Kineret anakinra: A Review of Clinical Efficacy The Methotrexate Combination Study

1
Kineret (anakinra)A Review of Clinical
EfficacyThe Methotrexate Combination Study

2
Kineret Has Been Evaluated in Five Randomised,
Placebo-Controlled Trials
n
Daily doses of Kineret
Description
Study
472
European Monotherapy Study
0560
30, 75, 150 mg
2.5, 10, 30 mg
141
Low Dose Monotherapy Study
960182
2.5, 10, 30 mg
419
MTX Combination Therapy Study
960180
0.04, 0.1, 0.4, 1.0, 2.0 mg/kg
501
100 mg
Confirmatory Efficacy Study
990145
1399
100 mg
Safety Study
990757
n number of patients who received at least one
dose of study drug MTX methotrexate
Five Placebo-Controlled Trials
3
Patient Disposition in Kineret
Placebo-Controlled Trials

Study 0560 960182 960180 990145 990757 European
Low Dose MTX Confirmatory Safety Monotherapy
Monotherapy Combination Efficacy Total
randomised (n) 473 141 419 506 1414 Never
received drug (n) 1 0 0 5 15 Completed
() 72.9 87.9 79.0 75.7 78.1 Withdrew
() 27.1 12.1 21.0 24.3 21.9 Reason for
withdrawal () Adverse event 17.3 5.7 7.2 10.9 1
0.4 Lack of efficacy 5.5 3.5 8.4 2.6 1.3
Other 4.2 2.8 5.5 10.9 9.9 Death 0.0 0.0 0.0 0.0
0.3
n total number of patients enrolled MTX
methotrexate
Five Placebo-Controlled Trials
4
Baseline Demographics of Patients in Kineret
Placebo-Controlled Trials

Study 0560 960182 960180 990145 990757 Europea
n Low Dose MTX Confirmatory Safety Monotherapy
Monotherapy Combination Efficacy Patients
(n) 472 141 419 501 1399 Female
() 75.0 76.6 77.6 77.0 74.7 Caucasian
() 98.7 100.0 88.5 86.8 88.3 Age (mean
years) 53.1 52.2 52.5 56.3 54.8 Mean body weight
(kg) 69.6 70.1 78.6 81.1 76.8
n number of patients who received at least one
dose of study drug MTX methotrexate
Five Placebo-Controlled Trials
5
Baseline Disease Characteristics of Patients in
Kineret Placebo-Controlled Trials

Study 0560 960182 960180 990145 990757 European
Low Dose MTX Confirmatory Safety Monotherapy
Monotherapy Combination Efficacy Patients
(n) 472 141 419 501 1399 Duration of RA
(years) 4.0 3.5 7.4 10.8 10.3 TJC
(068) 34.3 33.0 25.4 25.6 22.6 SJC
(066) 26.1 23.7 18.3 20.0 18.7 HAQ
(03) 1.57 1.64 1.40 1.34 1.41 CRP
(mg/dL) 4.14 3.17 1.91 2.63 2.67 ESR
(mm/h) 49.5 43.2 36.7 42.2 N/A
n number of patients who received at least one
dose of study drug CRP C-reactive protein
ESR erythrocyte sedimentation rate HAQ
Health Assessment Questionnaire MTX
methotrexate SJC swollen joint count TJC
tender/painful joint count
Five Placebo-Controlled Trials
6
Concomitant Medications in Patients in Kineret
Placebo-Controlled Trials

Study 0560 960182 960180 990145 990757 European
Low Dose MTX Confirmatory Safety Monotherapy
Monotherapy Combination Efficacy Patients
(n) 472 141 419 501 1399 Use at baseline ()
Corticosteroids 42.6 44.0 64.2 52.7 57.8
NSAIDs 83.5 85.8 69.0 76.4 87.0 MTX
alone 0 0 100 100 31.1 Other DMARDs
0 0 0 0 25.4 excluding MTX MTX
other DMARDs 0 0 0 0 22.3
n number of patients who received at least one
dose of study drug DMARDs disease-modifying
antirheumatic drugs MTX methotrexate NSAIDs
nonsteroidal anti-inflammatory drugs
Five Placebo-Controlled Trials
7
MTX Combination Therapy StudyTrial Design

