Biologic License Application:anakinra (KINERET) for

rheumatoid arthritisArthritis Advisory Committee

August 16, 2001

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).

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

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

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

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 2 141 2.5, 10 30 mg

Lower doses

990757 3 1414 100 mg Safety

20000125 3 58 100 mg Open-label Enbrel combo

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

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

990145: Study Conduct

Placebo Anakinra

Randomized 253 (100%) 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%) 0 (0%)

Other 6 (2%) 8 (3%)

990145: Baseline Disease Activity

  Placebo (N=251) Anakinra (N=250)

RF positive 196 (78%) 189 (76%)

NSAID use 194 (77%) 189 (76%)

Corticosteroid use 131 (52%) 133 (53%)

MTX dose (mg/wk, mean)

15.6 15.6

Duration of RA (yrs, mean)

10.4 11.1

990145: Disease Activity (cont.)

Placebo(N=251)

Anakinra(N=250)

TJC (0-68) 24 27

SJC (0-66) 20 20

MD global (0-100) 57 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

990145: ACR Responses

Placebo(N=251)

Anakinra(N=250)

P value

ACR20

6 mo 22% (55) 38% (94) P<0.001

ACR50

6 mo 8% (20) 17% (43)

ACR70

6 mo 2% (5) 6% (14)

990145: Time Course

990145: ACR Components

Baseline (mean)

Placebo(N=251)

Anakinra(N=250)

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) 57 -12 -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 P<0.001

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)

05

1015202530354045

AC

R20

Res

po

nse

s (%

)

< 65 yrs (N=365)

>=65 yrs (N=141)

Placebo

Anakinra

990145: Subset by Age

990145: Subset by RF Status

0

10

20

30

40

50

AC

R20

Res

po

nse

s (%

)

RF neg (N=103)

RF pos (N=385)

Placebo

anakinra

990145: Subset by ESR

0

5

10

15

20

25

30

35

40

ESR < 30(N=139)

ESR >=30(N=362)

Placebo

Anakinra

Additional Efficacy Trials

• Study 560 and 960180: 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

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

Study 560: Patient Population

• Similar baseline characteristics to 990145 with respect to: age, gender, corticosteroid use, RF+, baseline ESR

• Differences noted in 560:– > 98% caucasian– Shorter duration of RA: 4 yrs vs. 11

560: Clinical Responses

Placebo(N=119)

30 mg(N=119)

75 mg(N=116)

150 mg(N=117)

Week 12

Responders (n) 23% (27) 34% (41) 33% (38) 33% (38)

p-value 0.053 0.075 0.103

Week 24

Responders (n) 27% (32) 40% (47) 34% (39) 43% (49)

p-value 0.05 0.28 0.01

Study 960180

• Similar baseline characteristics to 990145 with respect to: age, gender, RF+, baseline disease activity, ESR

• Differences noted in 960180:– Higher corticosteroid use: 64% vs. 53%– Shorter duration of RA: 7 years vs. 11

960180: Clinical Responses

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 for dose response: p=0.004 at 6 mo

960180: Sustained Responses

0

10

20

30

40

50

60

70

80P

rop

ort

ion

of

Su

bje

cts

(%

)

Placebo 0.04mg/kg

0.1mg/kg

0.4mg/kg

1 mg/kg

2 mg/kg

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

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

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)

560: Larsen Scores` Placebo 30 mg 75 mg 150 mg

Randomized (N) 121 119 116 117

M-ITT (N) 83 89 89 86

Baseline (0-180)

Mean 15.4 16.7 14.9 12.1

Median 11 13 12 7

6 month change

Mean 6.5 3.5 4.2 3.9

p-value 0.07 0.15 0.09

FDA Analysis of Larsen Scores, Non-Parametric Analysis

Placebo 30 mg 75 mg 150 mg

N 83 89 89 86

Mean 6.4 3.6 3.8 4.0

Median 6 3 2 2

P-valuea 0.04 0.02 0.06

a Wilcoxon test

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

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

Safety: Overall Exposure

Study: 0560 & 960180

990145 990757 Total

Total exposed

559 250 1116 1925

6 months or longer

318 197 875 1390

1 year or longer

175 0 0 175

560 & 960180: 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%)

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

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 & 960180– 8/696 (1%) discontinued for leukopenia

(<3500/mm3) – 1/3 in first 100 days; 1/3 in after >200 days

Leukopenia

• Most leukopenia was an increase of 1 grade (e.g. above 4400/mm3 to 3300-4400 range)

• 11/696 (2%) patients went from normal to grade 2 (e.g. >4400/mm3 to 2200-3300)

• In only 1 case was leukopenia associated with an infection: a non-serious UTI that resolved– ANC at time of withdrawal: 1,800/mm3

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

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

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

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

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%

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

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

• 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

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 Yes 5.5% (6/109)

No 1.7% (17/990)

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

Study 0125

• 36% withdrew before 6 months (21/58)– 11 for AEs (19%), 8 for withdrawal of consent

(14%)

• No deaths

• 7 SAEs– 4 infectious (7% of subjects)– 2 pneumonia, 2 cellulitis

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

Leukopenia and Serious Infections

0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

1 s t 2 n d 3 r d

M e a s u r e m e n t s

AN

C (

/mm

3)

S u b j e c t 1S u b j e c t 2

Serious Infections in Anakinra Trials

Study # of patients Incidence (%)

95% CI

All placebo 5/729 0.7% 0.2-1.6%

560, 0180, 145

14/946 1.5% 0.8-2.5%

990757 23/1116 2.1% 1.3-3.1%

20000125 4/58 7% 1.9-17%

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

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.