anakinra for the treatment of rheumatoid arthritis august 16, 2001

Anakinra for the Treatment of Rheumatoid Arthritis

August 16, 2001

Agenda

• Overview

– Roger M. Perlmutter, MD, PhD

• Clinical Experience

– Moraye Bear, MS, MA

– Pirow Bekker, MD, PhD

• Therapeutic Role of Anakinra

– Stanley Cohen, MD

Proposed Indication for Anakinra

Anakinra is indicated for the reduction in signs and symptoms of active rheumatoid arthritis, in patients 18-years of age or older who have failed 1 or more disease-modifying antirheumatic drugs (DMARDs).

Anakinra can be used alone or in combination with other DMARDs.

Cytokines and Cytokine Inhibitors in Rheumatoid Arthritis (partial list)

ReferencesFeldmann et al. (1993) Progress in Growth Factor Research 4, 247-255Feldmann et al. (1996) Annu. Rev. Immunol. 14, 397-440

Pro-Inflammatory Anti-Inflammatory

IL-1 IL-1Ra

TNF- p55-sTNF-RI

IL-6 p75-sTNF-RII

GM-CSF IL-10

IL-8 TGF

IL-1: A Proinflammatory Cytokine

Activates monocytes/

macrophages

Activates chondrocyt

Induces fibroblastproliferation

Activates osteoclasts

Inflammation Synovial pannus formation

Cartilage breakdown

Bone resorption

Fig. 4. Synergistic interaction between IL-1 and TNF.

The total numbers of PMNs ( ) or monocytes ( ) in the joint cavity 24 h after injecting 10 ng IL-1 , 250 ng TNF- or a combination of cytokines is shown.

The results are expressed as mean s.e.m. of 9 animals.

The figures in the lower part of the right hand columns give the degree of synergy compared with the sum of cellular accumulation produced by individual cytokines.

*P<0.02 compared to the number of PMN induced by IL-1. **P<0.001 compared to the number of monocytes induced IL-1.

infilt

ng leuco

IL-1 TNF- IL-1 IL-1 TNF- IL-1

TNF- TNF-+ +

2.8 1.6

Arthritogenic Actions of Recombinant IL-1 and

TNF in the Rabbit: Evidence for Synergistic Interactions Between Cytokines In Vivo

B.Henderson and E.R. Pettipher Clin. Exp. Immunol. 75 (1989) 306-310

IL-1 Induces Chronic Arthritis

• Repeated intra-articular injections of IL-1 in rat knees induces arthritis– Chandrasekhar et al. Clin. Immunol. Immunopathol. 1990, 55:382-

• Continuous infusion of IL-1 into rabbit knees induces arthritis– Feige et al. Int. J. Tiss. React. 1989, 11:225-38

• IL-1 injection or infusion triggers onset of arthritis in mice– Hom et al. J. Immunol. 1988, 141:834-841– Hom et al. Clin. Immunol. Immunopathol. 1990, 55:109-119

• Intraarticular expression of IL-1 in rabbit synovium by gene transfer induces arthritis

– Ghivizzani et al., J. Immunol. 1997; 159:3604-3612

• IL-1 transgenic mice develop arthritis early– Niki et al., J. Clin. Invest. 2001, 107:1127-1135

• Mice lacking IL-1ra develop spontaneous arthritis– Horai et al., J. Exp. Med. 2000; 191:313-320

Endogenous IL-1Ra:

A Naturally Occurring Antagonist of IL-1

• IL-1Ra

– Is a member of IL-1 family

– Is structurally related to IL-1

– Is produced constitutively and during inflammation

– Binds to IL-1 receptors (IL-1R)

– Occupies but does not activate IL-1R

– Does not allow docking of IL-1R Accessory Protein (AcP)

– Is a pure receptor antagonist

ACTIVATION ACTIVATIONBLOCKED

Nucleus Nucleus

SignalingSignaling No Signaling

IL-1RI IL-1RIIL-1R-AcP IL-1R-AcP

IL-1 IL-1Ra

Activated Macrophage

IL-1Ra Blocks Cellular Activation

Bresnihan. BioDrugs. 2001; 18:87-97.

Animal Models of Arthritis:

General Overview

Inject Type II collagen, or

Adjuvant

Arthritis develops

TherapeuticTreatment

Period

8 to 10 days 7 to 14 days

Anakinra Treatment

(SC, IP or infusion)

Assessments: paw swelling, histology, bone markers, x-ray

Collagen-Induced Arthritis:Treatment Effects on Inflammation

Bendele et al. Arthritis & Rheumatism 1999; 42: 498-506.

Day of Arthritis

0 1 2 3 4 5 6 7

Mean ±

e Join

0.04 mg/kg/hr

Untreated Normal

Vehicle

5 mg/kg/hr

1 mg/kg/hr

0.2 mg/kg/hr

N = 8 per group

*p < 0.05, 2-tailed t-test to vehicle control

Treatment

Collagen-Induced Arthritis:

Treatment Effects on Histological Scores

Bendele et al. Arthritis & Rheumatism 1999; 42:498-506. *p0.05, 2-tailed t-test to vehicle control

0 0.04 0.2 1 50

IL-1ra [mg/kg/hr]

INFLAMMATION SCORE

PANNUS SCORE

0 0.04 0.2 1 50

4CARTILAGE SCORE

0 0.04 0.2 1 50

IL-1ra [mg/kg/hr]

