Background Certolizumab pegol is a pegylated humanised Fab’ fragment of a monoclonal antibody...
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Transcript of Background Certolizumab pegol is a pegylated humanised Fab’ fragment of a monoclonal antibody...
Background
Certolizumab pegol is a pegylated humanised Fab’ fragment of a monoclonal antibody with high specificity for human TNF α
Phase II studies have demonstrated the efficacy and tolerability of sc certolizumab pegol 400mg 4-weekly (Q4W) in patients with moderate to severe Crohn’s disease (CD)
PRECiSE 1 and 2 are large well controlled studies demonstrating the safety and efficacy of certolizumab pegol in inducing and maintaining response and remission in patients with moderate to severe CD
UCB vision
To build a global biopharmaceutical leader,
based on unique blending of innovation,
entrepreneurship and proven experience,
bringing to specialists new medicines to
heal patients suffering from severe diseases
UCB: a biopharmaceutical leader
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2.1 Revenues 2004 (€ billion)
World pharmaceutical market: $500 billion(+ 8%)
Pharmaceuticals – Top 15 in 2003
Global sales range $ 2.5 – 9.2 billion
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Annual growth 46%
UCB key strengths
Leader in fields of epilepsy, allergy, and monoclonal antibody research
Proven productivity in research with an exciting pipeline
Global presence in over 40 countries
Strong partnerships and experienced management
Crohn’s disease
Chronic inflammatory disease of the gastrointestinal tract
considerable unmet need
Prevalence:
over 1 million patients worldwide
Only around 15% and around 8% of Crohn’s patients are currently treated with anti-TNFs in US and Europe respectively
Remicade® (infliximab), administered by infusion, the only anti-TNF biologic currently approved
Certolizumab Pegol (CIMZIATM), a humanised anti-TNF PEGylated Fab' fragment, is safe
and effective in the maintenance of response and remission following induction in active Crohn’s disease: a Phase III study
(PRECiSE 2)
Stefan Schreiber,1 Munaa Khaliq-Kareemi,2 Ian Lawrance,3 Stephen Hanauer,4 Juliet McColm,5 Ralph Bloomfield,5 William Sandborn6
1Christian-Albrechts-Univ., Kiel, Germany; 2Dalhousie Univ., Halifax, Canada; 3Univ. of Western Australia, Fremantle Hosp, Australia; 4Univ. of Chicago Medical Center, Chicago, USA; 5 UCB, Slough, UK; 6Mayo
Clinic, Rochester, USA
Background
Certolizumab pegol is a pegylated humanised Fab’ fragment of a monoclonal antibody with high specificity for human TNF α
Phase II studies have demonstrated the efficacy and tolerability of sc certolizumab pegol 400mg 4-weekly (Q4W) in patients with moderate to severe Crohn’s disease (CD)
PRECiSE 1 and 2 are large well controlled studies demonstrating the safety and efficacy of certolizumab pegol in inducing and maintaining response and remission in patients with moderate to severe CD
Aim
Determine the efficacy and safety of certolizumab pegol maintenance treatment compared to three doses of certolizumab followed by placebo in patients with moderate to severe Crohn’s disease
PRECiSE 2 study design
CDAI score 220–450 points inclusive
Stratified for:– CRP <10 mg/L or ≥10 mg/L– baseline steroids and
immunosuppressants
Respondersa
NonrespondersDiscontinue
Certolizumab Q4W
Placebo Q4W
Primary endpoint
a Defined as patients with ≥100-point fall from Week 0 CDAI score
Doses
Weeks 0 2 4 6 268 1612 20 24
IdentifyResponders,a
Randomise 1:1
Randomised, double-blind maintenance
phase
Certolizumab open-label
induction phase
Efficacy Measures
Primary efficacy: Clinical Response (≥ 100 point decrease from Baseline CDAI)
at Week 26 in patients with baseline CRP10 mg/L
Secondary efficacy (selected): Clinical Response (≥100 points) irrespective of baseline CRP Clinical Remission (CDAI≤150 points) in overall population and
in patients with CRP ≥ 10 mg/L Patients with change in IBDQ ≥ 16 points
Patient Disposition
Responders RandomizedN=428
Placebo n=212
(102,110)
Certolizumab n=216
(113,103)
ITTn=215
(112,103)
ITTn=210
(101,109)
Completed 26 weeksn=109 (51.9%)
(46 ;45.5%, 63; 57.8%)
Completed 26 weeksn=150 (69.8%)
(77; 68.8%, 73; 70.9%)
Entered InductionN=668