• Design randomised, double-blind,
  placebo-controlled
• Dosage placebo or Kineret at 0.04, 0.1, 0.4,
  1.0, or 2.0 mg/kg/day via subcutaneous injection
• Patients 419 patients with active disease
  receiving MTX 1525 mg/week
• Duration 12 weeks, amended to 24 weeks
• Location 36 centres in the USA, Australia, and
  Canada
• 1o endpoint ACR20 response at 12 weeks
• 2o endpoints ACR20 response at 24 weeks ACR50
  and ACR70 responses at 12 and 24 weeks

ACR American College of Rheumatology MTX
methotrexate
Cohen S, et al. Arthritis Rheum. 200246614-624.
MTX Combination Therapy Study
8
ACR20 Response With Kineret According to Study
Week Early Onset of Action
50



40


30
Patients Achieving an ACR20 Response ()

20
Placebo MTX 0.4 mg/kg MTX 1.0 mg/kg MTX 2.0
mg/kg MTX
10
0
0
4
8
12
16
20
24
2
6
10
14
18
22
Study Week
Intent-to-treat with non-responder imputation
ACR American College of Rheumatology MTX
methotrexate P lt0.05, P lt0.01, P 0.001 vs
placebo
Cohen S, et al. Arthritis Rheum. 200246614-624
Amgen Inc. Kineret?(anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
MTX Combination Therapy Study
9
Kineret Was Associated With a Dose-Related ACR20
Response Rate at Week 12
55 50 45 40 35 30 25 20 15 10 5 0
Overall dose response P 0.001
P 0.001
P 0.007
P 0.014
P 0.523
P 0.378
Patients Achieving an ACR20 Response () SE
46
37
35
25
25
19
Placebo MTX (n 74)
0.04 mg/kg MTX (n 63)
0.1 mg/kg MTX (n 74)
0.4 mg/kg MTX (n 77)
1.0 mg/kg MTX (n 59)
2.0 mg/kg MTX (n 72)
Intent-to-treat with non-responder imputation
ACR American College of Rheumatology MTX
methotrexate
MTX Combination Therapy Study
Cohen S, et al. Arthritis Rheum. 200246614-624.
10
Kineret Was Associated With a Dose-Related ACR20
Response Rate at Week 24
55 50 45 40 35 30 25 20 15 10 5 0
Overall dose response P 0.004
P 0.018
P 0.118
P 0.143
P 0.505
Patients Achieving an ACR20 Response () SE
P 0.538
42
36
35
30
23
19
Placebo MTX (n 48)
0.04 mg/kg MTX (n 63)
0.1 mg/kg MTX (n 46)
0.4 mg/kg MTX (n 55)
1.0 mg/kg MTX (n 59)
2.0 mg/kg MTX (n 46)
Intent-to-treat with non-responder imputation
ACR American College of Rheumatology MTX
methotrexate
MTX Combination Therapy Study
Cohen S, et al. Arthritis Rheum. 200246614-624.
11
A Sustained Clinical Response With Kineret Was
Achieved Over 24 Weeks
50 45 40 35 30 25 20 15 10 5 0
Overall dose response P 0.002
P 0.013
P 0.039
P 0.062
P 0.302
Patients Achieving a Sustained ACR20 Response ()
SE
P 0.687
35
31
30
22
15
13
Placebo MTX (n 48)
0.4 mg/kg MTX (n 55)
1.0 mg/kg MTX (n 59)
2.0 mg/kg MTX (n 46)
0.04 mg/kg MTX (n 63)
0.1 mg/kg MTX (n 46)
Intent-to-treat with non-responder imputation
sustained response ACR20 response for ?4 out
of 6 months, with at least one response at the
12- and 24-week time points ACR American
College of Rheumatology MTX methotrexate
MTX Combination Therapy Study
Cohen S, et al. Arthritis Rheum. 200246614-624.
12
Kineret Produced Dose-Related Improvements in
Clinical Response at Week 24
50 45 40 35 30 25 20 15 10 5 0
ACR20 ACR50 ACR70

