1. Arthritis Advisory Committee August 16, 2001
Biologic License Application: anakinra (KINERET) for rheumatoid arthritis
Arthritis Advisory Committee
August 16, 2001

2. Anakinra: Proposed Indication
Kineret is indicated for the reduction in signs and symptoms of moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs). Kineret can be used alone or in combination with other disease‑modifying antirheumatic drugs (DMARDs).

3. Anakinra: Background
The agency accepted a BLA filing in December, 1999, that contained the results of 2 randomized trials in RA
At the time of BLA filing, the agency recommended that Amgen begin additional studies to address issues not covered by existing data

4. Background (cont.)
Amgen began several additional clinical trials in RA in 2000:
1 year trial of radiographic progression
6 month randomized safety study with long-term open-label extension
JRA
Combination with TNF antagonists

5. Kineret BLA
Upon review of the originally submitted data, the agency informed Amgen that the data were suggestive of biologic activity, but that additional safety and efficacy data would be needed
Amgen responded to agency request with data from 3 additional trials

6. Trials of Anakinra Study Phase Subjects Doses Notes 990145 3 506
100 mg
Clinical, x-ray EP
0560 2
473
30, 75, 150 mg
Phase 2 
960180
2/3
419
.04,.1, .4, 1, 2 mg/kg
Phase 2/3 
960182
141
2.5, mg
Lower doses
990757
1414
Safety 58
Open-label Enbrel combo

7. Study 990145 10 radiographic EP: 1 yr 10 clinical EP: 6 mo
Interim analysis of 506 subjects randomized as of May 18, 2000
Study remains blinded

8. 990145: Study Design
Patients with active RA,  1 bony erosion, on stable dose MTX
1:1 randomization to anakinra 100 mg sc qd or placebo
Independent blinded joint assessors
10 EP: ACR20 at 6 mo
* Stable doses of NSAIDs and low dose corticosteroids were allowed

9. 990145: Study Conduct Placebo Anakinra Randomized 253 (100%)
Received  1 dose
251 (99%)
250 (99%)
Completed 6 months
186 (74%)
197 (79%)
Reasons for not completing:
Adverse event
22 (9%)
33 (13%)
Subject request
29 (12%)
12 (5%)
RA progression
10 (4%)
3 (1%)
Death
0 (0%)
Other
6 (2%)
8 (3%)
The mean age was approximately 56 year old and the BL demographics were well balanced between study arms.

10. 990145: Baseline Disease Activity
Placebo (N=251)
Anakinra (N=250)
RF positive
196 (78%)
189 (76%)
NSAID use
194 (77%)
Corticosteroid use
131 (52%)
133 (53%)
MTX dose (mg/wk, mean)
15.6
Duration of RA (yrs, mean)
10.4
11.1

11. 990145: Disease Activity (cont.)
Placebo
(N=251)
Anakinra
(N=250)
TJC (0-68) 24 27
SJC (0-66) 20
MD global (0-100) 57
Patient global (0-100) 52 53
Pain, VAS (0-100) 56 59
HAQ (0-3)
1.3
1.4
CRP (mg/Dl)
2.6
2.7
ESR (mm/hr) 43 42

12. 990145: ACR Responses Placebo (N=251) Anakinra (N=250) P value ACR20
6 mo
22% (55)
38% (94)
P<0.001
ACR50
8% (20)
17% (43)
ACR70
2% (5)
6% (14)
Higher responses also seen in subjects without ISRs

13. 990145: Time Course

14. 990145: ACR Components Baseline (mean) Placebo (N=251) Anakinra
P value
TJC (0-68) 26
-8.6
-12
P=0.006
SJC (0-66) 20
-6.4
-6.8
P=0.7
MD global (0-100) 57
-20
-25
P=0.01
Patient global (0-100) 53
-8.9
-18
P<0.001
Pain (VAS, 0-100)
-19
P=0.003
HAQ (0-3)
1.3
-0.18
-0.29
P=0.02
CRP (mg/dL)
2.6
-0.10
-0.51
P=0.001
ESR (mm/hr) 42
-6.0
-16

15. 990145: Subset Analysis
Similar clinical response seen in patient populations subsetted by:
Male vs. female
Ethnicity
Disease duration < 15 yrs (upper quartile)
TJC > 30 (upper quartile)