BONE DAMAGE SCORE

IL-1 and TNF: Proinflammatory Cytokines in the Rheumatoid Joint

Neutrophils

Capsule

SynovialSpace

SynovialMembrane

Osteoclasts

Cartilage

Osteoblasts

Chondrocytes

HighEndothelial

Venule

PGE2IL-8

PannusOsteoclasts Osteoblasts

TNF- IL-1

Amgen Inc. - unpublished dataAmgen Inc. - unpublished data

Differential Regulation of MMP-3 Production by IL-1 and TNF- in Human Chondrocytes

IL-1b IL-1b (pM)(pM) TNF-a TNF-a (pM)(pM)

IL-1 and TNF Play Different Roles in Various Models of Arthritis

Arthritis Model

Species Early Inflammation

Erosive Arthritis

TNF IL-1 TNF IL-1

SCW-A Mouse ++ - - ++SCW-flare

Mouse + + - ++

SCW-flare

Rat + + ++

AIA Mouse ± ± ++AIA Rabbit + + ± ++AIA flare Mouse ± + - ++CIA Mouse + ++ + ++ICA Mouse - ++ - ++AA Rat + + + +

See: W. van den Berg, Arthrit Res 3 (2001) 18-26

**p<0.05, 2-tailed p<0.05, 2-tailed tt-test to control-test to controlBendele et al. Arthritis Rheum. 2000; 43:2648-2659.Bendele et al. Arthritis Rheum. 2000; 43:2648-2659.

Treatment group

0 Arthritis Anakinra sTNF-RI Anakinra 100mg/kg +

control 100mg/kg 3mg/kg sTNF-RI 3mg/kg

Mean±

(0–5

) ankl

e join

InflammationPannusCartilage damageBone resorption*

Collagen-Induced Arthritis:

Anakinra and PEG sTNF-RI

Development of Anakinra:

Recombinant N-methionyl Human IL-1ra

• Gene isolated from IgG-stimulated human mononuclear phagocyte (monocyte) library (Eisenberg et al, 1990)

• Initial rDNA manufacturing process 1990

• Drug substance (active ingredient)

– Recombinant protein

– 153 amino acids

– 17.3 kd

• Final dosage form

– Daily injectable

– 100 mg, fixed dose, prefilled syringes

Preclinical Safety Studies of Anakinra

• Toxicity of anakinra has been studied in rats and macaques

– No neutralizing antibodies in studies up to 6-month duration

– Safety margins exceeded 90-fold in rats and 30-fold in monkeys based on AUC

– Tested alone and in combination with MTX, TNF inhibitors

• Animal studies have shown injection site inflammation, but no other target organ toxicity at any dose

Anakinra PK Profiles in RA Patients After SC Administration (Study 0501)

Time (h)

0 6 12 18 24

4000 0.5 mg/kg (n=4)1 mg/kg (n=4)2 mg/kg (n=4)4 mg/kg (n=4)6 mg/kg (n=4)

Regulatory Submissions

0560 960180 960182

December 1999 License Application

Selected Dose

100 mg/day

990757Safety

990145Efficacy and Safety

March 2001 Complete Response

Anakinra Rheumatoid Arthritis Patients

Number of Patients

Placebo Anakinra

Randomized placebo-controlled 759 2332studies and extensions

Supportive studies 3 199

Pharmacokinetic studies 15 75

Total 777 2606

Duration of Exposure in RA Patients

Number of Patients

All Anakinra

100 mg Doses

Duration of Exposure

< 6 months 484 795

6 months 1379 1791

1 year 237 551

2 years 77 351

3 years 26 160

4 years 13 41

5 years 5 19

Agenda

• Overview

Study Description Daily Doses of Anakinra N

0560 Monotherapy Study 0, 30, 75, 150 mg 472

960182Low Dose Monotherapy Study 0, 2.5, 10, 30 mg 141

960180 MTX Combination Study0, 0.04, 0.1, 0.4, 1.0, 2.0 mg/kg 419

990145Confirmatory Efficacy Study 0, 100 mg 501

990757 Safety Study 0, 100 mg 1399

Total293

Randomized Placebo-Controlled Trials

N = Number of subjects who received at least 1 dose of study drug.

Earlier Efficacy Studies

Signs & Symptoms

(150 mg/day)

RA Efficacy Trial Results

960182

Lower Doses Ineffective

( 30 mg/day)

Confirms Signs and Symptoms Efficacy

100 mg/day

Study 990145

960180

Signs & Symptoms

(1-2 mg/kg/day)

Patient Disposition

Baseline Demographics

Baseline Disease Status

Baseline RA Medications

Study Description N

0560 Monotherapy Study 472

960182 Low Dose Monotherapy Study 141

960180 MTX Combination Study 419

990145 Confirmatory Efficacy Study 501

990757 Safety Study 1399

Total293

Protocol 0560

Monotherapy Study

Design: Randomized, Blinded, Placebo-Controlled

Dosage: 0, 30, 75, 150 mg daily SC

No MTX or other DMARDs

Patients: 472

Duration: 24 weeks

Location: Europe

Primary endpoint: ACR20 at 24 weeks

Secondary endpoint: Larsen score at 24 weeks

(Radiographic endpoint)

Study 0560

Primary Endpoint: ACR20 at Week 24

M-ITT LOCF Imputation Proportion of Subjects Achieving an ACR20 Response at Week 24 (DRAFT)

/stat/il1ra/fda_slides/analysis/i0560/statfiles/graphs/g_acr20.sasBiostatistics: 03AUG2001

Placebo(N = 119)

30 mg(N = 119)

75 mg(N = 115)

150 mg(N = 115)

39%p = 0.047

34%p = 0.276

43%p = 0.014

Study 0560

ACR20 Response by Study Week

M-ITT LOCF Imputation Proportion of Subjects Achieving an ACR 20 Response (DRAFT)

