Epratuzumab Demonstrates Clinically Meaningful Improvements in ...

Epratuzumab demonstrates clinically meaningful
improvements in patients with moderate-to-severe
systemic lupus erythematosus (SLE):
results from EMBLEM
Gordon C 1 , Petri M 2 , Kalunian K 3 , Strand V 4 , Houssiau F 5 , Pike M 6 ,
Kilgallen B 7 , Kelley L 7 , Wallace DJ 8
1
University of Birmingham, Birmingham, UK 2 The Johns Hopkins University, Baltimore, MD, USA;
3
UCSD School of Medicine, La Jolla, CA, USA; 4 Stanford University, Stanford, CA, USA; 5 Université
Catholique de Louvain, Brussels, Belgium; 6 Massachusetts General Hospital, Boston, MA, USA;
7
UCB, Smyrna, GA, USA; 8 UCLA, Los Angeles, CA, USA
The EMBLEM study was funded by UCB, Inc

Disclosures
Actelion
Amgen
Aspreva
Biogen
BMS
Genentech
GSK
HGS
Immunomedics
MedImmune
Merck Serono
Roche
UCB
Vifor Pharma
Consultant/received honoraria from UCB and Immunomedics

Epratuzumab
• Humanised IgG1
• Targetting-CD22 monoclonal
antibody
• Causes rapid but only partial
decrease in B cell numbers
• No obvious CDC and
apoptosis, but partial ADCC of
B cells in vitro
• Induces phosphorylation and
internalisation of CD22;
potential for effects on
signalling through CD22
• Alters expression of adhesion
molecules
• Modulates activation,
proliferation and migration of
B cells
Epratuzumab was licensed by Immunomedics to
UCB for all autoimmune disease indications
Fab
(CD22 binding)
IgG 1 Fc
Brown D, et al. Ann Rheum Dis 2010;69(Suppl3):490
Hu C, et al. Clin Exp Immunol 2009;157:181–190
Wallace DJ, et al. Arthritis & Rheum 2009;61:1168–1178
Levesque MC. Clin Exp Immunol 2009;157:198–208
Jacobi AM, et al. Ann Rheum Dis 2008;67:450–457
Daridon C, et al. Arthritis Res Ther 2010; 12:R204

Epratuzumab clinical trial program leading
up to EMBLEM
• Open-label pilot study suggested benefit in SLE
– few significant adverse events and no evidence of
immunogenicity
• In 2 placebo-controlled, randomized trials in moderate or severe
SLE, epratuzumab (360 or 720 mg/m 2 ) was associated with:
– clinically meaningful reductions in disease activity
– improved health-related quality of life
– reduced corticosteroid consumption compared with placebo
Dorner T, et al. Arthritis Res Ther 2006;8:R74
Petri M, et al. Arthritis Rheum 2008;57(suppl):1087
Strand V, et al. Arthritis Rheum 2008;57(suppl):1086
Wallace D, et al. Arthritis Rheum 2008;57(suppl):1088

EMBLEM study groups and design
A 12-week, multi-center, randomized, double-blind, placebo-controlled, phase IIb
study to assess the efficacy and safety of epratuzumab and to determine a dose
regimen in patients with moderate to severe SLE
Screening
Day –14 to –1
227 patients
randomized
Stratified by
disease
severity
and IS use
Double-blind period
Placebo, n=38
Epratuzumab 200 mg cd (100 mg EOW) n=39
Epratuzumab 800 mg cd (400 mg EOW) n=38
Epratuzumab 2,400 mg cd (600 mg weekly) n=37 a
Epratuzumab 2,400 mg cd (1,200 mg EOW) n=37
Epratuzumab 3,600 mg cd (1,800 mg EOW) n=38
Safety follow-up
or entry into
open-label
extension study
0 1 2 3 12
24
Primary end point
Infusions
Weeks
a
2 patients randomized but never received drug; safety population, n=225
cd = cumulative dose; EOW = every other week; IS = immunosuppressants

