24 June 2003 Arthritis Advisory Committee Meeting

Briefing Document for ENBREL^^ (etanercept)

For the Treatment of Ankylosing Spondylitis

28 May 2003

**AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION**

Amgen Inc.\
One Amgen Center Drive\
Thousand Oaks, CA 91320-1799

Table of Contents

[1. Executive Summary 1](#executive-summary)

[1.1 Background and Rationale 1](#background-and-rationale)

[1.2 Clinical Development of Etanercept for the Treatment of Patients
with Ankylosing Spondylitis
1](#clinical-development-of-etanercept-for-the-treatment-of-patients-with-ankylosing-spondylitis)

[1.3 Summary of Efficacy 1](#summary-of-efficacy)

[1.4 Summary of Safety 2](#summary-of-safety)

[1.5 Conclusion 2](#conclusion)

[2. Rationale for Etanercept use in the Treatment of Ankylosing
Spondylitis
3](#rationale-for-etanercept-use-in-the-treatment-of-ankylosing-spondylitis)

[2.1 Etanercept Background 3](#etanercept-background)

[2.2 Ankylosing Spondylitis 3](#ankylosing-spondylitis)

[2.2.1 Description of the Disease Setting
3](#description-of-the-disease-setting)

[2.2.2 Description of Currently Available Therapies
4](#description-of-currently-available-therapies)

[2.2.3 Role of Tumor Necrosis Factor in Ankylosing Spondylitis
4](#role-of-tumor-necrosis-factor-in-ankylosing-spondylitis)

[3. Development of Disease Response Criteria in Ankylosing Spondylitis
4](#development-of-disease-response-criteria-in-ankylosing-spondylitis)

[3.1 Ankylosing Spondylitis Assessment (ASAS) Working Group Criteria
4](#ankylosing-spondylitis-assessment-asas-working-group-criteria)

[3.2 Disease Controlling Anti-Rheumatic Therapy (DCART)
6](#disease-controlling-anti-rheumatic-therapy-dcart)

[4. Description of the Etanercept Development Program for Ankylosing
Spondylitis
7](#description-of-the-etanercept-development-program-for-ankylosing-spondylitis)

[4.1 Overview of the Program 7](#overview-of-the-program)

[4.2 Proof of Principle (Study 16.0626)
7](#proof-of-principle-study-16.0626)

[4.3 Pivotal Program 8](#pivotal-program)

[4.3.1 Study Designs 8](#study-designs)

[4.3.2 Study Endpoints 9](#study-endpoints)

[4.4 Statistical Analyses 10](#statistical-analyses)

[5. Results for Pivotal Program 11](#results-for-pivotal-program)

[5.1 Study Populations 11](#study-populations)

[5.1.1 Baseline Demographics and Disease Characteristics
11](#baseline-demographics-and-disease-characteristics)

[5.1.2 Study Completion 14](#study-completion)

[5.2 Efficacy Results 14](#efficacy-results)

[5.2.1 Primary Endpoint: Protocol-Defined ASAS Response
14](#primary-endpoint-protocol-defined-asas-response)

[5.2.2 Individual Components of ASAS 20
17](#individual-components-of-asas-20)

[5.2.3 Additional Measures of Disease Activity
19](#additional-measures-of-disease-activity)

[5.2.4 Disease-Controlling Anti-Rheumatic Therapy Response
21](#disease-controlling-anti-rheumatic-therapy-response)

[5.2.5 Subgroup Analyses for Study 016.0037
22](#subgroup-analyses-for-study-016.0037)

[5.3 Summary of Efficacy Results 23](#summary-of-efficacy-results)

[6. Safety Results 24](#safety-results)

[6.1 Overview of Safety Results 24](#overview-of-safety-results)

[6.2 Serious Adverse Events 24](#serious-adverse-events)

[6.3 Medically Important Infections 25](#medically-important-infections)

[6.4 Withdrawals Because of Adverse Events
25](#withdrawals-because-of-adverse-events)

[6.5 Noninfectious Adverse Events 26](#noninfectious-adverse-events)

[6.6 Infections 27](#infections)

[6.7 Malignancies 28](#malignancies)

[6.8 Clinical Laboratory Results 28](#clinical-laboratory-results)

[6.9 Antibody Results 29](#antibody-results)

[6.10 Safety Summary and Conclusions
29](#safety-summary-and-conclusions)

[6.11 Safety Profile in Ankylosing Spondylitis is Comparable to
Established Etanercept Safety Profile in Rheumatic Diseases
30](#safety-profile-in-ankylosing-spondylitis-is-comparable-to-established-etanercept-safety-profile-in-rheumatic-diseases)

[6.11.1 Clinical Trials in Subjects with Rheumatoid Arthritis and
Psoriatic Arthritis
30](#clinical-trials-in-subjects-with-rheumatoid-arthritis-and-psoriatic-arthritis)

[6.11.2 Comparison of Etanercept Safety Results in Ankylosing
Spondylitis with Rheumatoid Arthritis and Psoriatic Arthritis
Populations
30](#comparison-of-etanercept-safety-results-in-ankylosing-spondylitis-with-rheumatoid-arthritis-and-psoriatic-arthritis-populations)

[7. Risk-Benefit Assessment 31](#risk-benefit-assessment)

[8. References 32](#references)

List of Tables

[Table 3‑1. Ankylosing Spondylitis Assessment Group Preliminary
Definition of Short-Term Improvement in Ankylosing Spondylitis (Anderson
et al, 2001) 6](#__RefHeading___Toc41869681)

