# Presentation: 515509

## 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

**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)

*References*
*Feldmann et al. (1993) Progress in Growth Factor Research 4, 247-255*
*Feldmann 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
- chondrocytes

- Induces fibroblast
- proliferation

- Activates osteoclasts

- Inflammation

- Synovial pannus formation

- Cartilage breakdown

- Bone resorption

**IL-1**

## Arthritogenic Actions of Recombinant IL-1 and TNF in the Rabbit:  Evidence for Synergistic Interactions Between Cytokines In Vivo

- 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.

- 6

- 5

- 3

- 2

- 1

- 4

- *

- **

- Total numbers of infiltrating leucocytes (x 10-6)

- 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, 55:382-400*
- 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

## IL-1Ra Blocks Cellular Activation

- ACTIVATION

- ACTIVATION
- BLOCKED

**Nucleus**

**Nucleus**

- Signaling

- No Signaling

- IL-1RI

- IL-1RI

- IL-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

***Animal Models of Arthritis: *****General Overview**

- Inject Type II collagen, or  Adjuvant

**Arthritis ****develops**

**Therapeutic**
**Treatment ****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

**Collagen-Induced Arthritis:****Treatment Effects on Inflammation**

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

- Day of Arthritis

- 0.36

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- Mean ± SE Ankle Joint Diameter (inches)

**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**

- 0.34

- 0.32

- 0.30

- 0.28

- 0.26

- 0.24

## Collagen-Induced Arthritis: Treatment Effects on Histological Scores

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

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

- 0

- 0.04

- 0.2

- 1

- 5

- 0

- 1

- 2

- 3

- 4

- 0

- 0.04

- 0.2

- 1

- 5

- 0

- 1

- 2

- 3

- 4

- IL-1ra [mg/kg/hr]

**INFLAMMATION**** ****SCORE**

**PANNUS SCORE**

- 0

- 0.04

- 0.2

- 1

- 5

- 0

- 1

- 2

- 3

- 4

**CARTILAGE SCORE**

- 0

- 0.04

- 0.2

- 1

- 5

- 0

- 1

- 2

- 3

- 4

- IL-1ra [mg/kg/hr]

**BONE DAMAGE SCORE**

- *

- *

- *

- *

- *

- *

- *

- *

- *

- *

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

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

***Amgen Inc. - unpublished data***

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

- IL-1b (pM)

- TNF-a (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*

## Collagen-Induced Arthritis:Anakinra and PEG sTNF-RI

*Bendele et al. Arthritis Rheum. 2000; 43:2648-2659.*

***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)

## Regulatory Submissions

- 0560

- 960180

- 960182

*December 1999 License* *Application*

- Selected Dose
- 100 mg/day

- 990757
- Safety

- 990145
- Efficacy and Safety

*March 2001 Complete Response*

## Anakinra Rheumatoid Arthritis Patients

***Anakinra***** ****Rheumatoid Arthritis Patients**

**                                                                      ****	****   ****Number of Patients**
**                                                                   ****Placebo              Anakinra**
- Randomized placebo-controlled	759	2332
- studies 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

**Agenda**

*Overview *
- Roger M. Perlmutter, MD, PhD
*Clinical Experience*
- Moraye Bear, MS, MA
- Pirow Bekker, MD, PhD
*Therapeutic Role of Anakinra*
- Stanley Cohen, MD

## Randomized Placebo-Controlled Trials

| Study | Description | Daily Doses of Anakinra | N |
| --- | --- | --- | --- |
| 0560 | Monotherapy Study | 0, 30, 75, 150 mg | 472 |
| 960182 | Low Dose Monotherapy Study | 0, 2.5, 10, 30 mg | 141 |
| 960180 | MTX Combination Study | 0, 0.04, 0.1, 0.4, 1.0, 2.0 mg/kg | 419 |
| 990145 | Confirmatory Efficacy Study | 0, 100 mg | 501 |
| 990757 | Safety Study | 0, 100 mg | 1399 |
|  |  | Total | 2932 |