/stat/il1ra/fda_slides/analysis/i0560/statfiles/graphs/unfinished/g_acr20_byvisiBiostatistics: 14MAY2001

Placebo (N = 119) 30 mg (N = 119)75 mg (N = 115) 150 mg (N = 115)

Study Week

0 2 4 6 8 10 12 14 16 18 20 22 24

Change From Baseline (M-ITT LOCF Repeated Measures Mixed Model)

Study 0560 Individual ACR Components by Study Week

Tender/Painful

0 4 8 12 16 20 24

Swollen

0 4 8 12 16 20 24

Physician's Global

0 4 8 12 16 20 24

Subject's Global

0 4 8 12 16 20 24

Subject's Pain

0 4 8 12 16 20 24

Log CRP

0 4 8 12 16 20 24

-16-14-12-10

-8-6-4-20246

0 4 8 12 16 20 24

Individual ACR Components Change From Baseline

Biostatistics: 24JUL2001 /stat/il1ra/fda_slides/analysis/i0560/statfiles/graphs/g_8endptsm.sas

___ Placebo ___ 30 mg ___ 75 mg ___ 150 mgStudy Week

Study 0560

Summary of Results

• Effective in reducing signs and symptoms of RA

– In a monotherapy setting

Study Description N

990757 Safety Study 1399

Total 2932

Protocol 960182

Low Dose Monotherapy Study

Dosage: 0, 2.5, 10, 30 mg daily SCNo MTX or other DMARDs

Patients: 141

Duration: 12 weeks

Location: Europe

Study 960182 Primary Endpoint: ACR20 at Week 12

ITT Nonresponder ImputationProportion of Subjects Achieving an ACR20 Response at Week 12 (DRAFT)

/stat/il1ra/fda_slides/analysis/i960182/statfiles/graphs/unfinished/g_acr20.sasBiostatistics: 14MAY2001

Placebo(N = 30)

2.5 mg(N = 42)

10 mg(N = 40)

30 mg(N = 29)

43%43%

26%p = 0.059

28%p = 0.137

34%p = 0.507

Study 960182

Summary of Results

• Signs and symptoms endpoint not achieved

– Doses 30 mg not effective

– Small sample size and low statistical power

– Greater than expected placebo response rate

Study Description N

990757 Safety Study139

Total293

Protocol 960180

MTX Combination Study

Dosage: 0, 0.04, 0.1, 0.4, 1.0, 2.0 mg/kg daily SC

MTX background (15 - 25 mg/wk)

Patients: 419

Duration: 12 weeks, amended to 24 weeks

Location: US, Canada, Australia

Secondary endpoint: ACR20 at 24 weeks

Study 960180

Primary Endpoint: ACR20 at Week 12

Placebo(N = 74)

0.04 mg/kg(N = 63)

0.1 mg/kg(N = 74)

0.4 mg/kg(N = 77)

1.0 mg/kg(N = 59)

2.0 mg/kg(N = 72)

Overall dose-response: p = 0.001

25%p = 0.523p = 0.523

35%p = 0.014p = 0.014

25%p = 0.378p = 0.378

46%p = 0.001p = 0.001

38%p = 0.007p = 0.007

Study 960180

Secondary Endpoint: ACR20 at Week 24

Placebo(N = 48)

0.04 mg/kg(N = 63)

0.1 mg/kg(N = 46)

0.4 mg/kg(N = 55)

1.0 mg/kg(N = 59)

2.0 mg/kg(N = 46)

19%p = 0.538p = 0.538

30%p = 0.505p = 0.505 36%

p = 0.117p = 0.117 42%p = 0.018p = 0.018

35%p = 0.143p = 0.143

Study 960180

ITT Nonresponder Imputation Proportion of Subjects Achieving an ACR20 Response

/stat/il1ra/fda_slides/analysis/i960180/statfiles/graphs/g_acr20_byvisit.sasBiostatistics: 26JUL2001

Placebo (N = 74) 0.4 mg/kg (N = 77)1.0 mg/kg (N = 59) 2.0 mg/kg (N = 72)

Study Week

0 4 8 12 16 20 24

Study 960180

Sustained ACR20 Response

Proportion of Subjects Achieving a Sustained ACR20 Response (DRAFT)

/stat/il1ra/fda_slides/analysis/i960180/statfiles/graphs/unfinished/g_susacr.sasBiostatistics: 04MAY2001

Placebo(N = 48)

0.04 mg/kg(N = 63)

0.1 mg/kg(N = 46)

0.4 mg/kg(N = 55)

1.0 mg/kg(N = 59)

2.0 mg/kg(N = 46)

13%p = 0.687

30%p = 0.062

22%p = 0.302

31%p = 0.039

35%p = 0.013

Response for at Least 4 of 6 MonthsITT Nonresponder Imputation

Study 960180

ACR20, ACR50, and ACR70 at Week 24

ITT Nonresponder ImputationACR Improvement of at Least 20% at Week 24 (DRAFT)

/stat/il1ra/fda_slides/analysis/i960180/statfiles/graphs/unfinished/g_acrlevel.sBiostatistics: 14MAY2001

ACR20ACR50ACR70

Placebo(N = 48)

0.04(N = 63)

0.1(N = 46)

0.4(N = 55)

1.0(N = 59)

2.0(N = 46)

* p < 0.05

Study 960180Individual ACR Components by Study Week

Tender/Painful

0 4 8 12 16 20 24

Swollen

0 4 8 12 16 20 24

Physician's Global

0 4 8 12 16 20 24

Subject's Global

0 4 8 12 16 20 24

Subject's Pain

0 4 8 12 16 20 24

Change From Baseline by Treatment Group

/stat/il1ra/fda_slides/analysis/i960180/statfiles/graphs/g_8endptsm.sasBiostatistics: 30JUL2001