[Table 4‑1. Study 16.0626: Efficacy Results at Week 16
8](#__RefHeading___Toc41869682)

[Table 5‑1. Baseline Demographics and Therapy in the Pivotal Program
12](#__RefHeading___Toc41869683)

[Table 5‑2. Baseline Disease Characteristics in the Pivotal Program
13](#__RefHeading___Toc41869684)

[Table 5‑3. Study 016.0037: Primary Endpoint: ASAS 20 at Weeks 12 and 24
16](#__RefHeading___Toc41869685)

[Table 5‑4. Study 016.0037: Secondary Endpoints: ASAS 50 and 70, and
Partial Remission at Weeks 12 and 24 16](#__RefHeading___Toc41869686)

[Table 5‑5. Study 47687. Primary and Secondary Endpoints: ASAS 20, 50,
70, and Partial Remission at Week 12 18](#__RefHeading___Toc41869687)

[Table 5‑6. Study 016.0037: Results for Individual Components of
Protocol‑Defined ASAS 20 19](#__RefHeading___Toc41869688)

[Table 5‑7. Study 47687: Results for Individual Components of the
Protocol‑Defined ASAS 20 at Week 12 19](#__RefHeading___Toc41869689)

[Table 5‑8. Study 016.0037: Results for BASDAI, Spinal Mobility, Acute
Phase Reactants, Assessor Global, and Peripheral Joint Counts.
21](#__RefHeading___Toc41869690)

[Table 5‑9. Study 47687: Results for BASDAI, Spinal Mobility, Acute
Phase Reactants, and Assessor Global at Week 12
22](#__RefHeading___Toc41869691)

[Table 5‑10. Study 016.0037: DCART 20 and DCART 40 Responses
23](#__RefHeading___Toc41869692)

[Table 6‑1. Overall Summary of Adverse Events in Studies 016.0037 and
47687: Number (%) of Subjects Reporting Adverse Events
25](#__RefHeading___Toc41869693)

[Table 6‑2. Study 016.0037: Summary of Serious Adverse Events
26](#__RefHeading___Toc41869694)

[Table 6‑3. Study 016.0037: Summary of Adverse Events Causing Withdrawal
27](#__RefHeading___Toc41869695)

[Table 6‑4. Noninfectious Adverse Events in ≥ 5% of Subjects in
Either Study or Treatment Group 28](#__RefHeading___Toc41869696)

[Table 6‑5. Infections in ≥ 5% of Subjects in Either Study or Treatment
Group 29](#__RefHeading___Toc41869697)

List of Figures

[Figure 5‑1. Study 016.0037: Percent of Subjects Achieving
Protocol-Defined ASAS 20, 50, and 70 Over Time
17](#__RefHeading___Toc41869680)

# Executive Summary

## Background and Rationale

Ankylosing spondylitis (AS) is a chronic disease characterized by
ankylosis of the spine, inflammation at the insertions of tendons, and
occasionally peripheral arthritis. AS occurs predominantly in men, with
onset before age 30, and produces pain and stiffness as a result of
inflammation of the sacroiliac, intervertebral, and costovertebral
joints. The disease afflicts approximately 350,000 patients in the
United States (Carter et al, 1979).

The only approved therapies for AS are nonsteroidal anti-inflammatory
agents (NSAIDs) (Toussirot and Wendling, 1998). These therapies reduce
symptoms but have no demonstrated effect on the progressive,
debilitating spinal immobility that is a hallmark of the disease.
Second-line therapies, typically borrowed from the armamentarium for
rheumatoid arthritis (RA), have demonstrated little effect or have been
poorly studied. There is clearly a need for improved therapies for this
disease.

There is accumulating evidence that tumor necrosis factor (TNF) plays an
important role in AS, suggesting that anti-TNF therapies such as
etanercept could offer benefits not provided by current therapies. The
clinical data reviewed in this briefing package demonstrate that
etanercept has the potential to be a significant therapeutic advance in
the treatment of AS.

## Clinical Development of Etanercept for the Treatment of Patients with Ankylosing Spondylitis

The AS clinical development program evaluated etanercept 25 mg twice
weekly in 401 subjects in 3 randomized, double-blind, placebo-controlled
studies. A proof-of-principle study evaluated etanercept in 40 AS
subjects for 4 months. The results showed improvement in multiple
parameters of disease activity, including spinal mobility measures
(Gorman et al, 2002). Based on these data, Amgen initiated a 24-week
study of 277 subjects with AS (Protocol 016.0037) and Wyeth initiated a
similar 12-week study of 84 subjects (Study 0881A3-311-EU CSR 47687,
hereafter referred to as Study 47687).

## Summary of Efficacy

The efficacy of etanercept in subjects with AS is compelling. The
positive findings in the proof-of-principle study were confirmed in a
phase 3 study, Study 016.0037, where statistically significant responses
for etanercept were seen as early as 2 weeks and sustained at 12 and 24
weeks. The primary composite efficacy endpoint at week 12 was achieved
by 60% of etanercept-treated patients compared with 27% of placebo
patients (p \< 0.0001). Sustained improvements were apparent in each
component of the composite criteria, including inflammatory symptoms and
patient physical function, and in measures of spinal mobility and acute
phase reactants. The efficacy of etanercept in AS was again clearly
demonstrated in a supportive study, Study 47687.

## Summary of Safety

Etanercept was well tolerated by subjects with AS. Etanercept was
associated with a higher incidence of injection site reactions, upper
respiratory infections, and injury accidents than placebo. Few
significant laboratory abnormalities were observed in these studies.
Overall, the safety profile of etanercept in subjects with AS is similar
to that observed in subjects with RA and psoriatic arthritis (PsA).

