, 2006)
100
Types of infection

• Most common infections were URTIs,
  nasopharyngitis and other infections commonly
  found in an RA population
• No opportunistic infection
• No cases of tuberculosis (TB)

(van Vollenhoven et al, 2006)
101
Most frequent infections during double-blind
study periods (24 weeks, incidence gt1)
REFLEX REFLEX Pooled Phase II Pooled Phase II
Patients with AE () Placebo MTX (n209) Rituximab MTX (n308) Placebo MTX (n189) Rituximab MTX (n232)
Nasopharyngitis 6 8 7 6
URTI 7 8 5 6
Bronchitis 6 4 2 2
Rhinitis 2 3 1 3
Herpes simplex 3 1 2 2
Conjunctivitis 1 2 lt1 lt1
Lower RTI (LRTI) 1 lt1 lt1 2
Acute bronchitis 0 lt1 1 2
Cystitis lt1 1 0 lt1
Gastroenteritis (viral) lt1 1 lt1 lt1
Fungal skin infection 1 1 0 lt1
Herpes zoster 1 0 0 1
Vaginal mycosis lt1 1 1 1
(SmPC MabThera July 2006)
102
Acquired immunity is maintained (Week 24, DANCER
study)
Mumps Varicella Tetanus
Influenza A Pneumococcus
Mean change in titre
(Roche, data on file van Vollenhoven et al, 2005)
103
The incidence of infusion reactions is reduced
from the second infusion
Patients ()
(Roche, data on file)
104
Most frequent symptoms of acute infusion
reactions (REFLEX study)
Placebo MTX (n209) n () Rituximab MTX (n308) n ()
Any reaction 38 (18) 72 (23)
Headache 10 (5) 15 (5)
Hypertension 4 (2) 9 (3)
Nausea 2 (lt1) 8 (3)
Tachycardia 7 (3) 3 (lt1)
Pruritus 2 (lt1) 7 (2)
Urticaria 1 (lt1) 7 (2)
Diarrhoea 1 (lt1) 5 (2)
Flushing 2 (lt1) 5 (2)
Pyrexia 1 (lt1) 5 (2)
Dizziness 4 (2) 4 (1)
Occurring in 2 of patients in either group
during or after the first infusion
(Cohen et al, 2006)
105
DANCER study i.v. glucocorticoid premedication
reduces the incidence of acute infusion reactions
Patients ()
(Emery et al, 2006) 
106
Acute infusion reactions requiring dose
modification during the placebo-controlled study
period
Pooled data Pooled data
Reactions requiring dose modificationa Placebo MTX, (n398) Rituximab MTX, (n540)
1st course 2 10
aDose modification defined as stopping, slowing
or interruption of the infusion
(Rituxan prescribing information)
107
Immunogenicity

• 96 (9.2) patients have detectable HACA at or
  after Week 24
• The proportion with detectable HACA does not
  significantly rise with repeated treatment
• One patient had a high HACA value (gt400,000
  units) associated with a grade 3 infusion
  reaction following the second infusion of a
  subsequent course
• This patient did not deplete B cells following
  repeated treatment after the development of HACA
• Remaining patients with detectable HACA depleted
  normally, responded normally and had no other AEs

HACA Human anti-chimeric antibodies
(van Vollenhoven et al, 2006)
108
Rituximab a large safetydatabase from oncology
patients

• First licensed in 1997 (USA) and 1998 (worldwide)
  for use in patients with non-Hodgkins lymphoma
  (NHL)
• To date, experience gained in more than 730,000
  patients

(Cohen et al, 2006)
109
TNF inhibitors subsequent to rituximab therapy

• 78 patients received subsequent TNF inhibitor
  therapy
• Etanercept (n23)
• Infliximab (n23)
• Adalimumab (n26)
• Multiple TNF inhibitors (n7)

(Breedveld et al, 2006 Roche, data on file)
110
Serious infection rate in 78 patients who
received TNF inhibitors subsequent to rituximab
Before TNF inhibitor After TNF inhibitor
Total patient exposure (years) 57.4 52.5
Serious infections (n) 3 4
Serious infections per 100 patient-years (n) 5.23 7.62
Serious infections per patient-year (95 CI) (n) 0.05 (1.7, 16.2) 0.08 (2.9, 20.3)
BSR biological register serious infection rate
with de novo TNF inhibitors 6.4 per 100
patient-years
(Breedveld et al, 2006 Dixon et al, 2005)
111
Summary of safety rituximab is generally well
tolerated

• Most AEs are mildmoderate in intensity and are
  easily managed
• Infusions reactions are mainly mildmoderate in
  intensity, easily managed and reduced with
  further infusions
• Premedication with i.v. glucocorticoids reduces
  the incidence of infusion reactions
• The incidence and type of infections seen with
  rituximab are consistent with those reported in
  the general RA population
• The rate of serious infections does not appear to
  increase with repeated courses

(Cohen et al, 2006 van Vollenhoven et al, 2006)
112
Summary of safety rituximab is generally well
tolerated (contd)

• Favourable safety profile is unchanged with
  repeated courses
• The Ig levels (mainly IgM) tend to decrease but
  generally remain within the normal range
• Low IgM levels are not associated with an
  increased rate of serious infections
• Low incidence of HACA
• HACA is generally not associated with clinical
  deterioration or an increased risk of infusion
  reactions

(Cohen et al, 2006 van Vollenhoven et al, 2006)
113

• Overall conclusions

114
Rituximab conclusions

• First and only selective B cell therapy
• Sustained efficacy in controlling signs and
  symptoms of RA after only 2 infusions of 1000 mg
  per treatment course
• Unique and positive evidence of radiographic
  progression inhibition at 1 year in a TNF
  inhibitor IR population

115
Rituximab conclusions (contd)

• Most patients that receive further treatment
  courses, receive it after 6 to 12 months, based
  on disease activity
• Efficacy is maintained or further improved with
  repeated treatment courses
• Favourable safety profile
• Incidence and severity of infusion reactions are
  reduced from the second infusion. Most reactions
  are mild to moderate in severity
• Serious infection rate lies within the range
  reported in the general RA population
• Safety profile is unchanged with repeated courses
  
• Low incidence of HACA, generally with no impact
  observed on efficacy or tolerability