**Randomized Placebo-Controlled Trials**

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

## RA Efficacy Trial Results

**RA Efficacy Trial Results**

## Patient Disposition

## Baseline Demographics

## Baseline Disease Status

## Baseline RA Medications 

## Randomized Placebo-Controlled Trials

| 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 |
|  | Total | 2932 |

**Randomized Placebo-Controlled Trials**

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

## 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 Subject + SE**

## Study 0560ACR20 Response by Study Week

- M-ITT LOCF Imputation

**Proportion of Subjects**

## Study 0560 Individual ACR Components by Study Week 

***Study 0560 *****Individual ACR Components by Study Week **

**Adjusted Mean **_**+**_** SE**

## Study 0560 Summary of Results

- Effective in reducing signs and symptoms of RA
- In a monotherapy setting

## Randomized Placebo-Controlled Trials

| 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 |
|  | Total | 2932 |

**Randomized Placebo-Controlled Trials**

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

## Protocol 960182Low Dose Monotherapy Study

***Design:***	Randomized, Blinded, 	Placebo-Controlled
***Dosage:*** 	0, 2.5, 10, 30 mg daily SC
- 	No MTX or other DMARDs
***Patients:***	141
***Duration:***	12 weeks
***Location:***	Europe
***Primary endpoint:***	ACR20 at 12 weeks

## Study 960182 Primary Endpoint: ACR20 at Week 12 

***Study 960182***** ****Primary Endpoint: ACR****20**** at Week 12**

- ITT Nonresponder Imputation

**Proportion of Subjects + SE**

## 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

## Randomized Placebo-Controlled Trials

| 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 |
|  | Total | 2932 |

**Randomized Placebo-Controlled Trials**

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

## Protocol 960180MTX Combination Study

***Design:******	***Randomized, Blinded, 	Placebo-Controlled
***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
***Primary endpoint:****	*ACR20 at 12 weeks
***Secondary endpoint:******	***ACR20 at 24 weeks

## Study 960180Primary Endpoint: ACR20 at Week 12 

- ITT Nonresponder Imputation

**Proportion of Subjects + SE**

## Study 960180Secondary Endpoint: ACR20 at Week 24

- ITT Nonresponder Imputation

**Proportion of Subjects + SE**

## Study 960180ACR20 Response by Study Week 

- ITT Nonresponder Imputation

**Proportion of Subjects**

## Study 960180Sustained ACR20 Response

- Response for at Least 4 of 6 Months
- ITT Nonresponder Imputation

**Proportion of Subjects + SE**

## Study 960180ACR20, ACR50, and ACR70 at Week 24

- ITT Nonresponder Imputation

**Proportion of Subjects + SE**

## Study 960180Individual ACR Components by Study Week

- Change From Baseline (ITT Repeated Measures Mixed Model)

**Adjusted Mean **_**+**_** SE**

## Study 960180 Summary of Results

- Effective in reducing signs and symptoms of RA
- In combination with MTX

## Randomized Placebo-Controlled Trials

| 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 |
|  | Total | 2932 |

**Randomized Placebo-Controlled Trials**

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

## Protocol 990145Confirmatory Efficacy Study

***Design:***	Randomized, Blinded, 	Placebo-Controlled
***Dosage:***	0, 100 mg daily SC
- 	MTX 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

- ITT Nonresponder Imputation

**Proportion of Subjects + SE**

## Study 990145ACR20 Response by Study Week

- ITT Nonresponder Imputation

**Proportion of Subjects **_**+**_** SE**

## Study 990145Sustained ACR20 Response

- Response for at Least 4 of 6 MonthsITT Nonresponder Imputation

**Proportion of Subjects + SE**

## Study 990145ACR20, ACR50, and ACR70 at Week 24

- ITT Nonresponder Imputation

**Proportion of Subjects + SE**

## Study 990145Individual ACR Components by Study Week

- Change From Baseline (ITT Repeated Measures Mixed Model)

**Adjusted Mean **_**+**_** SE**

## 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 DataRadiographic Endpoints – 24 WeeksStudy 0560

## Study 0560Radiographic Methods

- Two Independent Validated Methods

| Larsen Score | Genant Modified Sharp Score |
| --- | --- |
| Radiologists
	Dr. Iain Watt
	Dr. Mark Cobby | Radiologist
	Dr. Harry Genant |