Overall dose response P 0.003
42
36
35
30

24
23

Patients Achieving an ACR20 Response () SE
20
19
17
13

11
10
7
7
5
4
2
0
Placebo MTX
0.04 mg/kg MTX
0.1 mg/kg MTX
0.4 mg/kg MTX
1.0 mg/kg MTX
2.0 mg/kg MTX
Intent-to-treat with non-responder imputation
ACR American College of Rheumatology MTX
methotrexate P lt0.05 vs placebo
Cohen S, et al. Arthritis Rheum. 200246614-624
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
MTX Combination Therapy Study
13
Kineret Produced Improvements in Individual ACR
Criteria Components (1)
TJC
0 2 4 6 8 10 12 14 16
Placebo MTX 0.4 mg/kg MTX 1.0 mg/kg MTX 2.0
mg/kg MTX
Adjusted Mean Score
24
16
8
4
0
12
20
Study Week
Physician Global Assessment
0 4 8 12 16 20 24 28 32
Adjusted Mean Score




20
16
8
4
0
12
24
Study Week
Intent-to-treat Repeated Measures Mixed Model
ACR American College of Rheumatology CRP
C-reactive protein SJC swollen joint count
TJC tender/painful joint count P lt0.05, P
lt0.01, P lt0.001 vs placebo
Cohen S, et al. Arthritis Rheum. 200246614-624
Bresnihan B, Cobby M. Rheumatology.
200342(suppl 1)22-28.
MTX Combination Therapy Study
14
Kineret Produced Improvements in Individual ACR
Criteria Components (2)
Patient Global Assessment
Patient Pain Score
0 4 8 12 16 20 24
4 0 4 8 12 16 20 24 28
Placebo MTX 0.4 mg/kg MTX 1.0 mg/kg MTX 2.0
mg/kg MTX
Adjusted Mean Score
Adjusted Mean Score






0
16
8
4
12
20
24
24
0
16
8
4
12
20
Study Week
Study Week
HAQ
0
0.1
0.2
0.3
Adjusted Mean Score
Adjusted Mean Score


0.4




0.5
0.6
0
24
16
8
4
12
20
Study Week
intent-to-treat Repeated Measures Mixed Model
ACR American College of Rheumatology ESR
erythrocyte sedimentation rate HAQ Health
Assessment Questionnaire P lt0.05, P lt0.01,
P lt0.001 vs placebo
Cohen S, et al. Arthritis Rheum. 200246614-624
Bresnihan B, Cobby M. Rheumatology.
200342(suppl 1)22-28.
MTX Combination Therapy Study
15
EULAR Moderate or Good Response With Kineret at
Week 24
55 50 45 40 35 30 25 20 15 10 5 0
60
Patients Achieving a EULAR Moderate or Good
Response ()
56
48
49
48
38
37
Placebo MTX (n 48)
0.04 mg/kg MTX (n 63)
0.1 mg/kg MTX (n 46)
0.4 mg/kg MTX (n 55)
1.0 mg/kg MTX (n 59)
2.0 mg/kg MTX (n 46)
Intent-to-treat with non-responder imputation
EULAR European League Against RheumatismMTX
methotrexate
MTX Combination Therapy Study
Data on file. Amgen Inc Thousand Oaks, Calif.
16
Improvements in HAQ Disease Index With Kineret
Were Clinically Relevant
Study Week
0
4
8
12
16
20
24
Placebo MTX(n 74) 0.04 mg/kg MTX(n
63) 0.1 mg/kg MTX(n 74) 0.4 mg/kg MTX(n
77) 1.0 mg/kg MTX(n 59) 2.0 mg/kg MTX(n
72)
0
0.1
0.2

