# Presentation: 811532

## Etanercept (Enbrel®) Safety ReviewMarch 4, 2003

**Notes:**
Good morning.  Members of the committee, the FDA, ladies and gentlemen. It is a pleasure to be here today to provide a safety review of etanercept, which, as you are all aware, has become well established as a significant therapy for patients with rheumatoid arthritis, juvenile rheumatoid arthritis and psoriatic arthritis.   The efficacy and safety of Etanercept has been discussed before this committee on several occasions including --  the  review associated with initial licensure in 1998, the review associated with the label extension in 2000  and --  the  comprehensive review of TNF antagonist safety in August 2001.    We welcome the opportunity to engage the committee, and have been asked by the FDA to focus attention today on safety observations relevant to lymphoma and heart failure.

## Presentation Outline

- Introduction			  		Dan Burge, MD
- Etanercept Clinical Profile
- Pharmacovigilance
- General Safety
- Malignancy/Lymphoma
- Epidemiology of Lymphoma in RA		Alan Silman, MD
- Lymphoma and Etanercept			Dan Burge, MD
- Heart Failure Experience
- Ongoing Pharmacovigilance
- Summary

**C2**

**Notes:**
We will begin by describing some of the unique characteristics of etanercept and aspects of the etanercept pharmacovigilance program. We will then share some general observations from the extensive experience accrued with etanercept.  Dr. Alan Silman will provide perspective on the epidemiology of lymphoma in RA patients.   We will then review our data regarding lymphoma and heart failure and conclude by reviewing our ongoing Pharmacovigilance program. 

The P75 receptor was cloned by Immunex in 1990. Immunex was acquired by Amgen in 2002. To avoid confusion I will refer to Immunex and Amgen collectively as Amgen for the remainder of the presentation.

## Consultants

**Jeffrey Borer, MD**
**Division of Cardiology**
**The New York Hospital**
**Cornell University Medical Center**
**New York, New York**
**Mary K. Crow, MD**
**Dept. of Rheumatology **
**Cornell University **
**Hospital for Special Surgery**
**New York, New York**
** **
**Annette Langer-Gould, MD****	**
**Dept. of Health Research and Policy**
**Stanford University School of Medicine**
**Palo Alto, California**

**Alan Silman, MD**
**Epidemiology Research Unit**
**University of Manchester Medical School**
**ARC Professor of Rheumatic Disease **
**Epidemiology,University of Manchester**
**Manchester, United Kingdom**
**Julie Vose, MD**
**Department of Internal Medicine**
**Section of Oncology/Hematology**
**University of Nebraska Medical Center**
**Omaha, Nebraska**** **

**C3**

**Notes:**
Several consultants have kindly consented to join us today:

Dr. Jeffrey  Borer from the Cornell University Medical Center

Dr. Mary Crowe from the Hospital for Special Surgery in New York

Dr.  Annette Langer-Gould from Stanford University

Dr. Alan Silman from the University of Manchester, United Kingdom

Dr.  Julie Vose from the University of Nebraska Medical Center 

## Etanercept: Distinctive Properties

- Only soluble receptor TNF antagonist
- Fully human protein
- Low immunogenicity
- Does not bind compliment and is not associated with compliment mediated cell lysis
- Dosing schedule maintains stable serum concentrations
- No pharmacokinetic interaction with methotrexate

**C4**

**Notes:**
Though etanercept is in the TNF antagonist class, it is distinct as the only soluble TNF receptor utilizing receptor binding specificity.
The human protein has low immunogenicity and no neutralizing anti-etanercept antibodies have been detected. Etanercept does not activate complement nor does it initiate complement mediated cell lysis.  The dosing schedule and pharmacokinetic profile of etanercept results in a relatively smooth concentration curve throughout the treatment period. As Etanercept may be administered alone or in combination with methotrexate, it is important to note that coadministration with methotrexate does not modify etanercept pharmacokinetics.  
We believe that these product specific differences in structure, function and pharmacokinetics are relevant to the Etanercept efficacy and safety profiles.

## Etanercept: Sustained Benefit With Corticosteroid Reduction

**4 Years**
**N=267**

**10**

**5**

**0**

**P< 0.0001**

**Prednisone (mg/day)**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**Time on Therapy (years)**

**Median Joint Count**

**TENDER**

**JOINTS**

**SWOLLEN**

**JOINTS**

**Reduction in Corticosteroids**

**Long-Term Efficacy**

**Median (Interquartile range)**

-  Moreland 2002 ACR abstract 1427

**C5**

**Baseline**
**N=385**

**Notes:**
Although the focus of today’s discussion is on safety issues, in order to appropriately assess the etanercept benefit/risk profile it is important to appreciate the efficacy of etanercept. 

The clinical improvement is rapid, substantial, and sustained for up to 6 years in clinical trials.....and  frequently permits tapering or discontinuation of concomitant  corticosteroids and methotrexate, each of which can be independently associated with safety issues.