## Study 0560Larsen and Modified Sharp Total Scores

- 24-week Change From Baseline

***Study 0560*****Larsen and Modified Sharp Total Scores**

**Adjusted Mean + SE**

## Study 0560Modified Sharp Score:  Sub-scales

- 24-week Change From Baseline

***Study 0560*****Modified Sharp Score:  Sub-scales**

**Adjusted Mean + SE**

## Efficacy DataRadiographic Endpoints – 48 WeeksStudies 0560/0564

## Studies 0560 and 0564Study Schema

**Study 0560**

**Study 0564**

**Weeks 1 to 24**

**Weeks 24 to 48**

- RANDOMIZED

- COMPLETERS

- Placebo
- N = 121

- 75 mg
- N = 116

- 30 mg
- N = 119

- 150 mg
- N = 116

- 75 mg
- N = 79

- 30 mg
- N = 81

- 150 mg
- N = 73

- 75 mg
- N = 24

- 30 mg
- N = 30

- 150 mg
- N = 22

- Randomized

## Studies 0560 and 0564 Larsen and Modified Sharp Total Score

- Change From Baseline
- M-ITT Repeated Measure Mixed Model

**Adjusted Mean **_**+**_** SE**

## Studies 0560 and 0564 Modified Sharp Score:  Sub-scales

- Change From Baseline
- M-ITT Repeated Measure Mixed Model

**Adjusted Mean **_**+**_** SE**

## 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

**Agenda**

*Overview *
- Roger M. Perlmutter, MD, PhD
*Clinical Experience*
- Moraye Bear, MS, MA
- Pirow Bekker, MD, PhD
*Therapeutic Role of Anakinra*
- Stanley Cohen, MD

## Anakinra Rheumatoid Arthritis Clinical Trials

**Randomized, Placebo-controlled, **
**Blinded, Chronic Dosing**

*A = Anakinra*
*Pl = Placebo*

- Confirmatory Efficacy
- 990145
- A = 250; Pl = 251

- Safety
- 990757
- A = 1116; Pl = 283

- Monotherapy
- 0560
- A = 351; Pl = 121

- MTX Combination
- 960180
- A = 345; Pl = 74

- Low Dose Mono
- 960182
- A = 111; Pl = 30

**Notes:**
CS1 cores ratrial 5rct

## Anakinra Rheumatoid Arthritis Clinical Trials

**Randomized, Placebo-controlled, **
**Blinded, Chronic Dosing**

*A = Anakinra*
*Pl = Placebo*

**Pharmacokinetic and**
**Supportive**

- Confirmatory Efficacy
- 990145
- A = 250; Pl = 251

- Safety
- 990757
- A = 1116; Pl = 283

- Monotherapy
- 0560
- A = 351; Pl = 121

- MTX Combination
- 960180
- A = 345; Pl = 74

- Low Dose Mono
- 960182
- A = 111; Pl = 30

- Single-Dose PK
- 0501
- A = 20; Pl = 5

- Multi-Dose PK
- 0502
- A = 15

- 4-Day Cont. Infusion
- 970189
- A = 40; Pl = 10

- Dose & Frequency
- 0505
- A = 175

- Cont. Infusion
- 980220
- A = 18; Pl = 3

**Notes:**
CS2 cores ratrial suppra

## Anakinra Rheumatoid Arthritis Clinical Trials

**Randomized, Placebo-controlled, **
**Blinded, Chronic Dosing**

*A = Anakinra*
*Pl = Placebo*

**Pharmacokinetic and**
**Supportive**

- Confirmatory Efficacy
- 990145
- A = 250; Pl = 251

- Safety
- 990757
- A = 1116; Pl = 283

- Monotherapy
- 0560
- A = 351; Pl = 121

- MTX Combination
- 960180
- A = 345; Pl = 74

- Low Dose Mono
- 960182
- A = 111; Pl = 30

- Mono Extensions
- 0564, E1, E1, E3
- A = 309

- Combo Extension
- 960181
- A = 309

- Low Dose Extension
- 970102
- A = 112

- Single-Dose PK
- 0501
- A = 20; Pl = 5

- Multi-Dose PK
- 0502
- A = 15

- 4-Day Cont. Infusion
- 970189
- A = 40; Pl = 10

- Dose & Frequency
- 0505
- A = 175

- Cont. Infusion
- 980220
- A = 18; Pl = 3

- PK Extension
- 0502E
- A = 11

- Dose&Freq. Ext.
- 0512
- A = 148

**Notes:**
CS3 cores ratrial extension

## Anakinra Rheumatoid Arthritis RA Patients

**Notes:**
CS4 cores Allra exposureN nsubj

## Five Placebo-Controlled RA StudiesAnakinra Experience By Dose

***Five Placebo-Controlled RA Studies*****Anakinra Experience By Dose**

**Notes:**
CS5 cores 5rct exposure ptyrs

## Points of Discussion

- Overall Adverse Event Profile
- Injection Site Reactions (ISRs)
- FDA questions
- Infections
- WBC profile
- Anakinra/Etanercept Combination
- Pediatric Study

