Background Certolizumab pegol is a pegylated humanised Fab’ fragment of a monoclonal antibody...

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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

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

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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