## Etanercept: Consistent and Substantial Efficacy

- Percentage of Patients Achieving ACR 20

**Bathon *****J. N Engl J Med*****. 2000:343:1586-1593. Moreland LW, et al. *****N Engl J Med.***** 1997;337:141-147.   ****Weinblatt ME, et al. *****N Engl J Med.***** 1999;340:253-259. Moreland L, et al. *****Ann Intern Med.***** 1999;130:478-486.**
**European Etanercept Investigators Group. EULAR 2000, Nice, France.**

**Etanercept: Consistent and ****Substantial Efficacy**

**C6**

**Notes:**
In multiple clinical settings including early RA, patient with more advanced disease, pts treated with monotx or in combo with MTX, pts receiving etanercept consistently achieve ACR 20 responses in the 70% range.  This level of benefit is also observed in patients with JRA and psoriatic arthritis.

## Etanercept: Milestones

- 1990 	P75-TNF receptor cloned
- 1993 	First administration to RA patient
- 1998 	FDA approval for RA (alone or with  MTX)
- 1999 	FDA approval for JRA
- 2000 	FDA approval as initial therapy for RA
-  		FDA approval for inhibition of radiographic progression
- 2001 	FDA Arthritis Advisory re: TNF Antagonists Safety
- 2002 	FDA approval for psoriatic arthritis (alone or with MTX)
- 2002	FDA approval of three year efficacy and safety data in RA

**C7**

**Notes:**
The p75 TNF receptor was cloned at in 1990.  Etanercept was developed shortly thereafter, and was first administered to RA patients in 1993.  It was initially approved for commercial application in November 1998 for the reduction of signs and symptoms of rheumatoid arthritis as either monotherapy or as combination therapy with methotrexate.
 In May 1999, Etanercept was additionally approved for the treatment of children with juvenile rheumatoid arthritis.... and in June of 2000, Etanercept was approved  as a first-line disease modifying therapy for RA and for inhibition of  radiographic progression.
 In August of 2001, we provided a review of Etanercept safety information to this committee.  In 2002, Etanercept became the first Disease Modifying therapeutic approved for the treatment of psoriatic arthritis.

## Etanercept Pharmacovigilance Program

- Ongoing clinical studies (over 3,000 patients)
- Long-term open label extension studies (n ~1,600)
- 		North America and Europe
- Safety trial of RA patients with comorbidities (n=1,000)
- Combination DMARD studies (n ~ 800)
- Observational studies (over 12,000 patients)
- Juvenile rheumatoid arthritis registry (n=600)
- RADIUS I and II: observational studies (n=10,000)
- European RA registries (n ~ 1,600)
- Germany
- Sweden
- United Kingdom

**C8**

**Notes:**
We have long been committed to providing meaningful information regarding the safety of etanercept to patients and prescribers.  Even prior to product approval, Amgen and Wyeth jointly made a substantial commitment to the development of a comprehensive pharmacovigilance program.  During the 4 years since product approval, this program has been further expanded and includes multiple elements as outlined here. 
Multiple long-term open-label clinical trials remain ongoing in North America and in Europe, with over 1600 patients entered--some of whom have now been observed for over six years.
Studies of patients with comorbities, patients on combination therapies have been initiated to further explore the safety profile of etanercept.
Observational studies have been initiated in other special populations, such as children with JRA.
The RADIUS program is now nearing its goal of enrolling 10,000 RA patients.  This 5 year program will permit monitoring of the interaction between therapies, comorbidities, clinical status and safety.  Several national registries have also been established in Germany, Sweden and the UK. 

## Etanercept Pharmacovigilance Program (continued)

- Epidemiologic studies
- 	Ingenix UnitedHealthcare (n ~ 50,000 rheumatic disease patients): establishing background incidence of adverse events in rheumatic disease populations
- Continued surveillance of facilitated post-marketing adverse event reports
- 1.2 Million phone contacts in 150,000 patients
- Each call is an opportunity for reporting
- 88% adverse event reports are patient initiated
- Half of health care provider reports are patient initiated

**C9**

**Notes:**
As the background epidemiology for adverse events in patients with rheumatic diseases is often not well characterized, ...we have sponsored several epidemiologic studies, including a project with Ingenix UnitedHealthcare—a database with approximately 50,000 rheumatic disease patients—to establish the background rates of  adverse events in the RA, psoriatic arthritis and AS patient populations. 

Surveillance of adverse events has also been ongoing since product approval in November 1998.  Special programs have been in place, such as the ENLIVEN and ENROLLMENT programs. ENLIVEN is a patient support system and the enrollment program was in place to help facilitate drug distribution during the previous period of limited supply.  Over 1.2 million phone contacts with the 150,000 patients who have received etanercept therapy have facilitated adverse event reporting.  88% of all reports have been initiated by patients.  Follow up of patient reports with health care providers accounts for half of the health care provider reports. We believe that the increased interactions with patients improves safety surveillance.

## Over 230,000 Patient-Yearsof Etanercept Experience

**C10**

**Notes:**
At the time of initial approval, etanercept filled a significant unmet medical need for patients with RA.  Recognizing that the experience at the time of approval was limited, we initiated a significant number of additional clinical programs, some of which served to satisfy post approval commitments. 
In August 2001, we met again with the Committee and had the opportunity to present a safety update which reflected the greatly expanded experience, including more than 111,000 patients.
We are able to present here today our experience based on over 8,000 pt-years of clinical trial experience and over 230,000 pt-years of practice experience.  This includes over 1,000 patients in their 5th year of treatment and over 390 patients in their 6th year of treatment.