## Conclusion

Three randomized, double-blind, placebo-controlled trials demonstrate
that etanercept is effective in the treatment of subjects with AS,
providing improvement in functional ability, spinal mobility, and
acute-phase reactants. Etanercept is well tolerated in this patient
population with a safety profile similar to that observed in etanercept
clinical trials with other inflammatory rheumatic diseases. The risk
benefit profile of etanercept in treating AS subjects is highly
favorable. Based on these data, the following addition is proposed for
inclusion in the etanercept product label:

> Etanercept is indicated for reducing signs and symptoms of active
> ankylosing spondylitis.

# Rationale for Etanercept use in the Treatment of Ankylosing Spondylitis

## Etanercept Background

Etanercept (ENBREL^^) is a fully human dimer of 2 molecules of the
extracellular portion of the p75 tumor necrosis factor receptor (TNFR)
fused to the Fc portion of a type 1 human immunoglobulin (IgG1).
Etanercept binds both TNF and lymphotoxin alpha (LTα) with high
affinity.

Etanercept has been approved in the United States for reducing signs and
symptoms and inhibiting the progression of structural damage in subjects
with moderately to severely active RA; for reducing signs and symptoms
of moderately to severely active polyarticular-course juvenile
rheumatoid arthritis (JRA) in subjects who have had an inadequate
response to one or more disease-modifying antirheumatic drugs (DMARDs);
and for reducing signs and symptoms of active arthritis in subjects with
psoriatic arthritis (PsA).

Etanercept has been administered to 3389 subjects in rheumatic disease
clinical trials for currently approved indications and the postmarketing
worldwide commercial experience with etanercept includes more than
180,000 patients. Clinical trials in RA have shown that etanercept
remains safe and effective for over 6 years and allows subjects to
reduce or discontinue the use of concomitant corticosteroids or
methotrexate while maintaining clinical response.

## Ankylosing Spondylitis

### Description of the Disease Setting

Ankylosing spondylitis (as) is a chronic inflammatory arthritis and
enthesopathy involving the spine and peripheral joints. It occurs
predominantly in men, with onset typically before age 30, and is
associated with pain and stiffness resulting from inflammation of the
sacroiliac, intervertebral, and costovertebral joints. It is one of the
spondyloarthropathies (SpA) marked by absence of plasma rheumatoid
factor and an association with HLA‑B27. These diseases also include
psoriatic arthritis (PsA), reactive arthritis (ReA), and arthritis
associated with inflammatory bowel disease.

The prevalence of SpA is estimated to be 0.6% to 1.9% and is similar to
the prevalence of RA (0.8%) (Braun and Sieper, 2002). It is estimated
that there are currently over 350,000 AS patients in the United States
(Carter et al, 1979).

A recent study showed that the degree of pain and disability among
patients with AS is similar to that among patients with rheumatoid
arthritis (Zink et al, 2000). Moreover, many patients with AS have
severe inflammatory symptoms even decades after diagnosis of the disease
(Ward, 1999; Gran and Skomsvoll, 1997; Kennedy et al, 1993; Goodacre et
al, 1991; Ringsdal and Andreasen, 1989; Taylor et al, 1998).

### Description of Currently Available Therapies

Traditional therapies, including NSAIDs, corticosteroids, and DMARDs,
are inadequate for AS patients (Toussirot and Wendling, 1998). NSAIDs
are often used for symptomatic relief but may not control disease
activity and appear incapable of effecting the progressive spinal
immobility that is characteristic of AS (Toussirot and Wendling, 1998).
Sulfasalazine, while somewhat effective in treating peripheral
arthritis, does little for axial disease (Dougados et al, 1995). A small
controlled study of methotrexate demonstrated no effect on AS
(Roychowdhury et al, 2001). In small studies, azathioprine showed some
benefit in the treatment of ReA (Creemers et al, 1994). D-penicillamine,
cyclophosphamide, levamisole, and methylprednisolone have yielded
conflicting results (Creemers et al, 1994). Oral gold, corticotropin, or
antimalarials are not effective in AS (Amor 1995; Creemers et al, 1994).
Radiation treatment for synovitis has been abandoned because of its
serious long-term side effects (Creemers et al, 1994). Treatment options
for SpA are extremely limited.

### Role of Tumor Necrosis Factor in Ankylosing Spondylitis

Tumor necrosis factor (TNF) plays a major role in the pathogenesis of
AS. TNF levels are elevated in serum (Toussirot and Wendling, 1994,
Gratacos 1994) and in synovial tissue (Canete et al, 1997; Grom et al,
1996) of patients with AS. These findings suggested that interfering
with the pro-inflammatory effects of TNF could reduce the clinical signs
and symptoms of AS and improve quality of life for patients with AS. As
a result, Amgen initiated a clinical program to investigate the
potential of etanercept as a new treatment for AS.

# Development of Disease Response Criteria in Ankylosing Spondylitis

## Ankylosing Spondylitis Assessment (ASAS) Working Group Criteria 

AS is a systemic inflammatory disease that manifests variable clinical
signs and symptoms. Assessment of patient status and response to
treatment has been problematic. Since no disease-altering therapies were
historically available, patients and physicians learned to accommodate
to progressive debility from AS by addressing the symptoms related to
pain and inflammation. Definitive measures of AS had not been developed
to assess the fundamental aspects of disease course.