“n” for CRP≥ 10 /< 10
Demographic & Baseline Characteristics (ITT)
3 inj. + Placebo
(N=210)
Certolizumab
(N=215)
Age (years) Mean (SD) 37.6 (12.07) 37.5 (11.21)
Range 18-69 18-67
Gender Male 109 (51.9%) 92 (42.8%)
Female 101 (48.1%) 123 (57.2%)
Duration of Disease Mean 7.3 8.6
(years) Median 4.5 6.7
Range <1-43 <1-33
Resection Performed
Previous Infliximab
Yes
Yes
73 (34.8%)
51 (24.3%)
64 (29.8%)
52 (24.2%)
Concurrent Use of Crohn’s Treatment at Baseline* (ITT)
3 inj. + Placebo
(N=210)
Certolizumab
(N=215)
Corticosteroids (CS) 78 (37.1%) 75 (34.9%)
Mesalazine 82 (39.0%) 86 (40.0%)
Sulfasalazine 35 (16.7%) 32 (14.9%)
Immunosuppressants (IS) 86 (41.0%) 87 (40.5%)
AZA 62 (29.5%) 73 (34.0%)
MTX 9 (4.3%) 9 (4.2%)
6-MP 16 (7.6%) 6 (2.8%)
CS and IS 34 (16.2%) 28 (13.0%)
* Patients could be on multiple therapies
Clinical Response at Week 6, Open Label (All Patients, N=668)
64.1 63.4
0
20
40
60
80
100
All, N=668 CRP≥ 10, N=339
% o
f P
ati
en
ts
Certolizumab 400 mg at week 0, 2 and 4
Clinical Response at Week 26 (ITT)
36.2 33.7
62.8 61.6
0
20
40
60
80
100
All CRP≥ 10
% o
f P
ati
en
ts
3 inj. + Placebo Certolizumab 400 mg
N=210 N=215 n=101 n=112
p < 0.001 p <0.001
Clinical Response over Time CRP 10 (ITT)
0
20
40
60
80
100
6 8 10 12 14 16 18 20 22 24 26
Weeks
% o
f P
ati
en
ts
Certolizumab (n=112) 3 inj. + Placebo (n=101)
p < 0.001
† Non overlapping confidence interval
††
†
Clinical Response over Time All (ITT)
0
20
40
60
80
100
6 8 10 12 14 16 18 20 22 24 26
Weeks
% o
f P
ati
en
ts
Certolizumab (n=215) 3 inj. + Placebo (n=210)
p < 0.001
† Non overlapping confidence interval
††
† †
Clinical Remission at Week 26 (ITT)
28.6 25.7
47.942
0
20
40
60
80
100
All CRP≥ 10
% o
f P
ati
en
ts
3 inj. + Placebo Certolizumab 400 mg
N=210 N=215 n=101 n=112
p<0.01 p<0.01
Clinical Remission over Time CRP 10 (ITT)
0
20
40
60
80
100
6 8 10 12 14 16 18 20 22 24 26
Weeks
% o
f P
ati
en
ts
Certolizumab (n=112) 3 inj. + Placebo (n=101)
p < 0.01
† Non overlapping confidence interval
†
Clinical Remission over Time All (ITT)
0
20
40
60
80
100
6 8 10 12 14 16 18 20 22 24 26
Weeks
% o
f P
ati
en
ts
Certolizumab (n=215) 3 inj. + Placebo (n=210)
p < 0.001
† Non overlapping confidence interval
† †
Clinical Response at Week 26 by Use of Immunosuppressants (CRP≥10 mg/L, ITT)
26.8
38.3
62.2 61.2
0
20
40
60
80
100
With IS No IS
% o
f P
ati
en
ts
3 inj. + Placebo Certolizumab 400 mg
n= 41 n=45 n=60 n=67
p = 0.002 p = 0.014
Clinical Response at Week 26 by prior Anti-TNF Use
All (ITT)
39.6
25.5
68.7
44.2
0
20
40
60
80
100
No prior Anti-TNF Prior Anti-TNF
% o
f P
atie
nts
Placebo Certolizumab 400 mg
n=159 n=163 n=51 n=52
*
Patients with Increase in IBDQ ≥16 Points at Week 26 (ITT)
42.936.6
60.3 58.9
0
20
40
60
80
100
All CRP ≥ 10 mg/L
% o
f P
ati
en
ts
3 inj. + Placebo Certolizumab 400 mg
p<0.05p<0.001
N=210 N=214 n=101 n=112
Safety Profile – Open Label
Any AE
Intensity
Mild
Moderate
Severe
Related
SAE
AE leading to withdrawal
AE leading to death
Certolizumab (N=668)
1094 (392, 58.7%)
675 (290, 43.4%)
348 (193, 28.9%)
71 (54, 8.1%)
336 (161, 24.1%)
56 (47, 7.0%)
65 (51, 7.6%)
1 (1, 0.1%)
Number of AEs
(number of patients, % of patients)
Safety
Any AE
Intensity
Mild
Moderate
Severe
Related
SAE
AE leading to withdrawal
Certolizumab (N=216)
411 (140, 64.8%)
254 (105, 48.6%)
135 (70, 32.4%)
22 (16, 7.4%)
87 (49, 22.7%)
19 (12, 5.6%)
25 (18, 8.3%)
Number of AEs
(number of patients, % of patients)
3 inj. + Placebo (N=212)
394 (143, 67.5%)
211 (97, 45.8%)
154 (84, 39.6%)
29 (19, 9.0%)
120 (58, 27.4%)
19 (14, 6.6%)
34 (28, 13.2%)
Greater incidence of injections site reactions with placebo 1 case of TB Low incidence of antibodies to certolizumab (8%)
Conclusions
Treatment with certolizumab pegol 400 mg Q4W was superior in maintaining response and remission in patients with CD compared to three injections of certolizumab followed by placebo (p<0.001)
Efficacy (Response & Remission) statistically significantly different between maintenance with certolizumab and three injections of certolizumab followed by placebo, irrespective of baseline CRP Significant difference achieved in patients previously exposed
to infliximab
Certolizumab pegol was well tolerated and its safety profile did not identify any signals of concern