Key inclusion and exclusion criteria
Inclusion criteria
• Aged ≥18 years
• Positive for anti-nuclear antibody
(≥1:40) at screening
• Current SLE according to ACR
revised criteria (excluding neuro)
• BILAG level A in ≥1 body/organ
system or level B in ≥2 systems
involving mucocutaneous,
musculoskeletal or
cardiovascular/respiratory
• SLEDAI total score ≥6
• On stable dosages of oral
corticosteroids and antimalarials,
azathioprine, methotrexate or
mycophenolate
Exclusion criteria
• Active, severe neuropsychiatric SLE
• Renal impairment, any of:
– Active severe renal disease
(defined by BILAG renal level A
or Grade III or higher WHO
nephritis)
– Serum creatinine >2.5 mg/dL
– Significant serum creatinine
increase within the 28 days prior
to Visit 1 (screening)
– Proteinuria >3.5 gm/day
• Pregnant or lactating
• Evidence of an immunosuppressive
state

Patient disposition
Randomized (ITT)
n=227
Placebo
n=38
Epratuzumab
200 mg cd
(100 mg EOW)
n=39
Epratuzumab
800 mg cd
(400 mg EOW)
n=38
Epratuzumab
2,400 mg cd
(600 mg weekly)
n=37
Epratuzumab
2,400 mg cd
(1,200 mg EOW)
n=37
Epratuzumab
3,600 mg cd
(1,800 mg EOW)
n=38
Premature
discontinuations,
n=2 (5.3%):
adverse event ,
n=1;
lack of efficacy,
n=1
Premature
discontinuations,
n=6 (15.4%):
lack of efficacy,
n=3;
loss of efficacy,
n=2;
withdrew
consent, n=1
Premature
discontinuations,
n=6 (15.8%):
adverse event,
n=1;
lack of efficacy,
n=4;
protocol
violation, n=1
Premature
discontinuations,
n=8 (21.6%):
adverse event,
n=2;
lack of efficacy,
n=1;
loss of efficacy,
n=1;
protocol
violation, n=2;
other reasons,
n=2
Premature
discontinuations,
n=3 (8.1%):
adverse event,
n=1;
lack of efficacy,
n=1;
loss of efficacy,
n=1
Premature
discontinuations,
n=3 (7.9%):
adverse event,
n=1;
lack of efficacy,
n=1;
loss of efficacy,
n=1
Completed
12 weeks
n=36
(94.7%)
Completed
12 weeks
n=33
(84.6%)
Completed
12 weeks
n=32
(84.2%)
Completed
12 weeks
n=29
(78.4%)
Completed
12 weeks
n=34
(91.9%)
Completed
12 weeks
n=35
(92.1%)

Patient demographics and disease
characteristics
Epratuzumab
Epratuzumab
Placebo
(n=38)
600 mg weekly
(n=35)
1,200 mg EOW
(n=37)
Mean age (years)
41.1
36.8
37.2
Range
22–64
19–68
18–57
Female (%) 86.8 100 100
Racial group (%)
Caucasian/Black/Asian* 78.9/5.3/13.2 85.7/8.6/5.7 67.6/10.8/16.2
Mean total BILAG score a (SD) 15.6 (5.8) 14.34 (6.8) 14.9 (7.6)
Mean total SLEDAI score (SD) 15.5 (7.1) 14.4 (8.5) 16.02 (6.2)
Immunosuppressants (%) 47.4 37.1 48.6
Anti-malarials (%) 47.4 45.7 48.6
Corticosteroid use (mg/day prednisone equivalent)
Mean (SD) 13.4 (10.6) 13.2 (10.6) 16.1 (9.9)
Dosage >30 mg/day (%) 7.9 8.6 2.7
*Asian included Indian and Hong Kong sites.
a
Total BILAG-2004 index score based on convention of A=9; B=3; C=1; D=0; E=0
BILAG, British Isles Lupus Assessment Group; SD, standard deviation; EOW, every other week;
SLEDAI, SLE Disease Activity Index