## Serious Adverse Event Rates in Etanercept Patients Similar to Placebo and Stable Over Time

|  |  |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 
 | Control | Etanercept | Yr 1 | Yr 2 | Yr 3 | Yr 4 | Yr 5 | Yr 6 | Overall |
| Early RA | 0.11 | 0.09 | 0.11 | 0.08 | 0.08 | 0.08 | 0.19 | -- | 0.09 |
| Advanced RA | 0.20 | 0.13 | 0.14 | 0.13 | 0.16 | 0.11 | 0.12 | 0.25 | 0.14 |

**Controlled Trials**

**Long-Term Etanercept**

**C11**

**Serious Adverse Event Rates in ****Etanercept Patients Similar to Placebo and Stable Over Time**

**Notes:**
Serious adverse events, as defined by ICH, are carefully reported and evaluated.  In clinical trials, the rate of serious adverse events are similar in the etanercept treated patients and the control groups. 

[Describe slide]
	control v etanercept
	over time
	early disease v more advanced disease

Interestingly, one can see that the rate of serious adverse events is higher, in both control and etanercept groups, in patients with more advanced disease.  This supports the widely held impression of practicing rheumatologists, that patients with more advanced disease have more intercurrent illness.

## Serious Infection Rates in Etanercept Patients Similar to Placebo and Stable Over Time

- Serious Infections / patient-year in North America

|  |  |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 
 | Control | Etanercept | Yr 1 | Yr 2 | Yr 3 | Yr 4 | Yr 5 | Yr 6 | Overall |
| Early RA | 0.031 | 0.024 | 0.031 | 0.022 | 0.030 | 0.028 | 0.034 | -- | 0.028 |
| Advanced RA | 0.050 | 0.043 | 0.054 | 0.033 | 0.048 | 0.037 | 0.050 | 0.00 | 0.044 |

**Controlled Trials**

**Open-label Etanercept**

**C12**

**Notes:**
Serious infections, defined as those associated with hospitalization or IV antibiotics have also been carefully monitored in clinical trials.
The rates of serious infection in the control groups is once again, similar to that seen in the etanercept groups.  Again, the rates do not increase with prolonged therapy, with up to 6 years experience.

## Presentation Outline

- Introduction			  		Dan Burge, MD
- Etanercept Clinical Profile
- Pharmacovigilance
- General Safety
**Malignancy**
- Epidemiology of Lymphoma in RA		Alan Silman, MD
- Lymphoma and Etanercept			Dan Burge, MD
- Heart Failure Experience
- Ongoing Pharmacovigilance
- Summary

**C13**

**Notes:**
I would like to refocus our attention on a general overview of malignancies before discussing lymphoma in detail.

We will begin by describing some of the unique characteristics of etanercept and aspects of the etanercept pharmacovigilance program. We will then share some general observations from the extensive experience accrued with etanercept.  Dr. Alan Silman will provide perspective on the epidemiology of lymphoma in RA patients.   We will then review our data from clinical trials and post marketing regarding lymphoma and will conclude with observations regarding etanercept and heart failure.   (DELETE??)

## The Surveillance, Epidemiology, and End Results (SEER) Program

- National Cancer Institute’s cancer registry
- Data based on 11 population-based cancer registries and 3 supplemental registries
- Covers approximately 14% of US population
- Provides incidence, prevalence and mortality data for cancers

**C14**

- Standardized Incidence Ratio = Observed/Expected

**Notes:**
When evaluating the incidence of malignancies in clinical experience, we have utilized the National Cancer Institutes database, called the Surveillance, Epidemiology and End Results or SEER Program.

This database collects population-based information from multiple regions, representing approximately 14% of the US population and provides data regarding incidence, prevalence and mortality for the various types of malignancies.

Utilizing age, gender and race-specific rates for the SEER database, one can calculate the expected number of cases in the general population relative to the trial cohort.  The expected rate can then be used as the denominator in calculating the standard incidence ratio, or SIR, as shown here.

## Total Malignancies Not Increased in Clinical Trials 

- 			         Controlled Trials	       All Trials
- 		                  Control             Etanercept	        Etanercept
- Observed	        5	                   11                     	55
- Expected* 	        3.57 	        8.80		56.2
- SIR		        1.40	        1.25		  0.98

**C15**

**Notes:**
This table represents data regarding malignancies observed in etanercept clinical trials.  

[Describe slide]
	control observed v expected
	etanercept observed v expected
	SIR for control and etanercept
	All etanercept clinical trial experience with SIR

Furthermore, when one evaluates the entire clinical trial experience, the number of malignancies observed is not above that expected from the general population with an SIR of 0.98.

## Malignancies Rates are Stable Over Time

- All Etanercept Clinical Trials
- Malignancies / 100 patient-years

| Controlled Trial |  |           All Etanercept Experience |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Control | Etanercept | Yr 1 | Yr 2 | Yr 3 | Yr 4 | Yr 5 | Yr 6 | Overall |
| 1.0 | 0.9 | 0.8 | 0.6 | 0.6 | 1.1 | 0.8 | 1.4 | 0.8 |

**C16**

**Notes:**
The rate of malignancies is shown on this slide as a rate, or events per 100 patient-years of observation.  Once again, the rate is similar between etanercept and controls and there is no increase over time. 

