Kineret anakinra: A Review of Safety Data

1
Kineret (anakinra)A Review of Safety Data

2
Kineret Recombinant N-Methionyl Human IL-1ra

• Recombinant nonglycosylated form of human
  interleukin-1 receptor antagonist (IL-1Ra)
• Produced by recombinant DNA technology in an
  Escherichia coli expression system
• 153 amino acids
• 17.3 kDa
• Similar to endogenous human IL-1Ra, except for
  the addition of a single methionine residue at
  its amino terminus

Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
3
Pharmacokinetic Properties of Anakinra

• Bioavailability 95 at subcutaneous (SC) dose
  of 70 mg
• Peak plasma concentration 37 h following SC
  administration at 12 mg/kg
• Terminal half-life 46 h after SC
  administration at 12 mg/kg
• Kidney is the major organ for clearance
• Subjects with end-stage renal disease on dialysis
  had substantially lower plasma clearance (18
  mL/min) and longer terminal half-life (7 h)
• Subjects with hepatic dysfunction also had lower
  clearance, which correlated with a decrease in
  plasma creatinine clearance
• No unexpected accumulation of anakinra observed
  after daily SC doses for up to 24 weeks
• Creatinine clearance and body weight are
  predictors of plasma clearance of anakinra

Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov Kineret? (anakinra) summary
of product characteristics.
4
Kineret? Studies in RA Patients A Large Safety
Database

Number of patients Placebo Kineret?
Randomised placebo-controlled 759 2338 studies
and extensions Supportive studies 3 193 Pharmacoki
netic studies 15 75 Total 777 2606
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
All Kineret? Trials
5
Significant Experience With Kineret

Number of patients Kineret? All
Kineret? Duration of exposure ?100
mg/day doses lt6 months 496 794 ?6 months 1379
1812 ?1 year 237 570 ?2 years 77 365 ?3 years
26 167 ?4 years 13 41 ?5 years 5 19
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
All Kineret? Trials
6
Kineret? Experience by Dose