To address the need for an effective clinical outcome measure optimal
for studying new therapeutic agents, the Ankylosing Spondylitis
Assessment (ASAS) Working Group was organized. This independent group of
AS experts has been meeting for approximately 8 years, and their efforts
toward establishing new AS assessment criteria have been published in
peer-reviewed journals (Anderson et al, 2001; van der Heijde et al,
1999; van der Heijde et al, 1997).

After considering over 100 potential clinical outcome measures, ASAS
identified a core set of 5 clinical domains considered essential for
characterizing changes in AS: physical function, pain, spinal mobility,
patient global assessment, and inflammation. Using data from clinical
trials of NSAIDs in the treatment of AS to validate potential candidate
response criteria from the 5 clinical domains, ASAS Working Group
developed the Ankylosing Spondylitis Assessment Group Preliminary
Definition of Short-Term Improvement in Ankylosing Spondylitis (ASAS
20), that included 4 of the 5 domains (Table 3-1 and Appendix 1) and
specified instruments for measuring them. Spinal mobility was not
included in the ASAS 20 because NSAIDs did not produce substantial
improvement in spinal mobility in the validation trials and therefore
the group did not consider it a good predictor of response. The ASAS 20
is modeled, at least in part, on composite outcome measures used in
studies of rheumatoid arthritis and osteoarthritis (Anderson et al,
2001).

[]{#__RefHeading___Toc41869681 .anchor}Table 3‑1. Ankylosing Spondylitis
Assessment Group Preliminary Definition of Short-Term Improvement in
Ankylosing Spondylitis (Anderson et al, 2001)

+-----------------------------------------------------------------------+
| An improvement of at least 20% and absolute improvement of at least   |
| 10 units on a scale of 0‑100 in at least 3 of the following 4         |
| domains:                                                              |
+-----------------------------------------------------------------------+
| > [Patient global assessment]{.underline} is represented by the VAS   |
| > global assessment score (0-100 scale)                               |
+-----------------------------------------------------------------------+
| > [Pain]{.underline} is represented by the VAS pain score (0-100      |
| > scale)                                                              |
+-----------------------------------------------------------------------+
| > [Function]{.underline} is represented by BASFI score (0-100 scale)  |
+-----------------------------------------------------------------------+
| > [Inflammation]{.underline} is represented either by (first choice)  |
| > the mean of the 2 morning stiffness-related BASDAI VAS scores, or   |
| > by (second choice) morning stiffness duration with a maximum of     |
| > 120 minutes (0-100 scale).                                          |
+-----------------------------------------------------------------------+
| Absence of deterioration in the potential remaining domain, where     |
| deterioration is defined as a change for the worse of at least 20%    |
| and net worsening of at least 10 units on a scale of 0 to 100         |
+-----------------------------------------------------------------------+
| VAS = visual analog scale                                             |
+-----------------------------------------------------------------------+

ASAS also defined a low level of disease activity as a "partial
remission" of AS represented by a value of \< 20 units (scale 1 to 100)
in each of 4 domains of the ASAS 20 (Anderson et al, 2001). This
endpoint was intended to provide a clinically meaningful definition of a
low disease state independent of change or improvement in the ASAS 20.

## Disease Controlling Anti-Rheumatic Therapy (DCART)

At a meeting convened October 30 to 31, 2002 to provide input for an FDA
Guidance for disease-modifying therapies in AS, an advisory group
including many members of the ASAS Working Group developed criteria for
disease controlling anti-rheumatic therapy (DCART). Two composite
response criteria were proposed.

The first, here called the DCART 20, combines the 4 criteria of the ASAS
20 with 2 additional criteria: improvement in spinal mobility and acute
phase reactants. The DCART 20 requires a 20% improvement in 5 of the 6
criteria, with no worsening in the remaining criterion.

The second, hereafter called the DCART 40, requires a 40% improvement
relative to baseline plus absolute improvement of at least 20 units in 3
of the 4 original ASAS 20 criteria, with no worsening in the remaining
criterion. The DCART 40 is an alternative to the DCART 20 that considers
different criteria (4 vs 6) and does not indicate a higher level of
response than the DCART 20.

# Description of the Etanercept Development Program for Ankylosing Spondylitis

## Overview of the Program

The development program for etanercept in AS enrolled and treated 401
subjects with uncontrolled AS despite the use of NSAIDs and other
therapies in 3 randomized, placebo-controlled studies. The first of
these was Study 16.0626, a 4-month, proof-of-principle study in 40
subjects that demonstrated encouraging clinical response to etanercept
(Gorman et al, 2002). With proof-of-principle established, 2 studies
were initiated: Study 016.0037 (Amgen; N = 277 subjects), a 6‑month
study in the United States, France, Germany, and the Netherlands; and
Study 0881A3-311-EU CSR 47687, hereafter referred to as Study 47687
(Wyeth; N = 84 subjects), a 3-month study in 8 European countries. These
studies confirmed the safety and efficacy of etanercept in subjects with
AS. Two open-label studies are ongoing and will allow for up to 2 years
of continuous etanercept therapy.

## Proof of Principle (Study 16.0626)

Study 16.0626 was a double-blind, proof-of-principle study that treated
40 subjects with AS (randomized 1:1) for 4 months with either etanercept
(25 mg) or placebo twice weekly (BIW) and offered 6 months of open-label
extension therapy. Inclusion criteria included: diagnosis of AS by
modified New York Clinical Criteria (van der Linden 1984), presence of
active disease (morning stiffness ≥ 45 minutes, inflammatory back pain,
patient and physician global assessment of moderate or severe disease
activity), and stable NSAIDs, steroids (≤ 10 mg of prednisone or
equivalent) or DMARDs (methotrexate, sulfasalazine, azathioprine,
6-mercaptopurine). Subjects were not eligible if other forms of SpA were
present, if they had received previous TNF inhibitor therapy, or if they
were positive for rheumatoid factor.