Mean Change From Baseline in HAQ Disease Index

0.3





0.4



0.5
0.6
Intent-to-treat analysis HAQ Health Assessment
Questionnaire MTX methotrexate P lt0.05, P
lt0.01 vs placebo
MTX Combination Therapy Study
Cohen S, et al Poster. EULAR June 13-16, 2001
Prague, Czech Republic.
17
Kineret Produced Improvements in Individual HAQ
Components Over Time (1)
Hygiene
Dressing and Grooming
0.3 0.2 0.1 0 0.1 0.2 0.3 0.4
0.1 0 0.1 0.2 0.3 0.4 0.5 0.6
Placebo MTX 1.0 and 2.0 mg/kg MTX
Change in HAQ Score
Change in HAQ Score


0
4
8
12
16
20
24
0
4
8
12
16
20
24
Study Week
Study Week
Reach
Arising
0.1 0 0.1 0.2 0.3 0.4 0.5 0.6
0.1 0 0.1 0.2 0.3 0.4 0.5 0.6
Change in HAQ Score
Change in HAQ Score


0
4
8
12
16
20
24
0
4
8
12
16
20
24
Study Week
Study Week
Intent-to-treat Repeated Measures Mixed Model
HAQ Health Assessment Questionnaire MTX
methotrexate P lt0.05, P lt0.01 vs placebo
Cohen S, et al Poster. EULAR June 13-16, 2001
Prague, Czech Republic.
MTX Combination Therapy Study
18
Kineret Produced Improvements in Individual HAQ
Components Over Time (2)
Eating
Grip
Placebo MTX 1.0 and 2.0 mg/kg MTX
0.1 0 0.1 0.2 0.3 0.4 0.5 0.6
0.1 0 0.1 0.2 0.3 0.4 0.5 0.6
Change in HAQ Score
Change in HAQ Score


0
4
8
12
16
20
24
0
4
8
12
16
20
24
Study Week
Study Week
Walking
Activities
0.1 0 0.1 0.2 0.3 0.4 0.5 0.6
0.1 0 0.1 0.2 0.3 0.4 0.5 0.6
Change in HAQ Score
Change in HAQ Score
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Study Week
Study Week
Intent-to-treat Repeated Measures Mixed Model
HAQ Health Assessment Questionnaire MTX
methotrexate P lt0.05, P lt0.01 vs placebo
Cohen S, et al Poster. EULAR June 13-16, 2001
Prague, Czech Republic.
MTX Combination Therapy Study
19
MTX Combination Therapy StudyKineret Improves
Signs and Symptoms of RA

• Kineret, in combination with MTX, improves HAQ
  scores in patients with RA
• Kineret, in combination with MTX, is effective
  in treating the signs and symptoms of patients
  with RA
• an ACR20 response was observed at 12 and 24 weeks
  in more Kineret recipients compared with placebo
  recipients
• ACR response was related to Kineret dosage
• an early onset of action was observed
• a sustained ACR20 response was shown
• an improvement in individual components of ACR
  criteria was demonstrated
• a moderate or good EULAR response was observed in
  more Kineret recipients compared with placebo
  recipients

ACR American College of Rheumatology EULAR
European League Against Rheumatism HAQ Health
Assessment Questionnaire MTX methotrexate
MTX Combination Therapy Study
20
Kineret is an Effective Treatment for RA

• Kineret, in combination with MTX, improves the
  signs and symptoms of RA
• improvements are statistically and clinically
  significant
• the effects of Kineret occur early in treatment
  and are sustained throughout treatment
• Kineret has a rapid and sustained effect on
  patient-reported outcomes
• Kineret, in combination with MTX, significantly
  improves HAQ scores in patients with RA

MTX methotrexate
21
Kineret is an Effective Treatment for RA

• Kineret, in combination with MTX, improves
  patient functionality and health-related quality
  of life
• Kineret, in combination with MTX, improves the
  signs and symptoms of RA
• improvements are statistically and clinically
  significant
• the effects of Kineret occur early in treatment
  and are sustained throughout treatment

MTX methotrexate