## SIR with 95% Confidence Intervals for 

**SIR with 95% Confidence Intervals for **
**All Malignancies in Clinical Trials**

- 	All Sites
- 	Breast
-   Digestive
-   Respiratory
- 	Female Genital
- 	Male Genital
- 	Urinary System
- 	Oropharyngeal
- 	Lymphoma
-   Endocrine
-   Skin1
-   Neurologic
- 	Leukemia
-   Myeloma
-   Other

**Risk Ratio**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**C17**

**Notes:**
This slide represents the SIR with confidence intervals for malignancies by organ system.  You can see that the confidence intervals for all groups include one. The distribution seen in post marketing is comparable.

## Presentation Outline

- Introduction			  		Dan Burge, MD
- Etanercept Clinical Profile
- Pharmacovigilance
- General Safety
- Malignancy/Lymphoma
**Epidemiology of Lymphoma in RA**	**Alan Silman, MD**
- Lymphoma and Etanercept			Dan Burge, MD
- Heart Failure Experience
- Ongoing Pharmacovigilance
- Summary

**C18**

**Notes:**
Now we would like to have a brief discussion about the epidemiology of lymphoma in RA.

We will begin by describing some of the unique characteristics of etanercept and aspects of the etanercept pharmacovigilance program. We will then share some general observations from the extensive experience accrued with etanercept.  Dr. Alan Silman will provide perspective on the epidemiology of lymphoma in RA patients.   We will then review our data from clinical trials and post marketing regarding lymphoma and will conclude with observations regarding etanercept and heart failure.  (Delete?)

## Background Epidemiology of Lymphoma in RA

- Alan Silman, MD
-     Director, Arthritis Research Campaign’s Epidemiology Research Unit
- University of Manchester Medical School
- ARC Professor of Rheumatic Disease
- Epidemiology,University of Manchester
- Manchester, United Kingdom

**C19**

**Notes:**
For this presentation, I would like to introduce Dr. Alan Silman, rheumatologist and epidemiologist from the Medical Research Council of the United Kingdom who is currently one of the lead investigators for the UK national RA registry. Dr Silman is Professor at the University of  Manchester and will  share some of his thoughts regarding the epidemiology of lymphoma in patients with RA  Dr. Silman...

## Components of Lymphoma Risk 

- Risk attributable to RA *per se*
- Increased risk attributable to severe RA
- Increased risk attributable to prior exposure to:
- Other immunosuppressives (azathioprine, methotrexate)
- Other biologic agents

**Components of Lymphoma Risk **
**in Etanercept Treated Patients**

**C20**

## Measures of Risk

- Standardized Incidence Ratio	=	Observed		Expected
- Attributable (Absolute) Risk	=	Observed – Expected
- Attributable Risk Fraction	=	Observed – Expected			Expected

**C21**

## Example

- Observed Incidence	=	3/1000 pyr
- Expected Incidence	=	2/1000 pyr
- SIR	=	3/2	=	1.5
- Absolute Risk	=	3/1000 – 2/1000 = 1/1000 pyr
- ARF	=	3/1000 – 2/1000	= 0.33 (33%)		        3/1000

**C22**

## Considerations in Determination of Risk

- Background incidence in comparable population
- Accurate exposure data
- Completeness of follow-up
- Population characterization (age, gender, race, etc.)
- Disease/treatment characterization
- Accurate and complete detection of incident cases
- Case ascertainment
- Case validation

**C23**

**Notes:**
Causality, prevalence or proportions give point estimate
Talk to ITT issue, discuss with Silman

## Other Methodological Issues

- Lymphoma rare and risk estimates have wide confidence intervals
- Surveillance bias – are early lymphomas likely to be due to drug or better detection
- Influence of dose
- Ever/never, duration etc
- Influence of length of follow up
- Follow up periods may not have equivalent risk

**C24**

## Variation in Lymphoma Incidence:RA Populations

**C25**

## Increased Risk of LymphomaIn RA Patients*

| Reference | SIR | Lower CL | Upper CL |
| --- | --- | --- | --- |
| Isomaki | 2.7 | 1.9 | 3.7 |
| Gridley | 1.9 | 1.3 | 2.6 |
| Mellenkjaer | 2.4 | 1.9 | 2.9 |
| Thomas | 2.1 | 1.7 | 2.6 |
| All | 2.2 | 2.0 | 2.5 |

**C26**

***Based on data generated prior to the availability of TNF antagonists**

**Notes:**
Dr. Silman speaks

Then Dan comes back to the podium.

Thank you Dr. Silman.

## Available Evidence on Lymphoma 

- Clinical Trials
- Post-Marketing Safety Surveillance
- Histology
- Conclusions

**C27**

**Notes:**
We would now like to discuss the available data on lymphoma from etanercept clinical trials and post-marketing experience.  We will review the histology of lymphoma reports and state the conclusions that can be drawn from this data.

## SIR for Lymphoma in Etanercept Clinical Trials Relative to General Population

**Lymphoma during clinical trials**

**C28**

**Notes:**
Recall that an accurate estimation of SIR is dependant on precise ascertainment of incident cases and the corresponding period of observation.  Clinical studies provide the only opportunity to accurately estimate the SIR for the treated population. 

In the etanercept clinical trials program, 6 cases of lymphoma have been reported on study.  Utilizing the SEER database, applied to a comparable cohort in the general population one would expect 2.59 cases yielding an SIR of 2.31. Note that the confidence interval includes one ... and the point estimate is similar to the 2.2 represented by Dr. Silman.

Note that this table will act as a reference on the next 3 slides for further analyses.