Kineret? (mg/day) Placebo lt1
00 100 gt100 All (n 759) (n 610) (n
1367) (n 196) (n 2173) Total
exposure 296.2 214.7 559.3 70.9 845.0(patientyea
rs) Median patient 24.0 23.9 24.4 24.0 24.1expos
ure (weeks)
Includes studies 0560, 960180, 960182, 990145,
990757 Kineret? exposure in all RA Studies
1872.9 patientyears
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Five Placebo-Controlled Trials
7
Incidence of Adverse Events Was Similar With
Kineret and Placebo
Kineret?
(mg/day) Placebo lt100 100 gt100 AllPatients
() (n 759) (n 610) (n 1367) (n 196) (n
2173) Any AE 645 (85.0) 538 (88.2) 1254
(91.7) 190 (96.9) 1982 (91.2) AE excl. ISR 623
(82.1) 491 (80.5) 1088 (79.6) 169 (86.2) 1748
(80.4) Serious AE 49 (6.5) 51 (8.4) 97 (7.1) 24
(12.2) 172 (7.9) Death 1 (0.1) 1 (0.2) 4 (0.3) 1
(0.5) 6 (0.3) Withdrawal 88 (11.6) 58 (9.5) 186
(13.6) 36 (18.4) 280 (12.9)due to AE
Excludes one death in the Confirmatory Efficacy
Study (data remains blinded)
AE adverse event ISR injection site reaction
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Five Placebo-Controlled Trials
8
Incidence of Serious Adverse Events Was Similar
With Kineret and Placebo
Kineret? (mg/day) Placebo lt100
100 gt100 AllPatients () (n 759) (n 610) (n
1367) (n 196) (n 2173) Any serious AE 49
(6.5) 51 (8.4) 97 (7.1) 24 (12.2) 172
(7.9) Worsening of RA 12 (1.6) 10 (1.6) 10
(0.7) 1 (0.5) 21 (1.0) Pneumonia 0 (0.0) 2
(0.3) 9 (0.7) 0 (0.0) 11 (0.5) Abdominal pain 2
(0.3) 5 (0.8) 4 (0.3) 0 (0.0) 9
(0.4) Arthralgia 1 (0.1) 3 (0.5) 1 (0.1) 2 (1.0)
6 (0.3) Abdominal hernia 0 (0.0) 0 (0.0) 3
(0.2) 2 (1.0) 5 (0.2) Dyspnoea 0 (0.0) 1
(0.2) 4 (0.3) 0 (0.0) 5 (0.2)
AE adverse event
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Five Placebo-Controlled Trials
9
Injection Site Reactions Were the Main Reason for
Withdrawal From Kineret
Kineret?
(mg/day) Placebo lt100 100 gt100 AllPatients
() (n 759) (n 610) (n 1367) (n 196) (n
2173) Any withdrawal 88 (11.6) 58 (9.5) 186
(13.6) 36 (18.4) 280 (12.9) due to AEs ISR 10
(1.3) 8 (1.3) 100 (7.3) 14 (7.1) 122
(5.6) Worsening of 47 (6.2) 29 (4.8) 25 (1.8) 9
(4.6) 63 (2.9)RA/arthralgia Headache 4 (0.5) 0
(0.0) 8 (0.6) 0 (0.0) 8 (0.4) Abdominal pain 3
(0.4) 1 (0.2) 7 (0.5) 0 (0.0) 8 (0.4)
AE adverse event ISR injection site reaction
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Five Placebo-Controlled Trials
10
Most Injection Site Reactions With Kineret Were
Mild-to-Moderate in Severity
Kineret?
(mg/day) Placebo lt100 100 gt100 AllPatients
() (n 759) (n 610) (n 1367) (n 196) (n
2173) Any ISR 204 (26.9) 281 (46.1) 973
(71.2) 145 (74.0) 1399 (64.4)
Mild-to-moderate 198 (97.1) 276 (98.2) 923
(94.9) 134 (92.4) 1333 (95.3) Typical
presentation Erythema 35 (4.6) 150 (24.6) 505
(36.9) 90 (45.9) 745 (34.3) Pruritus 14
(1.8) 60 (9.8) 412 (30.1) 36 (18.4) 508 (23.4)
Rash 10 (1.3) 61 (10.0) 315 (23.0) 32 (16.3) 408
(18.8) Pain 93 (12.3) 37 (6.1) 250 (18.3) 10
(5.1) 297 (13.7) Ecchymosis 94 (12.4) 59
(9.7) 200 (14.6) 15 (7.7) 274 (12.6)
Incidence calculated for patients with an ISR
ISR injection site reaction
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Five Placebo-Controlled Trials
11
Example of a Moderate Injection Site Reaction
12
Injection Site Reactions With Kineret? Are Most
Likely to Occur Within the First 4 Weeks
0.40
Placebo
100 mg/day
0.35
0.30
0.25
Hazard Rate for ISRs
Hazard Rate for ISRs
0.20
0.15
0.10
0.05
0.00
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Study Week
ISR injection site reaction
Confirmatory Efficacy and Safety Studies
Data on file. Amgen Inc Thousand Oaks, Calif.
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Injection Site Reactions With Kineret Are
Generally Mild-to-Moderate and Generally Occur
Within the First 4 Weeks of Therapy

• 64 of patients experienced an injection site
  reaction (ISR) only 6 withdrew because of the
  event
• Approximately 95 of ISRs were mild-to-moderate
  in severity
• Onset of ISRs generally occurred within the first
  4 weeks of initiating therapy estimated median
  time to occurrence was 11 days
• Patients who do not experience an ISR within 4
  weeks of initiating therapy are unlikely to
  experience any ISR

Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Five Placebo-Controlled Trials
14
Managing Kineret Injection Site Reactions

• Apply a cold pack to the injection site 23
  minutes before and immediately after injection

• Bruising at the injection site

• Itching at the injection site

• Apply a topical hydrocortisone cream

• Apply a cold pack to the injection site
  immediately after injection

• Swelling at the injection site

• Try different injection sites the abdomen may be
  best because of the low number of nerve endings
• Warm Kineret? solution to room temperature before
  injecting
• Apply a cold pack to the injection site 23
  minutes before and immediately after injection
• Allow the alcohol at the injection site to dry
  before injection the alcohol may cause stinging