___ Placebo ___ 0.4 mg/kg ___ 1.0 mg/kg ___ 2.0 mg/kgStudy Week

Change From Baseline (ITT Repeated Measures Mixed Model)

Study 960180 Summary of Results

• Effective in reducing signs and symptoms of RA

– In combination with MTX

Study Description N

990757 Safety Study139

Total293

Protocol 990145

Confirmatory Efficacy Study

Dosage: 0, 100 mg daily SCMTX background (10 - 25 mg/wk)

Patients: 906

Duration: 52 weeks

Location: US, Canada, Australia

Primary endpoint: Sharp scores at week 52

Signs and symptoms: ACR20 at week 24 (N = 501)

Study 990145

Signs and Symptoms—ACR20 at Week 24

Output: g_acr20.cgm (generated 14MAY2001)/stat/il1ra/fda_slides/analysis/i990145/statfiles/graphs/g_acr20.sas

Placebo(N = 251)

100 mg(N = 250)

p < 0.001

Study 990145

ITT Nonresponder Imputation Proportion of Subjects Achieving an ACR 20 Response

Output: g_acr20_byvisit.cgm (generated 18JUL2001)/stat/il1ra/fda_slides/analysis/i990145/statfiles/graphs/g_acr20_byvisit.sas

Placebo (N = 251) 100 mg (N = 250)

Study Week

0 4 8 12 16 20 24

* ****** ****

p < 0.05p < 0.01p < 0.001

Study 990145

Sustained ACR20 Response

Response for at Least 4 of 6 MonthsITT Nonresponder Imputation

Proportion of Subjects Achieving a Sustained ACR20 Response (DRAFT)

Output: g_susacr.cgm (generated 14MAY2001)/stat/il1ra/fda_slides/analysis/i990145/statfiles/graphs/g_susacr.sas

Placebo(N = 251)

100 mg(N = 250)

p < 0.001

Study 990145

ACR20, ACR50, and ACR70 at Week 24

ITT Nonresponder Imputation Proportion of Subjects by ACR Level of Improvement at Week 24

Output: g_acrlevel.cgm (generated 18JUL2001)/stat/il1ra/fda_slides/analysis/i990145/statfiles/graphs/g_acrlevel.sas

ACR 20ACR 50ACR 70

Placebo(N = 251)

100 mg(N = 250)

38% ***

17% **

2%6% *

* p < 0.05

** p < 0.01

*** p < 0.001

Study 990145Individual ACR Components by Study Week

Change From Baseline (ITT Repeated Measures Mixed Model)

Tender/Painful

0 4 8 12 16 20 24

Swollen

0 4 8 12 16 20 24

Physician's Global

0 4 8 12 16 20 24

Subject's Global

0 4 8 12 16 20 24

Subject's Pain

0 4 8 12 16 20 24

Log CRP

0 4 8 12 16 20 24

-20-18-16-14-12-10

-8-6-4-202

0 4 8 12 16 20 24

Change From Baseline

Output: g_8acrcomp.cgm (generated 10MAY2001)/stat/il1ra/fda_slides/analysis/i990145/statfiles/graphs/g_8acrcomp.sas

___ Placebo ___ 100 mg

Study Week

Study 990145

Summary of Results

• Confirms Efficacy: Signs and Symptoms of RA

– ACR20 response at 24 weeks

– Early onset of action

– Sustained ACR20 response

– Magnitude of response: ACR50 and ACR70

– Components of ACR

Efficacy DataRadiographic Endpoints – 24 WeeksStudy 0560

Study 0560

Radiographic Methods

Two Independent Validated Methods

Larsen ScoreGenant Modified Sharp Score

Radiologists

Dr. Iain Watt

Dr. Mark Cobby

Radiologist

Dr. Harry Genant

24-week Change From Baseline

Study 0560

Larsen and Modified Sharp Total Scores

Larsen Score

ANOVA Main Effect: p = 0.239

** * ** **

Modified Sharp Total Score

Placebo(n=83)

30 mg(n=89)

75 mg(n=88)

150 mg(n=86)

Anakinra(n=263)

Placebo(n=78)

30 mg(n=87)

75 mg(n=85)

150 mg(n=79)

Anakinra(n=251)

Radiographic Scores Change From Baseline at 6 Months (DRAFT)

Output: g_6mo_bone.cgm (generated 10MAY2001)/stat/il1ra/fda_slides/analysis/i0564/statfiles/graphs/unfinished/g_6mo_bone.sas

p < 0.05p < 0.01

Study 0560

Modified Sharp Score: Sub-scales

*** * **

Joint Space Narrowing

Erosion

Placebo(n=78)

30 mg(n=87)

75 mg(n=85)

150 mg(n=79)

Anakinra(n=251)

Placebo(n=78)

30 mg(n=87)

75 mg(n=85)

150 mg(n=79)

Anakinra(n=251)

p < 0.05p < 0.01

Efficacy DataRadiographic Endpoints – 48 WeeksStudies 0560/0564

Studies 0560 and 0564

Study Schema

Study 0560 Study 0564

Weeks 1 to 24 Weeks 24 to 48

RANDOMIZED

COMPLETERS

PlaceboN = 121

75 mgN = 116

30 mgN = 119

150 mgN = 116

75 mgN = 79

30 mgN = 81

150 mgN = 73

75 mgN = 24

30 mgN = 30

150 mgN = 22

Randomized

Studies 0560 and 0564 Larsen and Modified Sharp Total Score

PlaceboAnakinra

Larsen Score

PlaceboAnakinra

Study Week

0 24 48

Study Week

0 24 48

Radiographic Scores Change From Baseline at 48 Weeks (DRAFT)