Study 16.0626 was designed and conducted before the ASAS 20 was
developed. The investigator prospectively defined response based on 5
clinical domains. The primary efficacy endpoint was the proportion of
subjects in each group achieving a 20% improvement (compared with
baseline) at week 16 in 3 of 5 response criteria (patient global
assessment, nocturnal spinal pain, duration of morning stiffness, Bath
Ankylosing Spondylitis Functional Index (BASFI), swollen joint score).
For determination of efficacy, improvement in spinal pain or morning
stiffness was required and worsening in the remaining 2 criteria was not
permitted. The study also looked at multiple exploratory secondary
endpoints.

The results of this study showed convincing efficacy for etanercept in
the composite response criteria and its individual components (Table
4-2), as well as a reassuring safety profile with an absence of serious
adverse events.

[]{#__RefHeading___Toc41869682 .anchor}Table 4‑2. Study 16.0626:
Efficacy Results at Week 16

+--------------------------+-------------+--------------+-------------+
|                          | Placebo     | Etanercept   | P-value ^a^ |
|                          |             |              |             |
|                          | n = 20      | n = 20       |             |
+--------------------------+-------------+--------------+-------------+
| **Composite Response     |             |              |             |
| Criteria: number (%)     |             |              |             |
| achieving response**     |             |              |             |
+--------------------------+-------------+--------------+-------------+
| Responders               | 5 (25)      | 15 (75)      | 0.0038 ^b^  |
+--------------------------+-------------+--------------+-------------+
|                          |             |              |             |
+--------------------------+-------------+--------------+-------------+
| **Individual components  |             |              |             |
| of composite response:   |             |              |             |
| mean (median) %          |             |              |             |
| improvement**            |             |              |             |
+--------------------------+-------------+--------------+-------------+
| BASFI                    | -7.2 (-6.7) | 48.7 (47.1)  | 0.0003      |
+--------------------------+-------------+--------------+-------------+
| Nocturnal Back Pain      | 14.4 (21.5) | 61.2 (66.7)  | 0.0014      |
+--------------------------+-------------+--------------+-------------+
| Patient Global           | 10.8 (0.0)  | 28.0 (33.3)  | 0.0177      |
| Assessment               |             |              |             |
+--------------------------+-------------+--------------+-------------+
| Duration of morning      | (18.3)      | (76.4)       | 0.0116      |
| stiffness^c^             |             |              |             |
+--------------------------+-------------+--------------+-------------+
|                          | n = 11      | n = 8        |             |
+--------------------------+-------------+--------------+-------------+
| Swollen Joint Score      | 14.2 (0.0)  | 46.9 (62.7)  | 0.2743      |
+--------------------------+-------------+--------------+-------------+
| ^a^ Wilcoxon rank-sum    |             |              |             |
| test                     |             |              |             |
|                          |             |              |             |
| ^b^ Fisher's exact test  |             |              |             |
|                          |             |              |             |
| ^c^ Mean % change is not |             |              |             |
| represented as it is     |             |              |             |
| highly influenced by a   |             |              |             |
| small number of subjects |             |              |             |
+--------------------------+-------------+--------------+-------------+

Significant improvement was also seen in some exploratory endpoints
including total pain, joint pain/tenderness score, physician global
assessment, Dougados Functional Index (DFI), Krupp's Fatigue Measure,
modified Schober's Test, occiput-to-wall measurement, Westergren ESR,
and the physical component summary score (PCS) of the SF-36.

Based on these results, the 2 larger studies were initiated.

## Pivotal Program

### Study Designs

Studies 016.0037 and 47687 were randomized, double-blind,
placebo-controlled, phase 3 trials that randomized subjects in a 1:1
ratio (with stratification by baseline DMARD use) to receive etanercept
(25 mg) or placebo BIW. In Study 016.0037, subjects were followed during
24 weeks of double-blind treatment, and in Study 47687, treatment and
observation was for 12 weeks. Subjects 18 to 70 years old were diagnosed
with AS as defined by Modified New York Criteria for Ankylosing
Spondylitis. They had active disease defined by values ≥ 30 on a 0 to
100 point VAS for duration/intensity of morning stiffness and 2 of the
following 3 parameters: patient global assessment, average of VAS values
for nocturnal back pain and total back pain, or average of 10 questions
on the BASFI. Subjects were not allowed to enroll if they had clinical
or radiographic evidence of complete ankylosis of the entire spine; had
a history of active or recurrent infection; had ever received etanercept
or other TNFα inhibitors; had received any investigational drug therapy
within 30 days; had used DMARDs other than hydroxychloroquine,
sulfasalazine, or methotrexate within 4 weeks of baseline evaluation; or
had changed their dose of NSAIDs or prednisone (≤10 mg/ day or
equivalent) within 2 weeks of baseline. Subjects were assessed for
safety and efficacy at baseline and weeks 2, 4, 8, and 12 in both
studies, and additionally at week 24 in Study 016.0037.

### Study Endpoints

**Efficacy**

The pivotal program was developed before publication of the ASAS 20
(Anderson et al, 2001) and used an endpoint that differed slightly. The
protocol-defined ASAS 20 used an average of total pain and nocturnal
pain scores on the 100-mm visual analog scale (VAS) to represent the
pain domain where the published ASAS 20 included only the total pain
score. The difference in response criteria had no impact on the
significance of the results.