• Pain during and/or after injection

• Thoroughly inform patients about ISRs prior to
  initiating treatment

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Incidence of Any Infectious Episode Was Similar
With Kineret and Placebo
Kineret? (mg/day) Placebo lt100 1
00 gt100 AllPatients () (n 759) (n 610) (n
1367) (n 196) (n 2173) Any IE 275 (36.2) 227
(37.2) 544 (39.8) 84 (42.9) 855 (39.3)
Serious 5 (0.7) 7 (1.1) 25 (1.8) 4 (2.0) 36
(1.7) Withdrawal 6 (0.8) 3 (0.5) 16 (1.2) 2
(1.0) 21 (1.0)
IE infectious episode
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Five Placebo-Controlled Trials
16
Incidence of Common Infectious Episodes Was
Similar With Kineret and Placebo
Kineret? (mg/day) Placebo lt100 1
00 gt100 AllPatients () (n 759) (n 610) (n
1367) (n 196) (n 2173) URI 95 (12.5) 63
(10.3) 174 (12.7) 23 (11.7) 260
(12.0) Sinusitis 36 (4.7) 25 (4.1) 86 (6.3) 8
(4.1) 119 (5.5) Flu-like 35 (4.6) 29 (4.8) 74
(5.4) 14 (7.1) 117 (5.4)symptoms
URI upper respiratory infection
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Five Placebo-Controlled Trials
17
Serious Infectious Episodes No Reports of
Opportunistic Infections
Kineret? (mg/day) Placebo lt1
00 100 gt100 AllPatients () (n 759) (n
610) (n 1367) (n 196) (n 2173) Any serious
IE 5 (0.7) 7 (1.1) 25 (1.8) 4 (2.0) 36
(1.7) Pneumonia 0 (0.0) 2 (0.3) 12 (0.9) 0
(0.0) 14 (0.6) Cellulitis/abscess 1 (0.1) 1
(0.2) 7 (0.5) 1 (0.5) 9 (0.4) Other RI 2 (0.3) 2
(0.3) 3 (0.2) 1 (0.5) 6 (0.3) GI infection 1
(0.1) 0 (0.0) 3 (0.2) 0 (0.0) 3 (0.1) Bursitis 0
(0.0) 1 (0.2) 1 (0.1) 1 (0.5) 3 (0.1) UTI 1
(0.1) 1 (0.2) 0 (0.0) 1 (0.5) 2
(0.1) Osteomyelitis 0 (0.0) 0 (0.0) 2 (0.1) 0
(0.0) 2 (0.1) Pelvic inflammation 0 (0.0) 0
(0.0) 0 (0.0) 1 (0.7) 1 (0.1) Herpes zoster 0
(0.0) 0 (0.0) 0 (0.0) 1 (0.5) 1 (0.0)
No cases of Mycobacterium tuberculosis,
Pneumocystis carinii, Listeria monocytogenes, or
histoplasmosis
GI gastrointestinal IE infectious episode
RI respiratory infection UTI urinary tract
infection
Amgen Inc. Kineret? (anakinra) FDA arthritis
advisory board slides http//www.fda.gov/ohrms/do
ckets/ac/01/slides/3779s1_01_Amgen.PPT
Five Placebo-Controlled Trials
18
Mean White Blood Cell and Mean Neutrophil Counts
Remained Within the Reference Range With Kineret
Placebo (n 534) 100 mg/day (n 1366)
White Blood Cells
Neutrophils
11 10 9 8 7 6 5 4 3
8 7 6 5 4 3 2 1 0
Mean Count (x 103/?L) ? SE
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Study Week
Study Week
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Confirmatory Efficacy and Safety Studies
19
Mean Haemoglobin and Mean Platelet Counts
Remained Within the Reference Range With Kineret
Placebo (n 534) 100 mg/day (n 1366)
Platelet Count
Haemoglobin
15.9
400
374
15.5
348
15.1
322
14.7
296