## SIR for Lymphoma in Etanercept Clinical Trials Relative to General Population

**Lymphoma during clinical trials**

- Time to onset:   Median years (range): 2.6 (0.4-4.8)

**C29**

| Population | Cases | Patient-years | Expected | SIR | 95% Confidence Intervals |
| --- | --- | --- | --- | --- | --- |
| Early | 2 | 1942 | 0.582 | 3.44 | 0.42 – 12.41 |
| Advanced | 4 | 6394 | 2.012 | 1.99 | 0.54 – 5.09 |

**Lymphoma SIR by disease duration**

**Notes:**
Etanercept has been evaluated in a broad range of patient populations.  The vast majority of patients regardless of disease duration, had moderate to severe RA with mean tender and swollen joint counts in the high 20s.  Other than the early RA study, patients had typically failed 3 or more DMARDs and had a mean disease duration of greater than 10 years. 
Evaluating the lymphoma SIR in early vs. more advanced disease we obtain numbers that are quite similar.
Additionally, time to onset is dispersed over time with a range of 0.4 - 4.8 years.

## SIR for Lymphoma in Etanercept Clinical Trials Relative to General Population

**Lymphoma during clinical trials**

**Lymphoma cases during and after clinical trials completion**

**C30**

**Notes:**
Three additional lymphomas have been reported after study completion in patients previously treated with etanercept  in clinical trials.  As the period of post-trial observation for all patients is not known, an accurate denominator cannot be calculated and we cannot derive an accurate SIR.  
However, if we consider only the patient time on study, and use the expected number of 2.59, this conservative SIR is 3.47.

## SIR for Lymphoma in Etanercept Clinical Trials Relative to RA Population

**Lymphoma during clinical trials (relative to general population)**

**Lymphoma cases in clinical trials (relative to RA population)***

***Benchmark factor of 2.2 for RA population**

**C31**

**Notes:**
The SIR calculated in the previous slides has been relative to the general population. Using the benchmark of 2.2 fold increased risk described by Dr. Silman for the RA population, we multiple the 2.59 expected cases in the general population by the 2.2 and derive an expected number of 5.7 for the RA population.The SIR for this analysis is 1.05.
Recognize that patients treated with etanercept have more severe disease than the general RA population which is known to confer greater risk than lymphoma. No adjustment for severe disease has been made.

## Post-Marketing Lymphoma Reports 

- Reported cases*:  			     70 / 140,000 pts
- Reporting rate:  			    0.3 / 1000 pt-yrs
- Demographic characteristics of patients
- 	Female 					 69%
- 	Mean age                			 61 years
- 	Past or concurrent MTX		 	 60%

- *Data through November 2, 2002

**C32**

**Notes:**
Lymphomas have been described in post-marketing reports in patients who have received etanercept therapy.   The reporting rate is 0.3 cases per 1000 patient-years.  The background incidence in the  general population is 0.3 per 1000 patient-years. Utilizing the adjustment of 2.2 would yield an incidence for the RA population of 0.66 per 1000 patient-years.  As would be expected in a predominantly rheumatoid arthritis population, most of the reports are from women, the mean age is 61 and the majority previously treated with methotrexate.

## Lymphoma Reporting Rates from Commercial Experience are Stable Over Time

**0**

**40**

**80**

**120**

**160**

**200**

**11/98-4/99**

**5/99-10/99**

**11/99-4/00**

**5/00-10/00**

**11/00-4/01**

**5/01-10/01**

**11/01-4/02**

**5/02-10/02**

**Reports per 100,000 pt-yrs**

**By report date**

**By diagnosis date**

- Data through November 2,2002.  Error bars represent the upper limit of exact 95% confidence intervals.

**Lymphoma Reporting Rates from Commercial Experience are**** Stable Over Time**

**C33**

**Notes:**
We have carefully tracked these reports since commercialization.  Shown here are the rate of reports by report date in yellow and by diagnosis date in blue.  As one can see, the reporting rate for  lymphoma, presented in 6 month intervals here,  are stable over the 4 years of commercial experience.

## Lymphoma Subtypes

- 	Clinical Trials and Post-marketing Reports (Pooled)

- *Proportions represented in SEER database

**C34**

**Notes:**
We have evaluated the distribution of subtypes of lymphoma in the clinical trials and post marketing experience.  As can be seen here, the distribution -- 14% Hodgkins and 86% Non-Hodgkins -- is nearly identical to that expected in the general population utilizing rates in the SEER database.

## Histology of Non-Hodgkin’s Lymphomas Similar to RA Population1

- 	**Histology****	****Etanercept Reports****2****	****RA****3****	****    Non-RA Controls****3**
-   **Diffuse large cell****	****43%****	****38%****	****43%**
**   ****Mantle cell****	****5%****	****0%****	****2%**
**   ****Peripheral T cell****	****8%****	****2%****	****4%**
**	****Follicular****	****16%****	****33%****	****27%**
**	****Small lymphocytic**
**         ****lymphoma/B-cell CLL****	****22%****	****14%****	****12%**
**	****Waldenstrom’s Macro.****	****5%****	****NA****	****NA**
**   ****Marginal zone****	****0%****	****7%****	****0%**
**   ****Other****	****NA****	****2%****	****2%**

- 1 Histopathology report available in 67% of lymphoma reports
- 2 Data through November 2, 2002, combined clinical trials and post-marketing reports
- 3 Kamel et al*. *J. Rheum.* *1999

**C35**

**Notes:**
We additionally obtain, whenever possible, pathology reports on cases of lymphoma and have them reviewed by an oncologist or hematopathologist for classification into histologic subtypes.  Histopathology was obtained for over two thirds of the reports.  The distribution of the NHL subtypes is compared here to the distribution reported in the literature for a rheumatoid arthritis population and to non-RA controls.  The distribution of histologic subtypes is similar in all three groups.  
Immunosuppression, such as that seen following organ transplantation, is commonly associated with an increase in the proportion of diffuse large B cell lymphomas....and this pattern is not seen with etanercept therapy as shown in the first line of this slide.