The primary endpoint in both studies was the protocol-defined ASAS 20
criteria for response at week 12. The conditional primary endpoint in
Study 016.0037, to be assessed if the primary endpoint was achieved, was
the ASAS 20 response at week 24.

Other endpoints in both studies included frequency and time to partial
remission, the individual components of the ASAS 20 (patient global
assessment, nocturnal and total back pain, BASFI, and the average of
duration and severity of morning stiffness from the Bath AS Disease
Activity Index (BASDAI), the assessor global assessment, BASDAI,
measurements of spinal mobility (the Schober test, measurement of chest
expansion, and occiput-to-wall distance), peripheral joint counts, and
laboratory assessment of inflammation (c-reactive protein \[CRP\] and
erythrocyte sedimentation rate \[ESR\]).

In addition to the ASAS 20 composite endpoints, the etanercept
development program included assessments of higher levels of response
based on the ASAS 20. The ASAS 50 and ASAS 70 are intended to parallel
the use of higher levels of standard composite response criteria used in
other rheumatic diseases. They are assessed identically to the ASAS 20
but require 50% and 70% improvement, respectively.

Responses were also assessed in Study 016.0037 with the DCART 20 and
DCART 40. Further details on efficacy endpoints are in Appendix 1.

**Safety**

Safety evaluations in both studies included adverse events evaluated
according to Common Toxicity Criteria, premature discontinuation,
serious adverse events, deaths on study or within 30 days of last dose
of study drug, vital signs and physical exams, hematology profile,
chemistry profile, and anti-etanercept antibodies. See Appendix 1 for
further details on safety endpoints.

## Statistical Analyses

The statistical methods for analyzing efficacy and safety data were the
same for Study 016.0037 and Study 47687 unless otherwise noted. Study
016.0037 and Study 47687 were analyzed using an intent-to-treat
approach. All randomized subjects who received at least 1 dose of study
medication were included in the analyses. All statistical tests were
2-sided and a significance level of 0.05 was used to declare statistical
significance between treatment groups. No adjustments were made for
multiple testing.

For binary efficacy endpoints, such as the ASAS 20, 50, and 70, and
partial remission, subjects who discontinued from the study were
declared nonresponders at all timepoints subsequent to their withdrawal.
The Cochran-Mantel-Haenszel test (as given by the row means test in PROC
FREQ from SAS), stratified by presence or absence of concomitant DMARDs
at baseline, was used to compare response percentages between treatment
groups.

For continuous efficacy endpoints, such as individual components of the
ASAS 20, change and percent change from baseline were compared between
the etanercept and placebo groups at each time point using a stratified
rank test as obtained in PROC FREQ from SAS using Modridit scores.
Baseline was considered to be the last observation before the first dose
of the study. Change and percent change from baseline were computed for
each endpoint such that a value greater than zero reflects improvement
unless otherwise noted. Change and percent change were measured at the
subject level and then summarized. Subjects with a zero score at
baseline were not included in the analysis of percent improvement for
the variable in question. A last-observation-carried-forward (LOCF)
approach was used to impute missing data.

**Safety endpoints:** Treatment groups were compared with respect to
incidence of adverse events and infections using Fisher's exact test for
both studies unless otherwise noted.

# Results for Pivotal Program

## Study Populations

### Baseline Demographics and Disease Characteristics

The treatment groups were well balanced within studies and were similar
across studies with regard to demographic characteristics and baseline
DMARDs (Table 5-3) and baseline disease characteristics (Table 5-4).

[]{#__RefHeading___Toc41869683 .anchor}Table 5‑3. Baseline Demographics
and Therapy in the Pivotal Program

+------------------------------+---------+---------+---+-------+--------+
|                              | Study   |         |   | Study |        |
|                              | 0       |         |   | 47687 |        |
|                              | 16.0037 |         |   |       |        |
+------------------------------+---------+---------+---+-------+--------+
| Baseline characteristic      | Placebo | Eta     |   | Pl    | Etan   |
|                              |         | nercept |   | acebo | ercept |
|                              | (N =    |         |   |       |        |
|                              | 139)    | (N =    |   | (N =  | (N =   |
|                              |         | 138)    |   | 39)   | 45)    |
+------------------------------+---------+---------+---+-------+--------+
| Mean age, yrs (range)        | 41.9\   | 42.1\   |   | 40.7\ | 45.3\  |
|                              | (18 --  | (24 --  |   | (19   | (28 -- |
|                              | 65)     | 70)     |   | --    | 63)    |
|                              |         |         |   | 66)   |        |
+------------------------------+---------+---------+---+-------+--------+
| Men, n (%)                   | 105     | 105     |   | 30    | 36     |
|                              | (76)    | (76)    |   | (77)  | (80)   |
+------------------------------+---------+---------+---+-------+--------+
| Mean duration of disease     | 10.5    | 10.1    |   | 9.7   | 15.0   |
| (years)                      |         |         |   |       |        |
+------------------------------+---------+---------+---+-------+--------+
| Mean weight (kg)             | 83.1    | 82.2    |   | 73.7  | 76.1   |
+------------------------------+---------+---------+---+-------+--------+
| Race, n (%):                 |         |         |   |       |        |
+------------------------------+---------+---------+---+-------+--------+
| White                        | 127     | 130     |   | 37    | 42     |
|                              | (91)    | (94)    |   | (95)  | (93)   |
+------------------------------+---------+---------+---+-------+--------+
| Other                        | 12 (8)  | 8 (6)   |   | 2 (5) | 3 (7)  |
+------------------------------+---------+---------+---+-------+--------+
| Baseline therapy, n (%):     |         |         |   |       |        |
+------------------------------+---------+---------+---+-------+--------+
| Any DMARD ^a,b^              | 43 (31) | 44 (32) |   | 16    | 16     |
|                              |         |         |   | (41)  | (36)   |
+------------------------------+---------+---------+---+-------+--------+
| Sulfasalazine                | 30 (22) | 29 (21) |   | 11    | 11     |
|                              |         |         |   | (28)  | (24)   |
+------------------------------+---------+---------+---+-------+--------+
| Methotrexate                 | 17 (12) | 15 (11) |   | 5     | 6 (13) |
|                              |         |         |   | (13)  |        |
+------------------------------+---------+---------+---+-------+--------+
| Hydroxychloroquine           | 1 (1)   | 3 (2)   |   | 1 (3) | 0      |
+------------------------------+---------+---------+---+-------+--------+
| NSAIDs ^c^                   | 128     | 126     |   | 33    | 40     |
|                              | (92)    | (91)    |   | (85)  | (89)   |
+------------------------------+---------+---------+---+-------+--------+
| Corticosteroids ^c^          | 20 (14) | 18 (13) |   | 6     | 7 (16) |
|                              |         |         |   | (15)  |        |
+------------------------------+---------+---------+---+-------+--------+
| ^a^ Baseline therapies       |         |         |   |       |        |
| continued throughout trial.  |         |         |   |       |        |
|                              |         |         |   |       |        |
| ^b^ Some subjects were       |         |         |   |       |        |
| taking more than one DMARD.  |         |         |   |       |        |
|                              |         |         |   |       |        |
| ^c^ Concomitant NSAIDS or    |         |         |   |       |        |
| corticosteroids taken within |         |         |   |       |        |
| 6 months of screening        |         |         |   |       |        |
| evaluation.                  |         |         |   |       |        |
+------------------------------+---------+---------+---+-------+--------+