Mean Count (x 103/?L) SE

14.3
270
Mean Haemoglobin (g/dL) SE
244
13.9
218
13.5
192
13.1
166
140
12.7
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Study Week
Study Week
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
Confirmatory Efficacy and Safety Studies
20
Neutrophil Count lt1.5 x 109/L Does Not Appear to
Increase Risk of Serious Infection With Kineret
Placebo
Kineret? ?1.5 x 109/L ?1.5 x 109/L ?1.5
x 109/L ?1.5 x 109/LPatients () (n 757) (n
2) (n 2126) (n 47) Serious 5
(0.7) 0 (0.0) 36 (1.7) 0
(0.0)infection Serious 0 (0.0) 0 (0.0) 14
(0.7) 0 (0.0)pneumonia
Amgen Inc. Kineret? (anakinra) FDA arthritis
advisory board slides http//www.fda.gov/ohrms/do
ckets/ac/01/slides/3779s1_01_Amgen.PPT
Five Placebo-Controlled Trials
21
Observed Incidence of Malignancies With Kineret
Was Similar to the Expected Incidence
All Kineret? patients Observed 95
CI Expected Total malignancies 16 9.70,
26.22 15.6 Leukaemias 0 0.00, 4.76 0.84
Non-Hodgkins lymphoma 1 0.00, 6.38 0.58 Women
All malignancies 9 4.51, 17.43 10.24 Breast
cancer 4 1.21, 10.76 3.53 Men All
malignancies 7 3.15, 14.70 5.38 Prostate
cancer 2 0.10, 7.84 1.82
Based on National Cancer Institute Surveillance
Epidemiology and End Results (SEER) statistics
CI confidence interval
Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
All Kineret? Trials
22
Development of Anti-Anakinra Antibodies Was
Transient and Not of Clinical Significance

• Only 0.8 of patients were positive in
  neutralising bioassay (10/1303 patients)
• Positive at only one time point in all 10
  subjects
• No apparent interference with efficacy or safety
  profile
• No clinical sequelae

Amgen Inc. Kineret? (anakinra) FDA Briefing
Information, August 16, 2001. Available at
http//www.fda.gov.
All Kineret? Trials
23
Kineret Has a Favourable Safety Profile

• Large Kineret safety database
• 2606 RA patients received at least one Kineret?
  dose
• 1873 patientyears total Kineret exposure
• includes patients on multi-drug RA therapy and
  with a range of comorbidities
• Most common adverse events associated with
  Kineret were injection site reactions and
  headaches
• Serious infections with Kineret at 100 mg/day
• low incidence Kineret (1.8), placebo (0.7)
• pneumonia (0.9) and cellulitis (0.3) most
  common
• no opportunistic infections reported
• a history of asthma may increase risk of serious
  infection
• Postmarketing data confirm that Kineret is well
  tolerated

Amgen Inc. Kineret? (anakinra) FDA Briefing
Information,http//www.fda.gov/ohrms/dockets/ac/01
/briefing/3779b1_01_Amgen.doc Periodic Safety
Update Report 1 for IL-1ra/anakinra (Kineret).
Amgen Inc. Thousand Oaks, Calif.
24
Special Warnings and Precautions for Use of
Kineret

• Allergic reactions
• rare in clinical trials
• Kineret should be discontinued in the event of
  severe allergic reaction
• Serious infections
• increased incidence of serious infection with
  Kineret relative to placebo in clinical trials
• caution should be exercised when administering
  Kineret in patients with a history of recurring
  infection or predisposition to infection
• Neutropenia
• Kineret should not be administered to patients
  with neutropenia
• Kineret should be discontinued in patients who
  become neutropenic during therapy

Kineret? Summary of Product Characteristics.
25
Special Warnings and Precautions for Use of
Kineret (continued)

• Immunosuppression
• use of Kineret in patients with pre-existing
  malignancy is not recommended
• Vaccinations
• live vaccines should not be administered
  concurrently with Kineret
• Elderly patients
• in clinical trials, no differences in efficacy
  and safety profile of Kineret were observed in
  patients ?65 years compared with younger patients
• caution should be exercised when administering
  Kineret in elderly patients because of increased
  incidence of infection in this population
• Concurrent Kineret and TNF antagonist treatment
• concurrent administration of Kineret Enbrel
  has been associated with an increased risk of
  serious infections and neutropenia compared with
  Enbrel alone
• concurrent administration of Kineret and Enbrel
  or other TNF antagonists is not recommended

Kineret? Summary of Product Characteristics.