Output: g_2mixed_bone_larsgent.cgm (generated 21MAY2001)/stat/il1ra/fda_slides/analysis/i0564/statfiles/graphs/unfinished/g_2mixed_bone.

p = 0.019

p = 0.143

n (Placebo)n (Anakinra)

p = 0.001

p = 0.015

Change From BaselineM-ITT Repeated Measure Mixed Model

Studies 0560 and 0564 Modified Sharp Score: Sub-scales

Change From BaselineM-ITT Repeated Measure Mixed Model

PlaceboAnakinra

Joint Space Narrowing

PlaceboAnakinra

Erosion

Study Week

0 24 48

Study Week

0 24 48

Radiographic Scores Change From Baseline at 48 Weeks (DRAFT)

Output: g_2mixed_bone_jtscersc.cgm (generated 21MAY2001)/stat/il1ra/fda_slides/analysis/i0564/statfiles/graphs/unfinished/g_2mixed_bone.

p = 0.002

p = 0.084

p = 0.047p = 0.006

Summary of Efficacy Results

• Effective in reducing the signs and symptoms of RA– 3 independent trials– Monotherapy and MTX combination– Results are robust and consistent

• Effects on radiographic disease progression are evident– Larsen Score

– Modified Sharp Score

Agenda

• Overview

Anakinra Rheumatoid Arthritis

Clinical TrialsRandomized, Placebo-controlled,

Blinded, Chronic Dosing

A = AnakinraPl = Placebo

Confirmatory Efficacy 990145

A = 250; Pl = 251

Safety990757

A = 1116; Pl = 283

Monotherapy0560

A = 351; Pl = 121

MTX Combination 960180

A = 345; Pl = 74

Low Dose Mono960182

A = 111; Pl = 30

Pharmacokinetic andSupportive

A = 250; Pl = 251

Safety990757

A = 1116; Pl = 283

Monotherapy0560

A = 351; Pl = 121

A = 345; Pl = 74

Low Dose Mono960182

A = 111; Pl = 30

Single-Dose PK0501

A = 20; Pl = 5

Multi-Dose PK0502

A = 15

4-Day Cont. Infusion970189

A = 40; Pl = 10

Dose & Frequency0505

A = 175

Cont. Infusion980220

A = 18; Pl = 3

Pharmacokinetic andSupportive

A = 250; Pl = 251

Safety990757

A = 1116; Pl = 283

Monotherapy0560

A = 351; Pl = 121

A = 345; Pl = 74

Low Dose Mono960182

A = 111; Pl = 30

Mono Extensions0564, E1, E1, E3

A = 309

Combo Extension960181A = 309

Low Dose Extension970102A = 112

Single-Dose PK0501

A = 20; Pl = 5

Multi-Dose PK0502

A = 15

4-Day Cont. Infusion970189

A = 40; Pl = 10

Dose & Frequency0505

A = 175

Cont. Infusion980220

A = 18; Pl = 3

PK Extension0502EA = 11

Dose&Freq. Ext.0512

A = 148

RA Patients

Five Placebo-Controlled RA Studies

Anakinra Experience By Dose

Points of Discussion

• Overall Adverse Event Profile

• Injection Site Reactions (ISRs)

• FDA questions

– Infections

– WBC profile

– Anakinra/Etanercept Combination

– Pediatric Study

Safety DataOverall Adverse Event Profile

Five Placebo-Controlled Studies

Safety Overview

All RA Studies

Deaths

19 subjects

n/N (%) Placebo Anakinra

Monotherapy Study 0/121 (0.0) 3/351 (0.9)

MTX Combination Study 0/74 (0.0) 0/345 (0.0)

Low Dose Monotherapy

Study0/30 (0.0) 0/111 (0.0)

Safety Study 1/283 (0.4) 4/1116 (0.4)

Confirmatory Efficacy

StudyBlinded 1/501 (0.2)

Uncontrolled Extension

Studies*10/913 (1.1)

*Studies 0564, 0564E1, 0564E2, 960181, 0512

Serious Adverse Events ( 0.2%)

All RA Studies

Malignancies

All RA Studies

Malignancies: Observed vs. Expected

Five Placebo-Controlled Studies Withdrawals Due to Adverse Events ( 0.3%)

Safety DataInjection Site Reactions

Injection Site Reactions ( 10%)

Safety and Confirmatory Efficacy Studies

Time to First Injection Site Reaction

Log-rank test: p < 0.001

Time to First Injection Site Reaction for Studies 990145 and 990757

Output: g_t2event_145757_isr.cgm (generated 27JUN2001)/stat/il1ra/fda_slides/analysis/allstudy/statfiles/graphs/g_t2event.sas

Placebo (N = 534, n = 152, median = 3 days)100 mg (N = 1366, n = 973, median = 11 days)

Study Week

0 4 8 12 16 20 24

All RA Studies

Anti-Anakinra Antibodies

• Only 10 of 1303 anakinra subjects (0.8%) positive in bioassay

– potentially clinically neutralizing antibodies

• Positive at only 1 time point in all 10 subjects

• No apparent interference with efficacy or safety profile

Safety DataInfections

Five Placebo-Controlled Studies Infectious Episodes

Serious Infectious Episodes

Serious Pneumonia

Age, Sex

Description Medical History Concomitant Meds

Outcome

42 F Pneumonia None Prednisone, MTX Withdrawn

56 F R. mid lobe pneum.

COPD, asthma MTX Continued

77 M Interstitial pneum.

None Prednisone, MTX Continued

64 M Pneumonia COPD, asthma Methyl-pred., MTX Continued62 M R. low lobe

pneum.CAD, CHF, CABG None Continued

66 M L. low lobe pneum.

Atopy, pneumonia, asthma, CHF

Prednisone, MTX Continued

59 F R. lung pneum., pl. effusion, empyema

Dyspnea, atopy, asthma, pneumonia

Methylprednisolone

Continued

46 M L. lung pneumonia

Pneumonia, COPD, bronchiectasis

Prednisone, MTX Withdrawn

51 F Pneumonia None Prednisone, azath.

Continued

62 F Bronchopneumonia

Asthma Prednisone, MTX Continued

72 M Strep. pneumonia

(L. lung infiltrates)

Dyspnea, COPD, pulm. fibrosis

Prednisone, azath.