If Remicade and/or Humira have a profile similar to transplant patients them bring in the created backup.

## ConclusionsLymphoma Incidence Consistent with Background RA

- Lymphoma reports with etanercept are rare
- Comprehensive pharmacovigilance program has been in place for 4-1/2 years
- The rate observed in clinical trials is consistent with the expected rate observed for RA (SIR=2.31)
- Post-marketing experience is compatible with clinical trial experience
- The proportion of histologic subtypes comparable with background
- Six years of sustained therapy has revealed no increase in incidence

**C36**

**Notes:**
In conclusion, lymphoma reports with etanercept are rare.  A comprehensive pharmacovigilance has been in place for 4-1/2 years.  The rate of lymphomas observed in clinical trials is consistent with the expected rate for RA patients with an SIR of 2.3.  Our post-marketing experience is compatible with clinical experience and the distribution of histologic subtypes is as expected.  With 6 years of sustained therapy we see no evidence of an increase in lymphoma incidence.

## Amgen Initiatives

- Update label to describe experience
- Submitted October 2002 (Adverse Reactions)
- Describes lymphoproliferative disorders from post-marketing and clinical studies
- Lymphoproliferative disorders, including lymphoma, have been reported from patients on etanercept
- Rates similar to RA population
- Presentations at scientific meetings
- ACR, *Sabath et al, Arth.Rheum., 2002*
- EULAR, *Sabath et al, Ann Rheum Dis., 2002*
- Large, long-term clinical trials
- Observational studies / registries in over 12,000 patients
- Epidemiologic studies
- Safety surveillance of post-marketing reports

**C37**

**Notes:**
Amgen supports proactive communication to health care providers and has initiated processes to assure timely dissemination of information. We therefore, in the latter part of 2002, submitted a proposal to the FDA to represent the lymphoma experience in the Adverse Events section of the etanercept package insert.  

The purpose of this proposal was two-fold—1) to inform physicians that the background incidence of lymphoma in RA was increased and 2) that “The observed incidence of lymphoproliferative disorders from clinical trials and the post-marketing reporting rate are similar to those expected.”
We have presented this data at scientific meetings for Rheumatologists.
We believe that the programs we have in place: long-term clinical trials, observational studies, further characterization of epidemiology, and continued safety surveillance are an important part of our commitment to patients.

## Presentation Outline

- Introduction			  		Dan Burge, MD
- Etanercept Clinical Profile
- Pharmacovigilance
- General Safety
- Malignancy/Lymphoma
- Epidemiology of Lymphoma in RA		Alan Silman, MD
- Lymphoma and Etanercept			Dan Burge, MD
**Heart Failure Experience**
- Ongoing Pharmacovigilance
- Summary

**C38**

## Etanercept CHF Trials Design

**Etanercept CHF Trials Design**

-  RENEWAL (n = 2048)

- Trials discontinued after pre-specified interim analysis determined study was unlikely to demonstrate benefit.

**C39**

**Analysis of**
**Combined**
**Data**

**Notes:**
The etanercept CHF program consisted of over 2000 patients in 2 studies. The global trial, called RECOVER, included 3 treatment groups:  placebo, etanercept 25 mg once weekly and 25 mg twice weekly. The North American Trial, called RENAISSANCE, also included 3 treatment groups:  placebo, and etanercept 25 mg twice and three times weekly.  The analysis of the combined studies was called RENEWAL.
	(Pause)
The program had in place predefined interim analyses for safety and efficacy. One of these analyses, a futility analysis, specified that the studies were to be discontinued if meaningful clinical benefit was not likely to be demonstrated. In March of 2001, the futility endpoint was met and the studies were stopped.  
These trials were discontinued when a pre-specified interim analysis determined that etanercept was unlikely to be associated with meaningful clinical benefit.

## Etanercept CHF Trials Primary Efficacy Endpoint:  All Cause Mortality/CHF Hospitalization

**Etanercept CHF Trials Primary Efficacy Endpoint:  All Cause Mortality/CHF Hospitalization**

***Unadjusted****** ******Analysis****

**Renaissance**
**	**** **25mg vs. placebo (2x/wk)
**	**** **25mg vs. placebo (3x/wk)
**Recover**
**	**** **25mg vs. placebo (1x/wk)
**	**** **25mg vs. placebo (2x/wk)** **
**Renewal **
**	****BIW + TIW vs. placebo**

**0.5**

**1.0**

**1.5**

**2.0**

**Risk Ratio**

**RR = 1.21, p = 0.17**

**RR = 1.23, p = 0.13**

**RR = 1.01, p = 0.97**

**RR = 0.87, p = 0.45**

**RR = 1.10, p = 0.33**

**C40**

**Notes:**
The primary efficacy endpoint of RENEWAL, an analysis of data from the combined studies, was time to all cause mortality or CHF hospitalization.  
This morbidity and mortality endpoint was also evaluated in the individual studies but was not the primary endpoint.