**Notes:**
CS6 cores outline

## Safety DataOverall Adverse Event Profile

## Five Placebo-Controlled Studies Safety Overview

***Five Placebo-Controlled Studies *****Safety Overview**

**Notes:**
CS7 cores 5rcts table 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 Study | 0/30 (0.0) | 0/111 (0.0) |
|     Safety Study | 1/283 (0.4) | 4/1116 (0.4) |
|     Confirmatory Efficacy Study | Blinded  1/501 (0.2) |  |
|     Uncontrolled Extension Studies* |  | 10/913 (1.1) |
| *Studies 0564, 0564E1, 0564E2, 960181, 0512 |  |  |

**Notes:**
CS8 cores allras bla amend death summary

## Five Placebo-Controlled Studies Serious Adverse Events ( 0.2%)

***Five Placebo-Controlled Studies *****Serious Adverse Events (******** 0.2%)**

**Notes:**
CS9 cores 5rcts SAE pterm table

## All RA StudiesMalignancies

**Notes:**
CS10 cores allras cancer table cause rate

## All RA StudiesMalignancies: Observed vs. Expected

**Notes:**
CS11 cores allras cancer SEER table

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

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

**Notes:**
CS12 cores 5rcts wdraw pterm table

## Safety DataInjection Site Reactions

## Five Placebo-Controlled Studies Injection Site Reactions ( 10%)

***Five Placebo-Controlled Studies *****Injection Site Reactions (******** 10%)**

**Notes:**
CS13 cores 5rcts isr pterm table

## Safety and Confirmatory Efficacy StudiesTime to First Injection Site Reaction

**Cumulative Probability**

**Notes:**
CS14 cores 145757s t2isr line

## 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

**Notes:**
CS15 Cores allras antibodies summary text

## Safety DataInfections

## Five Placebo-Controlled Studies Infectious Episodes

***Five Placebo-Controlled Studies****** *****Infectious Episodes**

**Notes:**
CS16 cores 5rcts infection overview table

## Five Placebo-Controlled Studies Serious Infectious Episodes

***Five Placebo-Controlled Studies *****Serious Infectious Episodes**

**Notes:**
CS17 cores 5rcts sie pterm group table

## Five Placebo-Controlled Studies 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 | Continued |
| 62 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 | Continued |
| 66 F | Legionella pneum. (L. lower lobe) | None | Prednisone, MTX | Withdrawn |

**Notes:**
CS18 cores 5rcts serious pneumonia listing

## Five Placebo-Controlled Studies Characteristics of Serious Pneumonia

|  | With Pneumonia                    (N = 14) | 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%) |

**Notes:**
CS19 cores 5rcts anakinra serious pneumonia table characteristics

## Five Placebo-Controlled Studies 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

**Notes:**
CS20 Cores 5rct sie serious infections risk factors text summary

## Five Placebo-Controlled Studies Serious Infection by History of Asthma 

**Notes:**
CS21 Cores 5rct sie table serious infection pneumonia history asthma

## Five Placebo-Controlled Studies Serious Infection by History of Pneumonia 

**Notes:**
CS22 Cores 5rct sie table serious infection pneumonia history

## Five Placebo-Controlled Studies Serious Infection by Corticosteroid Use 

**Notes:**
CS23 Cores 5rct sie table serious infection pneumonia concomitant steroids corticosteroids

## Five Placebo-Controlled Studies Serious Infections: Risk Factor Assessment

- Risk Factor vs No Risk Factor

**Relative Risk**

**Notes:**
CS24 5rcts sgraphs infection sie relative risk riskfactor

## Five Placebo-Controlled StudiesMost Common Infectious Events ( 5.0%)

***Five Placebo-Controlled Studies*****Most 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) | 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 Symptoms | 35 (4.6%) | 29 (4.8) | 74 (5.4) | 14 (7.1) | 117 (5.4) |