Withdrawn

64 F L. low lobe pneum.

None None Withdrawn

64 F Pneumonia, CHF CAD, COPD Pred., MTX, HCQ Continued66 F Legionella

pneum. (L. lower lobe)

None Prednisone, MTX Withdrawn

Characteristics of Serious Pneumonia

With Pneumonia (N

All Anakinra (5 PC

studies)(N = 2173)

Age, mean (SD) 60.8 (9.5) 54.2 (12.4)

Time to onset (days): mean, median

88.2, 79.5

Duration (days): mean, median 17.4, 11.5

Deaths 0 (0.0%)

Withdrawn from study 5 (35.7%)

Relevant medical history, n (%) 8 (57.1%)

Asthma, n (%) 5 (35.7%) 177 (8.1%)

COPD, n (%) 5 (35.7%) 255 (11.7%)

Pneumonia, n (%) 3 (21.4%) 162 (8.4%)

Relevant concomitant meds, n (%) 12 (85.7%)

Corticosteroids, n (%) 11 (78.6%) 1235 (56.8%)

Methotrexate, n (%) 9 (64.3%) 1219 (56.1%)

Other DMARDs, n (%) 3 (21.4%) 632 (29.1%)

Serious Infections: Risk Factors Evaluated

• Demographics:

– age

– gender

– weight

• Duration of RA

• Concomitant medications:

– corticosteroids

– corticosteroid dose

– methotrexate

– other DMARDs

• Medical history:

– asthma

– COPD

– CHF

– CAD

– diabetes mellitus

– pneumonia

• Neutrophil decrease

Serious Infection by History of Asthma

Serious Infection by History of Pneumonia

Serious Infection by Corticosteroid Use

Five Placebo-Controlled Studies Serious Infections: Risk Factor Assessment

Risk Factor vs No Risk Factor

History of Asthma Corticosteroid Use History of Pneumonia

5 Placebo-controlled Studies: Relative Risk of SIE forFactor vs Non-factor by Treatment Group

Output: g_infect_relrisk_rr_fact.cgm (generated 08AUG01)

PlaceboAnakinra

Five Placebo-Controlled StudiesMost Common Infectious Events ( 5.0%)

Anakinra (mg)

Pref . Term - n (%)

Placebo(N = 759)

< 100 (N = 610)

100(N = 1367)

>100(N = 196)

All(N = 2173)

Upper Resp.

Infect.

95 (12.5) 63

(10.3)

(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 Symptoms

35 (4.6%)

29 (4.8) 74 (5.4) 14 (7.1) 117 (5.4)

Safety DataWBC Profile

WBC and Neutrophil Counts

WBC (x10^3/uL)

Study Week

0 4 8 12 16 20 24

Neutrophils (x10^3/uL)

Study Week

0 4 8 12 16 20 24

Summary of Labs in Studies 990145 and 990757

Output: g_2labs_145757_hwbc_hneuta.cgm (generated 18JUL2001)/stat/il1ra/fda_slides/analysis/allstudy/statfiles/graphs/g_2labs_145757.sas

Treatment Group Placebo (N = 534) 100 mg (N = 1366)

Hemoglobin and Platelet Counts

Hemoglobin (g/dL)

Study Week

0 4 8 12 16 20 24

Platelet Count (x10^3/uL)

Study Week

0 4 8 12 16 20 24

Summary of Labs in Studies 990145 and 990757

Output: g_2labs_145757_hhgb_hpla.cgm (generated 18JUL2001)/stat/il1ra/fda_slides/analysis/allstudy/statfiles/graphs/g_2labs_145757.sas

Treatment Group Placebo (N = 534) 100 mg (N = 1366)

Five Placebo-Controlled StudiesWBCs and Neutrophils (WHO Tox Grades)

All RA StudiesSubjects with Neutrophil Count < 1 x 109/L (1)

Study Age Sex

Dose Day Bl. ANC

Lowest ANC

Duration (days)

Last ANC

Comments

960180

63 M 0.4 mg/kg

24 1.73* 0.96 4 1.48 Withdrawn

63 F 0.04 mg/kg

148 1.74* 0.90 23 2.71 Withdrawn

62 F 0.4 mg/kg

88 2.94 0.56 Unk. 0.56 (End Study

Tooth and eye infection, oral ulcers

0560 52 F 75 mg 57 2.35 0.95 4 2.27 Not withdrawn

*Baseline below 2 x 109/L; ANC = absolute neutrophil count; Bl. = baseline; Unk. = unknown

All RA StudiesSubjects with Neutrophil Count < 1 x 109/L (2)

Study Age Sex

Dose Day Bl. ANC

Lowest ANC

Duration

(days)

Last ANC

Comments

0560 62 M 150 mg 8 1.90* 0.91 9 1.06 Chest infection, not withdrawn

990757

58 F 100 mg 85 2.53 0.79 6 1.53 Withdrawn

0501 Unk. F

6.0 mg/kg

6h 1.76* 0.78 6.75 1.41

0502 58 F 4.0 & 1.0 mg/kg

11 1.03* 0.27 Unk. 0.41 Probable Felty, withdrawn

*Baseline below 2 x 109/L; ANC = absolute neutrophil count; Bl. = baseline; unk. = unknown