[]{#__RefHeading___Toc41869684 .anchor}Table 5‑4. Baseline Disease
Characteristics in the Pivotal Program

+-------------------------+----------+---------+---+----------+---------+
|                         | Study    |         |   | Study    |         |
|                         | 016.0037 |         |   | 47687    |         |
+-------------------------+----------+---------+---+----------+---------+
| Baseline characteristic | Placebo  | Eta     |   | Placebo  | Eta     |
|                         |          | nercept |   |          | nercept |
|                         | (N =     |         |   | (N = 39) |         |
|                         | 139)     | (N =    |   |          | (N =    |
|                         |          | 138)    |   |          | 45)     |
+-------------------------+----------+---------+---+----------+---------+
| Mean duration of AS,    | 10.5 (0  | 10.1 (0 |   | 9.7 (0.4 | 15.0    |
| years (range)           | -- 35.3) | --      |   | -- 29.6) | (0.2 -- |
|                         |          | 30.7)   |   |          | 37.3)   |
+-------------------------+----------+---------+---+----------+---------+
| Extra-spinal disease    |          |         |   |          |         |
| manifestations, n (%):  |          |         |   |          |         |
+-------------------------+----------+---------+---+----------+---------+
| History of Crohn's or   | 6 (4)    | 7 (5)   |   | 2 (5)    | 3 (7)   |
| ulcerative colitis      |          |         |   |          |         |
+-------------------------+----------+---------+---+----------+---------+
| History of uveitis or   | 43 (31)  | 39 (28) |   | 6 (15)   | 13 (29) |
| iritis                  |          |         |   |          |         |
+-------------------------+----------+---------+---+----------+---------+
| History of psoriasis    | 15 (11)  | 11 (8)  |   | 3 (8)    | 10 (22) |
+-------------------------+----------+---------+---+----------+---------+
| HLA-B27 positive, n (%) | 109 (84) | 108     |   | 34 (87)  | 38 (88) |
|                         |          | (84)    |   |          | ^a^     |
+-------------------------+----------+---------+---+----------+---------+
| ASAS 20 ^b^ components, |          |         |   |          |         |
| mean (range):           |          |         |   |          |         |
+-------------------------+----------+---------+---+----------+---------+
| Patient global          | 62.9     | 62.9    |   | 63.4     | 65.6    |
| assessment              | (9--100) | (1      |   | (31-86)  | (       |
|                         |          | 6--100) |   |          | 26-100) |
+-------------------------+----------+---------+---+----------+---------+
| Total back pain         | 63.5     | 61.1    |   | 56.5     | 61.9    |
|                         | (0--99)  | (       |   | (22-86)  | (2      |
|                         |          | 7--100) |   |          | 2--100) |
+-------------------------+----------+---------+---+----------+---------+
| BASFI ^c^               | 56.3     | 51.7    |   | 57.2     | 60.2    |
|                         | (11.     | (4.3    |   | (18.     | (13     |
|                         | 5--97.0) | --97.7) |   | 5--82.4) | .9-100) |
+-------------------------+----------+---------+---+----------+---------+
| Stiffness, duration and | 64.3     | 61.4    |   | 62.9     | 67.5    |
| intensity               | (7--100) | (1      |   | (2       | (       |
|                         |          | 7--100) |   | 2--99.5) | 28-100) |
+-------------------------+----------+---------+---+----------+---------+
| Spinal mobility         |          |         |   |          |         |
| measures, mean (SE):    |          |         |   |          |         |
+-------------------------+----------+---------+---+----------+---------+
| Modified Schober's      | 2.97     | 3.06    |   | 2.8      | 2.2     |
| score^c^, cm            | (0.13)   | (0.15)  |   | (0.22)   | (0.19)  |
+-------------------------+----------+---------+---+----------+---------+
| Chest expansion, cm     | 3.21     | 3.26    |   | 3.9      | 3.3     |
|                         | (0.15)   | (0.19)  |   | (0.35)   | (0.27)  |
+-------------------------+----------+---------+---+----------+---------+
| Occiput-to-wall, cm     | 5.33     | 5.59    |   | 4.6      | 7.3     |
|                         | (0.56)   | (0.50)  |   | (0.85)   | (0.92)  |
+-------------------------+----------+---------+---+----------+---------+
| BASDAI^c^, mean (SE)    | 59.6     | 58.1    |   | 58.6     | 61.0    |
|                         | (1.4)    | (1.5)   |   | (13.2)   | (15.7)  |
|                         |          |         |   | ^d^      | ^d^     |
+-------------------------+----------+---------+---+----------+---------+
| Acute phase reactants,  |          |         |   |          |         |
| mean (SE):              |          |         |   |          |         |
+-------------------------+----------+---------+---+----------+---------+
| CRP (mg/dL) ^e^         | 2.0      | 1.9     |   | 2.4      | 1.9     |
|                         | (0.2)    | (0.2)   |   | (4.2)    | (1.6)   |
|                         |          |         |   | ^d^      | ^d^     |
+-------------------------+----------+---------+---+----------+---------+
| ESR (mm/hr) ^f^         | 25.4     | 25.9    |   | 33.1     | 30.6    |
|                         | (1.9)    | (1.8)   |   | (23.9)   | (22.3)  |
|                         |          |         |   | ^d^      | ^d^     |
+-------------------------+----------+---------+---+----------+---------+
| ^a^ Not assessed for 2  |          |         |   |          |         |
| etanercept subjects     |          |         |   |          |         |
|                         |          |         |   |          |         |
| ^b^ See Appendix 1 for  |          |         |   |          |         |
| ASAS 20                 |          |         |   |          |         |
|                         |          |         |   |          |         |
| ^c^ See Appendix 1,     |          |         |   |          |         |
| section 3               |          |         |   |          |         |
|                         |          |         |   |          |         |
| ^d^ Mean (standard      |          |         |   |          |         |
| deviation)              |          |         |   |          |         |
|                         |          |         |   |          |         |
| ^e^ Normal range 0 to   |          |         |   |          |         |
| 1.0 mg/dL.              |          |         |   |          |         |
|                         |          |         |   |          |         |
| ^f^ Normal range 1 to   |          |         |   |          |         |
| 17 mm/hr (men), 1 to 25 |          |         |   |          |         |
| mm/hr (women)           |          |         |   |          |         |
+-------------------------+----------+---------+---+----------+---------+

