Biologic License Application: anakinra (KINERET) for rheumatoid arthritis Arthritis Advisory Committee August 16, 2001
Jan 16, 2016
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.