All RA StudiesWithdrawals due to Leukopenia/Granulocytopenia

Protocol-mandated withdrawal in earlier studies:

WBC Count Neutrophil Count

Monotherapy Study, Extension:

< 3.5 x 109/L

< 2.0 x 109/L

MTX Combination Study, Extension:

< 3.0 x 109/L

< 1.5 x 109/L

• 17 of 2606 subjects (0.7%)

• One severe neutropenia (< 0.5 x 109/L); Felty syndrome

• 7 of 17 (41.2%) received > 100 mg anakinra

• 2 of 17 (11.8%) neutrophil count never < 2.0 x 109/L

• 4 of 17 (23.5%) neutrophil count < 1.0 x 109/L

• No serious infections

• 2 UTI cases; 1 head cold

Infection by Neutrophil Count < 1.5 x 109/L

All RA Studies

WBC Profile

• In summary, severe neutropenia (< 0.5 x 109/L)

– occurred rarely (0.04%); 1 subject with probable Felty

• Neutrophil decrease below 1.0 x 109/L

– occurred uncommonly (0.31%)

– mostly (62.5%) in subjects neutropenic at baseline (< 2.0 x 109/L)

– did not lead to serious or severe infections

– was transient (median 7 days)

– was reversible in all subjects with available follow-up data

Safety DataAnakinra/Etanercept Combination

Study 20000125Anakinra/Etanercept Combination Study

Design: Open-label, single arm

Patients on etanercept (25 mg BIW SC)

Dosage: 1 mg/kg/d SC anakinra

Patients: 58

Duration: 24 weeks

Location: US

Primary endpoint:

Serious Adverse Events

Anakinra/Etanercept Combination Study

Baseline Characteristics

Mean (SD)

Anakinra

(N = 58)

Age 48.9 (10.1)

Women, n (%) 49 (84.5%)

Years on etanercept 1.2 (0.7) range 0.2 – 3.2

Years with RA 11.9 (8.0)

Tender/painful joint count 26.4 (14.0)

Swollen joint count 17.4 (7.3)

CRP (mg/dL) 2.2 (2.8)

Adverse Events

• No deaths

• 7 (12.1%) serious adverse events

– Cellulitis 2

– Pneumonia 2

– Accidental electrocution 1

– Opiate, barbiturate withdrawal 1

– Gastric ulcer hemorrhage 1

ACR Components

Tender/Painful

0 4 8 12 16 20 24

Swollen

0 4 8 12 16 20 24

Output: g_5acrcomp.cgm (generated 18JUL2001)/stat/il1ra/fda_slides/analysis/i20000125/statfiles/graphs/g_5acrcomp.sas

___ Anakinra/Etanercept

Study Week

Safety DataJuvenile Rheumatoid Arthritis Study

Study 990758Juvenile Rheumatoid Arthritis Study

Design: Randomized study Stage 1: 12 weeks open-label Stage 2: 16 weeks blinded, placebo-controlled

Dosage: 1 mg/kg/d SC anakinra (up to 100 mg)

Patients: Stage 1: 204 targetedStage 2: 68

Duration: 30 weeks (including 2 weeks follow-up)

Location: North and South America, Europe, and Australia

Primary endpoint:

Disease flare during blinded period

Juvenile Rheumatoid Arthritis Study

Study Schema

Week 12Responders

SubjectsEvaluated byJRA Core Set

Criteria

SCREENING

ENROLLMENT

Anakinra1.0 mg/kg/day(up to max of 100 mg/day)

Nonresponders

RANDOMIZE

Anakinra1.0 mg/kg/day(up to max of 100 mg/day)

Placebo

FOLLOW-UP

OFF-STUDY

Open Label Phase Blinded Phase

12 weeks 16 weeks

Week 12Responders

SubjectsEvaluated Using JRACore SetCriteria

Anakinra

Safety Summary and Conclusions

• Large anakinra safety database:

– 2606 RA patients received at least 1 anakinra dose

– 1873 patient years total anakinra exposure

• Serious infections:

– Low incidence; Anakinra (1.7%), Placebo (0.7%)

– Mostly pneumonia

– Risk possibly higher in patients with asthma

• Neutrophil decrease below 1.0 x 109/L:

– Rare (0.31%) in anakinra patients

– Reversible and not of clinical consequence

• In conclusion, anakinra has a favorable safety profile

Agenda

• Overview

Need for Future Therapies

• ACR20 responses for biologics and newer therapies in range of 40 to 70%

– 30 to 60% of patients still have active disease

• Chart review

– Within 9 months, 20/131 patients started on Infliximab discontinued therapy; similar drop off rate for Etanercept

Study 960180 (MTX Combination) Individual ACR Components by Study Week

Tender/Painful

0 4 8 12 16 20 24

Swollen

0 4 8 12 16 20 24

Physician's Global

0 4 8 12 16 20 24

Subject's Global

0 4 8 12 16 20 24

Subject's Pain

0 4 8 12 16 20 24

Change From Baseline by Treatment Group

/stat/il1ra/fda_slides/analysis/i960180/statfiles/graphs/g_8endptsm.sasBiostatistics: 30JUL2001

___ Placebo ___ 0.4 mg/kg ___ 1.0 mg/kg ___ 2.0 mg/kgStudy Week

Study 990145 (Confirmatory Efficacy Study) Individual ACR Components by Study Week