16. 990145: Subset by Age
* Lower rates of response in the older age group were not noted in other studies

17. 990145: Subset by RF Status

18. 990145: Subset by ESR

19. Additional Efficacy Trials
Study 560 and : phase 2, 2/3 randomized, double-blind, placebo-controlled trials of anakinra
Both studies:
Active RA by ACR criteria
Stable NSAIDs and prednisone
6 months blinded therapy
Study 560 also assessed radiographic progression

20. Studies 560 & 960180 560 960180 Concomitant meds None Background MTX
10 endpoint
6 mo ACR 20
3 mo ACR20
Doses
30, 75, 150 mg sc qd
.04, .1, .4, 1, 2 mg/kg sc qd
Location
Europe
US, Canada, Australia
In study , 6 mo ACR20 was an important 20 endpoint
Compare doses to 145 study

21. Study 560: Patient Population
Similar baseline characteristics to with respect to: age, gender, corticosteroid use, RF+, baseline ESR
Differences noted in 560:
> 98% caucasian
Shorter duration of RA: 4 yrs vs. 11
86% caucasian in
TJC 35 in 560 vs. 27 in

22. 560: Clinical Responses Placebo (N=119) 30 mg 75 mg (N=116) 150 mg
Week 12
Responders (n)
23% (27)
34% (41)
33% (38)
p-value
0.053
0.075
0.103
Week 24
27% (32)
40% (47)
34% (39)
43% (49)
0.05
0.28
0.01
All the response rates are higher for anakinra than placebo, but the data show some inconsistency, with a lower response rate at 75 mg than at 30 mg. The p values shown are nominal values since the analytic plan did not describe a plan for adjusting for multiple comparisons
Improvements were seen in all the components of the ACR

23. Study
Similar baseline characteristics to with respect to: age, gender, RF+, baseline disease activity, ESR
Differences noted in :
Higher corticosteroid use: 64% vs. 53%
Shorter duration of RA: 7 years vs. 11

24. 960180: Clinical Responses Test for dose response: p=0.004 at 6 mo
Placebo
(N=48)
0.4 mg/kg
(N=55)
1.0 mg/kg
(N=59)
2.0 mg/kg
(N=46)
Week 24
% Responders (n)
23% (11)
36% (20)
42% (25)
35% (16)
Test using Agresti Coull method
Only top 3 doses shown
The 3 month data were also highly statistically significant
Improvements were seen in all components of the ACR criteria
Test for dose response: p=0.004 at 6 mo

25. 960180: Sustained Responses
RA guidance document recommends collection of response data during course of trial and not just at beginning and end
Defined as patients with ACR20 at 4/6 monthly assessments with 1 assessment at 6 months

26. Signs & Symptoms: Summary
Three randomized trials show a higher proportion of ACR20 responses in anakinra-treated subjects than placebo
Responses seen within weeks and maintained to 6 months
Effects seen on all components of ACR criteria
Consistent effects across subsets of baseline demographics and baseline disease states

27. Radiographic Progression: RA Guidance Document
A claim of inhibition of structural damage may be based on:
A demonstration of efficacy for signs & symptoms, and
A 1 year study showing a decrease in structural damage based on a validated index
* Before beginning a discussion of the x-ray data, I wish to discuss the requirements for a claim of inhibition of inhibition of structural damage based on RA guidance document
RA guidance doc based on consultations with this committee

28. 560: Radiographic Assessment
Hand, wrist x-rays obtained at baseline and 6 months
Analyses:
Change in Larsen score pre-specified
Change in Sharp scores measured in post-hoc re-analysis
Baseline and follow-up x-rays available for 74% of subjects (347 of 472)

29. 560: Larsen Scores ` Placebo 30 mg 75 mg 150 mg Randomized (N) 121 119
116
117
M-ITT (N) 83 89 86
Baseline (0-180)
Mean
15.4
16.7
14.9
12.1
Median 11 13 12 7
6 month change
6.5
3.5
4.2
3.9
p-value
0.07
0.15
0.09
HIGHLIGHT large amount of missing data
HIGHLIGHT These data do not support a claim of inhibition of radiographic progression because they are 6 month and not 12 month data as specified in the RA guidance document. Nonetheless, they can be considered as evidence supportive of the primary finding.
M-ITT defined as patients with baseline and 1 post-baseline film. Note that there is much missing data
Note that means of baseline data are higher than medians, indicating skewed data
Baseline data are generally well balanced, except for 150 mg group