[Describe slide]
	confidence interval of all analyses includes one
	trend in Renaissance toward worse outcomes
	trend not replicated in Recover

The relative risk from the primary analysis,  was 1.1.

## Renaissance:  Randomization Imbalances Favor Placebo Group

**	****	****                   ****	****    ****Etanercept****	**
**	****	****Placebo****	**** 25 mg biw****	**** 25 mg tiw**
**	****	**** ****(n = 309) ****	****(n = 308)****	**** (n = 308)**
**	**** ****	**** ****	**
**Afib/flutter(%)****	****	****29****	****36****	****36****	****	****	**
**CABG (%)****	****	****33****	****42****	****41**
**SBP - mm Hg (median)****	****110****	****108****	****105**
**DBP - mm Hg (median) ****	****68****	****66****	****64**
**Anti-arrhythmics (%)****	****	****15****	****22****	****21**
**6-min walk - meters (median) ****	****295****	****293****	****288**

**Renaissance:  Randomization Imbalances Favor Placebo Group**

**C41**

**Notes:**
A number of patient characteristics known to have significant impact on heart failure outcomes were prospectively identified as covariates relevant to the interpretation of the trial findings.  In the Renaissance study, randomization of patients resulted in imbalances of some of these characteristics in favor of the placebo group.

For example, the percentage of patients with a history of afib or flutter is 29% in the placebo group and 36% in each of the etanercept groups.

## Etanercept CHF Trials Primary Efficacy Endpoint:  All Cause Mortality/CHF Hospitalization

**0.5**

**1.0**

**1.5**

**2.0**

**Risk Ratio**

**RR = 1.09, p = 0.55**

**RR = 1.11, p = 0.43**

**RR = 0.98, p = 0.92**

**RR = 0.90, p = 0.56**

**RR = 1.01, p = 0.90**

***Analysis with Covariates****

- *Results from Cox model. Both analyses include strata (NYHA class and use of beta-blockers)

***Unadjusted****** ******Analysis****

**Renaissance**
**	**25mg vs. placebo (2x/wk)
- 	25mg vs. placebo (3x/wk)
**Recover**
**	**25mg vs. placebo (1x/wk)
- 	25mg vs. placebo (2x/wk)** **
**Renewal **
**	**BIW + TIW vs placebo

**0.5**

**1.0**

**1.5**

**2.0**

**Risk Ratio**

**RR = 1.21, p = 0.17**

**RR = 1.23, p = 0.13**

**RR = 1.01, p = 0.97**

**RR = 0.87, p = 0.45**

**RR = 1.10, p = 0.33**

**C42**

**Notes:**
The left side of this slide represents the data previously shown.	
On the right side of the slide,is the relative risk after adjustment, using Cox proportional hazards regression, for the predictive and imbalanced covariates.  The trends seen in the RENAISSANCE study have diminished and the combined analysis results in a relative risk of 1.01.

## Etanercept CHF Trials: Analysis of All Cause Mortality (Secondary Efficacy Endpoint)

**Etanercept CHF Trials: Analysis of All Cause Mortality (Secondary Efficacy Endpoint)**

***Unadjusted****** ******Analysis****

**Renaissance**
**	**** **25mg vs. placebo (2x/wk)
- 	 25mg vs. placebo (3x/wk)
**Recover**
**	**** **25mg vs. placebo (1x/wk)
- 	 25mg vs. placebo (2x/wk)
**Renewal **
**	**** **BIW + TIW** **
**   **vs.** **placebo

**Risk Ratio**

**Risk Ratio**

***Analysis with Covariates****

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**RR = 1.27, p = 0.24**

**   ****RR = 1.13, p = 0.55**

**RR = 1.37, p = 0.12**

**RR = 1.22, p = 0.33**

**RR = 0.68, p = 0.16**

**RR = 0.66, p = 0.13**

**RR = 0.83, p = 0.47**

**RR = 0.85, p = 0.55**

**RR = 1.13, p = 0.39**

**RR = 0.96, p = 0.79**

**C43**

**Notes:**
This slide represents a secondary endpoint of time to all cause mortality.  The findings of this endpoint are similar to the primary endpoint shown previously.  There was a trend in worse outcomes in the RENAISSANCE study that was not duplicated in RECOVER . Again, after accounting for covariates, the trends diminish and the relative risk of the combined analysis was 0.96.
[go to slide for this description]

## New Onset CHF in North American Rheumatic Disease Trials

- Controlled Trials
- Control		  2
- Etanercept		  2
- All Trials
- Observed		  7
- Expected1		15.2

- 1. Kannel WB, *J Clin Epidemiol* 53 (2000)

**C44**

**Notes:**
In conjunction with the review of the data from patients with underlying heart disease, we also analyzed heart failure occurrences in rheumatic disease clinical trials, patients who were not known to have underlying heart disease.
The number of subjects developing new onset heart failure was equal in etanercept and control arms in the controlled trials. As much of our experience is from open label trials, where no comparator data is available, we have used benchmarks from the literature to calculate the expected number of cases. 
The number of cases of new onset CHF treated with etanercept, in rheumatic disease trials was 7 compared to an expected 15.2.  