**Notes:**
CS25 cores 5rcts upper respiratory infection sinusitis uri flu table

## Safety DataWBC Profile

## Safety and Confirmatory Efficacy Studies WBC and Neutrophil Counts

**Mean **_**+**_** SE**

**Notes:**
CS26 cores 145757s labs wbc neut line byvisit

## Safety and Confirmatory Efficacy Studies Hemoglobin and Platelet Counts

**Mean **_**+**_** SE**

**Notes:**
CS27 cores 145757s labs hgb hemoglobin platelets line byvisit

## Five Placebo-Controlled StudiesWBCs and Neutrophils (WHO Tox Grades)

**Notes:**
CS28 cores 5rcts labs wbc neut table whotox abnormalities

## All RA StudiesSubjects 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 |  |  |  |  |  |  |  |  |

**Notes:**
CS29 Cores allras listing neutropenia

## All RA StudiesSubjects 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 |  |  |  |  |  |  |  |  |

**Notes:**
CS30 Cores allras listing neutropenia

## All RA StudiesWithdrawals 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 |  |  |

**Notes:**
CS31 cores allras wdraw leukopenia neutropenia summary text

## Five Placebo-Controlled StudiesInfection by Neutrophil Count < 1.5 x 109/L 

**Notes:**
CS32 cores 5rcts stable infection byneutropenia summary

## 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

**Notes:**
CS33 cores allras lab neutropenia summary

## Safety DataAnakinra/Etanercept Combination

## Study 20000125Anakinra/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 |

**Notes:**
CS34 cores 20000125 intro text

## 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) |

**Notes:**
CS35 cores 20000125 baseline bl table

## Anakinra/Etanercept Combination Study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

**Notes:**
CS36 cores 20000125s death SAE summary

## Anakinra/Etanercept Combination StudyACR Components

**Mean Change  **_**+**_** SE**

**Notes:**
CS37 cores 20000125e acrcomp line

## Safety DataJuvenile Rheumatoid Arthritis Study

## Study 990758Juvenile 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 targeted
Stage 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 |

**Notes:**
CS38 Cores 990758s intro text design JRA juvenile pediatric

## Juvenile Rheumatoid Arthritis StudyStudy Schema

***Juvenile Rheumatoid Arthritis Study*****Study Schema**

**SCREENING**

**ENROL****LMENT**

**Anakinra**
**1.0 mg/kg/day**
**(up to max of **
**100 mg/day)**

**Non**
**responders**

**RANDOMIZE**

**1:1**

**Anakinra**
**1.0 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 12**
**Responders**
**Subjects**
**Evaluated **
**Using JRA**
**Core Set**
**Criteria**

**Notes:**
CS39 Cores 990758s schema design JRA juvenile pediatric

## 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

**Notes:**
CS40 cores allras summary

## Agenda

**Agenda**

*Overview *
- Roger M. Perlmutter, MD, PhD
*Clinical Experience*
- Moraye Bear, MS, MA
- Pirow Bekker, MD, PhD
*Therapeutic Role of Anakinra*
- Stanley Cohen, MD

## 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

**Adjusted Mean **_**+**_** SE**

**Notes:**
0560e acrcomp byvisit line

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

**Adjusted Mean **_**+**_** SE**

## Study 0560 (Monotherapy)Modified Sharp Total Scores

***Study 0560 (Monotherapy)*****Modified Sharp Total Scores**

**Adjusted Mean **_**+**_** SE**

## Anakinra Risk-Benefit AssessmentRisks

- 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

**Notes:**
Message – Tell how the drug will fit into the rheumatologist bag of tools.  

“ Today, we have seen data that shows anakinra has a favorable risk benefit profile in many of these  patient populations.  Other patient populations will likely benefit from this therapeutic option as well.”

## 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

**Notes:**
Message – Unique mechanism of action

Helps in the under-served market

 “Anakinra is different than the other biologics and provides unique attributes that help shape our treatment choice.”

Compare to challenges in removing patients off other therapies such as arava.

## Anakinra for the Treatment of Rheumatoid Arthritis

*	**August 16, 2001*

## Proposed Indication for Anakinra

**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.

## Anakinra for the Treatment of Rheumatoid Arthritis

*	**August 16, 2001*

***Slides presented in response to questions****** ***

## Study 0560Larsen Score by ACR20 Response at Week 24 

- Median Change From Baseline

**Notes:**
0560e r814 Bone sensitivity larsen acr20 line

## 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 |

**Notes:**
Sa4 allras deaths table cause

## Study 0560Larsen Score: No Progression at Week 24 

- ITT Nonresponder Imputation

**Notes:**
0560e r811a Bone sensitivity larsen progression bar itt nr

## Study 0560 Erosive Joint Count

- Anakinra

- Placebo

- 30 mg

- 75 mg

- 150 mg

- All

- 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

- -

- v

- alue

- 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)**** **

**Notes:**
0560e r892 Bone larsen erosive table mitt locf

## 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

**Notes:**
Sz15 990758s JRA study eligibility criteria summary text

## 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

**Notes:**
Sz17 990758s JRA study core set components summary text