Severe (BILAG A) disease at baseline
(safety population)
• 71% of patients with ≥1 BILAG-2004 index A score
• Most patients had BILAG A and B disease in multiple systems at baseline
BILAG body/organ
system (severe
disease can be
present in >1 system)
Placebo
(n=38)
Emab
100 mg
EOW
(n=39)
Emab
400 mg
EOW
(n=37)
Emab
600 mg
weekly
(n=35)
Emab
1,200 mg
EOW
(n=37)
Emab
1,800 mg
EOW
(n=39)
Mucocutaneous (%) 42.1 35.9 32.4 34.3 24.3 28.2
Musculoskeletal (%) 26.3 41.0 24.3 34.3 35.1 30.8
Cardiorespiratory (%) 23.7 12.8 21.6 11.4 16.2 28.2
Neuropsychiatric (%) 2.6 5.1 13.5 0 5.4 17.9
Constitutional (%) 2.6 5.1 2.7 2.9 5.4 0
Renal (%) 0 0 2.7 0 0 0
Ophthalmic (%) 0 0 2.7 2.9 0 0
Gastrointestinal (%) 2.6 0 0 2.9 0 2.6
Hematological (%) 0 0 2.7 0 0 0
Emab = epratuzumab; EOW = every other week

Primary end point: a combined responder index
“BILAG-based Combined Lupus Assessment”
(BICLA) at Week 12
Definition of a BICLA treatment response:
Improvement:*
1 All BILAG a level A scores improved to B/C/D and
2 All BILAG a level B scores improved to C/D
No worsening:*
1 No single new BILAG A & not > 1 new BILAG B scores and
2 No worsening of baseline SLEDAI total score and
3 No worsening in PGA (< 10% worsening from baseline)
No treatment failure*: Treatment failure defined as non-protocol treatment, e.g.
new or increased immunosuppressants or antimalarials;
and no requirement for prohibited concomitant medications
*Each requirement includes those listed below it in the table, i.e. improvement also
requires no worsening and no treatment failure.
a
BILAG-2004 version, scored by independent central efficacy reader

BICLA response at Week 12
(ITT population)
p=0.03
p=0.07
p=0.02
Placebo Emab Emab Emab Emab Emab Emab
(n=38) 100 mg 400 mg 600 mg 1,200 mg 2,400 mg 1,800 mg
EOW EOW weekly EOW combined EOW
(n=39) (n=38) (n=37) a (n=37) (n=74) (n=38)
a
2 patients randomized but not treated
Emab = epratuzumab; EOW = every other week
p values were not adjusted for multiple comparisons and are based on an exploratory post-hoc analysis
p value for all 6 treatment arms for overall treatment effect assessed in primary analysis = 0.148

Odds ratios and 95% confidence intervals
vs placebo (ITT population)
Emab 1,800 mg EOW (n=38)
1.2
Emab 2,400 mg combined (n=74)
Emab 1,200 mg EOW (n=37)
Emab 600 mg weekly (n=37) a
2.6
2.9
3.2
p=0.02
vs placebo
p=0.07
vs placebo
p=0.03
vs placebo
Emab 400 mg EOW (n=38)
1.3
Emab 100 mg EOW (n=39)
1.7
-1 0 1 2 3 4 5 6 7 8 9 10
Odds ratio versus placebo
a
2 patients randomized but never received drug
Emab = epratuzumab; EOW = every other week
p values were not adjusted for multiple comparisons and are based on an exploratory post-hoc analysis
p value for all 6 treatment arms for overall treatment effect assessed in primary analysis = 0.148