The rate of CHF is not increased in the etanercept clinical trials.

## Etanercept Label

**Precaution:  Patients with Heart Failure**
- 	Two large clinical trials evaluating the use of ENBREL in the treatment of heart failure were terminated early due to lack of efficacy. Although the studies did not demonstrate harm, there was a suggestion of worse heart failure outcomes with ENBREL treatment in one of the two trials. There have been post-marketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking ENBREL. Physicians should exercise caution when using ENBREL in patients who also have heart failure.

**C45**

**Notes:**
Despite no clear evidence of deleterious effect of etanercept in heart failure, we felt it was appropriate to communicate these findings to health care providers, particularly rheumatologists.  On that basis, in May of 2002, we added a precaution in the product label.

Additionally, the data from the heart failure trials was presented at scientific meetings for cardiologists and rheumatologists.

## Two large heart failure studies were discontinued due to lack of efficacy
One of two studies showed a trend toward worse heart failure outcomes that diminishes with adjustment for covariates
No evidence from rheumatic disease trials that etanercept increases risk for CHF
Proactive communication in product label and at scientific meetings

- One of two studies showed a trend toward worse heart failure outcomes that diminishes with adjustment for covariates
- No evidence from rheumatic disease trials that etanercept increases risk for CHF
- Proactive communication in product label and at scientific meetings

**C46**

**Conclusions**

**Notes:**
In conclusion,
Two large heart failure studies were discontinued due to lack of efficacy
Although, one of the two studies showed a trend toward worse heart failure outcomes that diminishes with adjustment for covariates, the second trial did not.  
Overall, there is no clear treatment effect of etanercept in heart failure patients.
Additionally, there is no evidence from rheumatic disease trials that etanercept increases risk for CHF
However we chose to inform prescribers through labeling and presentations at scientific meetings.

## Large, long term clinical trials
Epidemiologic studies
Observational studies and registries
Safety surveillance and post-marketing reports
Proactive risk communication

- Epidemiologic studies
- Observational studies and registries
- Safety surveillance and post-marketing reports
- Proactive risk communication

**Extensive Proactive Pharmacovigilance**

**C47**

**Notes:**
We have built a foundation of extensive long term safety experience with etanercept.  This experience encompasses the clinical trials discussed in the is presentation complimented by observational and epidemiologic studies and ongoing safety surveillance.  
Amgen is committed to proactive communication.

## Ongoing and Future             Pharmacovigilance Programs

| Prospective Program | 
Status | Planned Duration 
(yrs.) | Current or Planned Enrollment |
| --- | --- | --- | --- |
| North American long term clinical trials | 5 years experience | 10 | 1100 |
| EU long term clinical trials | 4 years experience | 4 | 549 |
| RADIUS I (all DMARDS) | Fully enrolled | 5 | 5000 |
| RADIUS II (etanercept) | 80% enrolled | 5 | 5000 |
| JRA Registry | > 50% enrolled | 3 | 600 |
| EU Registries | Enrolling | 5-8 | 1600 (approx.) |

**C48**

**Notes:**
This table summarizes the initiatives that are being conducted by Amgen and Wyeth.  We anticipate that these programs going forward will provide further insights into the safety issues discussed today. 

The long term clinical trials, where we have already accrued 5 years of experience, will be conducted for at least 10 years.  

Additionally, the ongoing RADIUS program will prospectively observe 10,000 RA patients for 5 years in the clinical practice setting. Furthermore, a JRA registry has been established in the US and National RA registries have been implemented in Germany, Sweden and the United Kingdom.

This comprehensive program will advance our understanding of etanercept and underscores Amgen and Wyeth’s commitment to patient safety. 

We believe long-term clinical trials, large observational studies, post-marketing surveillance and improved epidemiologic understanding support more-informed prescribing and better care for patients.

## Nearing Completion of Post-Marketing Commitment for Long Term Follow-up

- Submitted 3 year data: currently labeled
- Submitted 4 year data:  January 2003
- Plan to submit 5 year data:  August 2003
- 	Ongoing Amgen commitment: continued follow-up for additional 5 years for a total of 10 years

**C49**

**Notes:**
Three year safety and efficacy data from our long term trials 
have been included in our product label and we have submitted to the FDA our 4 year data. We plan to submit data regarding 5 years of etanercept experience to the FDA this Summer. These data have been included in the presentations this morning. 

Although we have nearly fulfilled our post-marketing commitment to the FDA, we will continue to follow these patients for an additional 5 years.

## Etanercept Summary

- Unique mechanism of action
- Established track record
- Over 9 years experience treating rheumatic disease patients
- Over 4 years of clinical practice experience
- Robust pharmacovigilance program
- Safety profile well established
- Benefit / risk highly favorable

**C50**

**Notes:**
In summary, the soluble receptor, Etanercept, has a unique structure, mechanism of action and pharmacokinetic profile, that we believe make etanercept a unique therapeutic. 
Etanercept has an established track record, with over 9 years of experience in treating rheumatic disease patients and over 4 years of clinical practice experience. This extensive experience --along with the robust pharmacovigilance program --  has allowed us to characterize the etanercept safety profile.
 With its highly favorable benefit/risk profile, etanercept remains a very important contribution in the therapy of patients with rheumatic diseases.