30. FDA Analysis of Larsen Scores, Non-Parametric Analysis
Placebo
30 mg
75 mg
150 mg N 83 89 86
Mean
6.4
3.6
3.8
4.0
Median 6 3 2
P-valuea
0.04
0.02
0.06
* Wilcoxon test used
a Wilcoxon test

31. 560: Sharp Scores
Amgen conducted an analysis of the Sharp scores, which suggested differences between study arms
Limitations of analysis:
Post-hoc, exploratory
133 fewer subjects included in Sharp readings compared to Larsen readings

32. Radiographic Assessments: Summary
Prespecified analysis showed trends towards improved radiographic outcomes, but not statistically significant
Post-hoc analyses also suggest activity of Kineret in inhibiting radiographic progression at 6 months, but firm conclusions cannot be reached due to limitations of analysis

33. Safety: Overall Exposure
Study:
0560 &
990145
990757
Total
Total exposed
559
250
1116
1925
6 months or longer
318
197
875
1390
1 year or longer
175

34. 560 & : Deaths and SAEs
Deaths: None occurred on blinded portion of trials
Incidence of SAEs similar between placebo and anakinra arms
Incidence of serious infections:
17/1240 on anakinra (1%) vs. 1/243 on placebo (<1%)
Incidence of serious infection on anakinra is somewhat higher, but not statistically significant
The incidence of malignancy was within the expected range, but follow-up was only for 6 months.

35. 990145: Deaths and SAEs
1 death: 80 year old man, worsening of underlying chronic lung disease
SAE: 12 on anakinra; 8 on placebo
3 infectious SAEs on anakinra; 1 on placebo
No malignancies in anakinra arm
Death occurred after D/C’ing study drug, p 10 wks on anakinra
Serious infections in 2 subjects: 2 pneumonia; 1 pulmonary infection
Apart from infections, no pattern of increased SAEs with anakinra

36. Abnormal Lab Values
Leukopenia and mild increase in eosinophil counts only lab abnormalities noted
Leukopenia seen in 12% (85/696) with anakinra vs. 4% with placebo (10/195) in studies 560 &
8/696 (1%) discontinued for leukopenia (<3500/mm3)
1/3 in first 100 days; 1/3 in after >200 days
*The incidence of leukopenia was not increased in the MTX combination trial compared to the trial of anakinra monotherapy

37. Leukopenia
Most leukopenia was an increase of 1 grade (e.g. above 4400/mm3 to range)
11/696 (2%) patients went from normal to grade 2 (e.g. >4400/mm3 to )
In only 1 case was leukopenia associated with an infection: a non-serious UTI that resolved
ANC at time of withdrawal: 1,800/mm3

38. AEs Occurring at a Higher Frequency with Anakinra
Placebo (N=195)
All anakinra (N=696) %
ISR 26 58
Headache 6 12
Abdominal Pain 4 7
Rash 3 5

39. 990757: Randomized Safety Study
Double-blind, randomized, multicenter trial of safety of adding anakinra 100 mg sc qd to background anti-rheumatic medications
US, Europe and Australia, 169 sites
1414 subjects: 4:1 randomization
6 months controlled, then 3 years open-label

40. 990757: Study Design Patient population:
Active RA
Stable DMARD regimen for at least 3 months
No uncontrolled medical conditions or recent malignancies
DMARDs allowed as monotherapy or combination
TNF antagonists not permitted
Changes in NSAIDs, corticosteroids, DMARDs allowed as clinically indicated
* Also excluded CellCept, cyclophosphamide, Prosorba column, cyclosporine

41. 990757: Patient Population
Similar demographic characteristics to other RA trials
DMARDs
52% receiving MTX
16% on MTX + another DMARD (175/1116)
6% receiving MTX + 2 or more DMARDs (67/1116)
57% receiving corticosteroids
No imbalances noted in baseline disease activity or demographics
COPD, h/o pneumonia, asthma, CAD, DM were each present in 5-10% of subjects
* Most common anti-rheumatic meds: MTX (52%), HQ (22%), SSA (14%), Arava (10%) gold (4%), azathioprine (4%)