Responders (%)
BICLA response rates
at Weeks 8 and 12 (ITT population)
50
40
Week 8
Week 12
37.8
45.9
35.1
40.5
30
20
21.1
21.1
30.8
30.8
28.9
26.3
18.4
23.7
10
0
Placebo Emab Emab Emab Emab Emab
(n=38) 100 mg 400 mg 600 mg 1,200 mg 1,800 mg
EOW EOW weekly EOW EOW
(n=39) (n=38) (n=37) a (n=37) (n=38)
Clinically meaningful responses observed at Week 8, with further improvement to Week 12
a
2 patients randomized but never received drug
EOW = every other week

Responders (%)
BILAG and enhanced BILAG
improvement (Week 12, ITT population)
70
60
BILAG response (primary end point)
Enhanced BILAG response
62.1
50
44.1
40
30
30.6
36.4
34.4
28.6
20
10
0
22.2
27.3
12.5
37.9 35.3
Placebo Emab Emab Emab Emab Emab
(n=38) 100 mg 400 mg 600 mg 1,200 mg 1,800 mg
EOW EOW weekly EOW EOW
(n=39) (n=38) (n=37) a (n=37) (n=38)
22.9
a
2 patients randomized but never received drug
Enhanced BILAG response = BILAG A/B scores at study entry in all body systems improving to C/D,
with ‘no BILAG worsening’ in other BILAG organ systems (no new BILAG A or ≥2 new BILAG B scores)
EOW = every other week

Improvement from baseline to Week 12 in
mucocutaneous body system
A (very active)
B (moderate activity)
C (mild activity)
D (no activity but
previously affected)
Placebo
(n=31) a
Epratuzumab
600 mg weekly
(n=32) a
Epratuzumab
1,200 mg EOW
(n=32) a
a
Number of patients with BILAG A/B at baseline (ITT population)

Improvement from baseline to Week 12 in
musculoskeletal body system
A (very active)
B (moderate activity)
C (mild activity)
D (no activity but
previously affected)
Placebo
(n=31) a
Epratuzumab
600 mg weekly
(n=35) a
Epratuzumab
1,200 mg EOW
(n=34) a
a
Number of patients with BILAG A/B at baseline (ITT population)

Improvement from baseline to Week 12 in
cardiorespiratory body system
A (very active)
B (moderate activity)
C (mild activity)
D (no activity but
previously affected)
Placebo
(n=17) a
Epratuzumab
600 mg weekly
(n=7) a
Epratuzumab
1,200 mg EOW
(n=9) a
a
Number of patients with BILAG A/B at baseline (ITT population)

Treatment-emergent adverse events
(safety population)
Placebo
(n=38)
Epratuzumab
600 mg
weekly (n=35)
Epratuzumab
1,200 mg EOW
(n=37)
Patients reporting ≥1 AE (%) 71.7 77.1 78.4
Infusion reactions (%) 10.5 14.3 16.2
AEs leading to discontinuation (%) 5.3 2.9 2.7
Drug-related AEs (%) 21.1 37.1 43.2
AEs possibly indicative of infection (%) 39.5 45.7 43.2
SAEs (%) 7.9 8.6 10.8
AE = adverse event; Emab = epratuzumab; EOW = every other week;
SAE = serious adverse event

Conclusions
• Epratuzumab at a cumulative dose of 2,400 mg* was associated
with meaningful and statistically significant improvements in
disease activity
– Epratuzumab 600 mg weekly associated with greater improvement
in BILAG-2004 scores (from A/B to C/D) than placebo in all 6
affected body systems
– Responder rates were more than twice those of placebo
• Epratuzumab was well tolerated
– Incidence of AEs comparable to placebo with no new
safety signals
• EMBLEM is the first study to use BICLA
– a BILAG-2004 index based composite end point
*Cumulative dose of 2,400 mg includes patients who received epratuzumab 600 mg weekly for 4 weeks
and patients who received epratuzumab1,200 mg every other week (EOW) for 2 weeks