Tender/Painful

0 4 8 12 16 20 24

Swollen

0 4 8 12 16 20 24

Physician's Global

0 4 8 12 16 20 24

Subject's Global

0 4 8 12 16 20 24

Subject's Pain

0 4 8 12 16 20 24

Log CRP

0 4 8 12 16 20 24

-20-18-16-14-12-10

-8-6-4-202

0 4 8 12 16 20 24

Output: g_8acrcomp.cgm (generated 10MAY2001)/stat/il1ra/fda_slides/analysis/i990145/statfiles/graphs/g_8acrcomp.sas

___ Placebo ___ 100 mg

Study Week

Larsen Score

** * ** **

Placebo(n=83)

30 mg(n=89)

75 mg(n=88)

150 mg(n=86)

Anakinra(n=263)

Placebo(n=78)

30 mg(n=87)

75 mg(n=85)

150 mg(n=79)

Anakinra(n=251)

p < 0.05p < 0.01

Study 0560 (Monotherapy)

Modified Sharp Total Scores

Anakinra Risk-Benefit Assessment

• Injection site reactions

• Serious infections

• Rare decreases in WBCs

• Daily Injectable

– Favorable patient compliance in studies

Practical Guidance for Looking After Anakinra Patients

• Proper patient selection

– Patients with moderate to severe RA

– Avoid patients with acute or chronic infection

• Proper patient education

– Injection site reactions

– Infection precautions

• Patients with a low baseline neutrophil count should be monitored

Which Patients Should Get Anakinra?

• DMARD failures

– Use as a monotherapy

• Patients who lack full response to DMARDs

– Use in combination therapy

• Patients who lack full response to biologic agents

– With more data, future combination of biologic agents

Summary: Anakinra Therapy

• Unique mechanism of action– First IL-1 inhibitor for rheumatoid arthritis

• Naturally-occurring anti-inflammatory

• Favorable Risk/Benefit profile– ACR benefit—early and sustained– Important effects on patient-reported outcomes– Effects on radiographic disease progression

are evident– Rapid clearance upon discontinuation of

therapy

August 16, 2001

Proposed Indication for Anakinra

Anakinra is indicated for the reduction in signs and symptoms of active rheumatoid arthritis, in patients 18-years of age or older who have failed 1 or more disease-modifying antirheumatic drugs (DMARDs).

Anakinra can be used alone or in combination with other DMARDs.

August 16, 2001

Slides presented in response to questions

Study 0560Larsen Score by ACR20 Response at Week 24

Median Change From Baseline

Responders

Placebo(N = 29)

30 mg(N = 44)

75 mg(N = 35)

150 mg(N = 44)

All(N = 123)

Nonresponders

Placebo(N = 54)

30 mg(N = 45)

75 mg(N = 53)

150 mg(N = 42)

All(N = 140)

Median Larsen Score Change From Baseline at Week 24 by ACR20 Response

/stat/il1ra/fda_slides/analysis/i0560/statfiles/graphs/g_acr20nr_larsen.sasBiostatistics: 25JUL2001

All RA Studies

Causes of Death

Anakinra 23 Cardiovascular disease (including CVA) 9 Cancer 5 Infection 4 Chronic lung disease (Pulmonary fibrosis) 1 Suicide 1 Asthma 1 Gastrointestinal hemorrhage 1 Unknown 1

Placebo 2 Cardiovascular disease (MI) 1 Cancer 1

Blinded 4 Cardiovascular disease 2 Chronic lung disease (Pulmonary fibrosis) 1 Unknown 1

Study 0560Larsen Score: No Progression at Week 24

ITT Nonresponder Imputation Larsen Score No Progression of Joint Damage at 24 Weeks

Output: g_larsprog_ittnr.cgm (generated 06AUG2001)/stat/il1ra/fda_slides/analysis/i0564/statfiles/graphs/g_larsprog.sas

Placebo(n = 121)

30 mg(n = 119)

75 mg(n = 116)

150 mg(n = 116)

All(n = 351)

30% 28%28%

* p < 0.05

** p < 0.01

*** p < 0.001

Study 0560

Erosive Joint Count

Anakinra

Placebo 30 mg

150 mg

Baseline n 83 89 89 86 264 Mean 5.02 5.72 5.81 4.03 5.20 SD 5.73 5.57 5.49 4.41 5.24 Median 4.00 5.00 5.00 2.00 4.00 Minimum 0 0 0 0 0 Maximum 29 27 20 17 27

Week 24 n 83 89 89 86 264 Mean Change 2.64 1.46 1.03 1.70 1.39 SE 0.43 0.32 0.35 0.36 0.20 p-value 0.0670 0.0004 0.0617 0.0016

Test for overall main effect for treatment adjusted for country group and treatment -by-country group: p < 0.0054 (week 24) interaction; data presented in table are untransformed values.

Change From Baseline (M-ITT LOCF Imputation)

JRA Study (990758) Key Eligibility Criteria

• 2-17 years old; 10 kg

• Active Polyarticular-Course JRA

– 5 swollen joints

– 3 joints with limited motion

• 4 week washout of other biologicals

• No clinically significant concurrent medical condition affecting safety/efficacy assessment

• If given, MTX only permitted DMARD (dose between 10 and 40 mg/m2/week)

• Maintain NSAID and corticosteroid doses stable for 4 weeks prior to study and during the study

JRA Study (990758) Key Efficacy Assessments

• JRA Core Set Components

– Subject pain

– Number of active joints

– T/P joint count

– Swollen joint count

– Limitation of motion

anakinra for the treatment of rheumatoid arthritis august 16, 2001

docking of il

receptors il

member of il

antagonist of il

continuous infusion

articular injections

arthritis earlyniki

ra tnfp55

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