42. 990757: Study conduct 80% completed 6 months of blinded therapy
Withdrawal for AEs more common in anakinra arm: 12% vs. 6%
Most common AE leading to withdrawal with anakinra was ISRs: 7%
Withdrawal for disease progression more common with placebo 2% vs. 1%

43. 990757: Deaths and SAEs
4 deaths on anakinra and 1 on placebo (both <1%)
Similar rate of SAEs overall
More SAEs in GI system: 2% (20/1116) vs. <1% (1/283)
No predominant pattern
More pulmonary SAEs: 2% (18/1116) vs. <1% (1/283)
Difference related to infections
Deaths on Kineret: interstitial fibrosis, suicide, metastatic melanoma, UGI bleed
Malignancies were not observed at a higher frequency in the anakinra group than placebo, but follow-up is only 6 months. Cannot reach firm conclusions until long-term follow-up is completed.

44. 990757: Serious Infections
Overall infection rate similar between study arms: 41% on anakinra vs. 44% on placebo
Serious infection rate higher on anakinra than on placebo:
2% on anakinra (23/1116) vs. <1% on placebo (1/283)
Most common: pneumonia, cellulitis, osteomyelitis
* Serious infections defined as SAEs that were infectious

45. Serious Infections None of the serious infections were fatal
All resolved except one case of osteomyelitis
Atypical infections uncommon:
1 patient developed MAI 1 mo after discontinuation
1 patient developed legionella
None associated with leukopenia

46. Serious Infections: Risk Factors
% with serious infection
All anakinra
2% (23/1116)
Male
2.8% (8/282)
Female
1.8% (15/834)
Corticosteroids (CS)
Yes
3% (19/636) No
0.8% (4/480)
Asthma
5.5% (6/109)
1.7% (17/990)
Mean dose of CS 8 mg/d vs. 7. Serious infections not associated with doses >10
The incidence of serious infection was not increased in patients on CS who were also receiving DMARDs
Use of particular DMARDs not associated
Not assoc w older age group, higher BL disease activity

47. Study 2000125 (0125): Enbrel Combination
Open-label pilot study of safety
58 patient with active RA
Patients previously on Enbrel for  3 mo, but no other DMARDs
Anakinra 1 mg/kg sc qd for 6 mo
* Mean age 49, RA x 12 yrs, TJC 26, SJC 17

48. Study 0125 36% withdrew before 6 months (21/58) No deaths 7 SAEs
11 for AEs (19%), 8 for withdrawal of consent (14%)
No deaths
7 SAEs
4 infectious (7% of subjects)
2 pneumonia, 2 cellulitis
* 1 case of cellulitis was associated with an injection site abscess; the other was a case of facial cellulitis

49. 0125: Lab Abnormalities 5 lab toxicities ( in grade of 2 or more)
2 WBC, 2 lymphs
2 of the cases of leukopenia occurred in subjects who also developed serious infections:
Cellulitis
Pneumonia

50. Leukopenia and Serious Infections
Measurement 1 = BL, 2 = 1 mo, 3 = 2 mo
#1: pneumonia 15 d after 2nd measurement; #2 10 d after 3rd measurement

51. Serious Infections in Anakinra Trials
Study
# of patients
Incidence (%)
95% CI
All placebo
5/729
0.7% %
560, 0180, 145
14/946
1.5% %
990757
23/1116
2.1% %
4/58 7%
1.9-17%

52. Summary: Etanercept Combination Study
Data strongly suggest that there may be a somewhat higher incidence of serious infections when anakinra is given with etanercept
Concurrent leukopenia observed before serious infection in 2 patients
The widespread use of the TNF antagonists etanercept and infliximab raises concerns that they may be used in combination with anakinra, if it is approved

53. Summary of Safety Majority of patients develop mild-moderate ISR
Minority develop low-grade leukopenia
Higher incidence of serious infections in one large trial
Concerns about combination with TNF antagonists
Although anakinra was generally well tolerated, long-term safety has not been assessed.