### Study Completion

Completion rates for Study 016.0037 at the 12-week (primary) time point
was 96% placebo (134) and 96% etanercept (132). Completion rates at week
24 in this study were 86% placebo (120) and 91% etanercept (126).
Reasons for premature withdrawal in Study 016.0037 included adverse
events (7 etanercept subjects, 1 placebo), lack of efficacy (3
etanercept, 13 placebo), lost to follow-up (2 etanercept, 1 placebo),
voluntary withdrawal (2 placebo), and lack of compliance with protocol
(2 placebo).

In Study 47687, 84 subjects were enrolled; 2 subjects in the etanercept
group withdrew from study for nonmedical reasons unrelated to safety.

## Efficacy Results

### Primary Endpoint: Protocol-Defined ASAS Response

Substantial etanercept-related improvement was evident in the results of
the primary endpoint, the protocol-defined ASAS 20, as well as in the
protocol-defined ASAS 50, protocol-defined ASAS 70, and partial
remission criteria in Study 016.0037 at both the primary (week 12) and
conditional primary (week 24) time points (Figure 5-1). Almost half the
subjects in the study achieved and maintained a protocol-defined ASAS
50, and almost a third achieved a protocol-defined ASAS 70. Superior
response was evident for etanercept-treated subjects at all levels of
the protocol-defined ASAS score by week 2 and was maintained throughout
the study (p \< 0.01 at all visits). Seventeen percent of
etanercept-treated subjects achieved partial remission at week 24
compared with 4% in the placebo group, and etanercept subjects achieved
it faster than subjects in the placebo group (log-rank
p‑value \< 0.0001).

Results in Table 5-5 are presented using both the protocol-defined ASAS
20 (see Section 4.3.2) and the ASAS 20 (per Anderson et al, 2001).
Results for both analyses were similar.

The number of subjects receiving concomitant DMARDs were 44 (etanercept)
and 43 (placebo). The responses were similar in etanercept subjects with
or without concomitant DMARDs, 61% and 60%, respectively.

Secondary endpoints are presented in Table 5-6.

The magnitude and time course of etanercept-related improvement was
similar in Study 47687 (Table 5-7), but did not achieve statistical
significance for all secondary endpoints, possibly due to the smaller
sample size.

[]{#__RefHeading___Toc41869685 .anchor}Table 5‑5. Study 016.0037:
Primary Endpoint:\
ASAS 20 at Weeks 12 and 24

+-------------+-------+----------+-------+---+--------+---------+-------+
|             | P     |          |       |   | ASAS   |         |       |
|             | rotoc |          |       |   | 20 ^b^ |         |       |
|             | ol-De |          |       |   |        |         |       |
|             | fined |          |       |   |        |         |       |
|             | ASAS  |          |       |   |        |         |       |
|             | 20    |          |       |   |        |         |       |
|             | ^a^   |          |       |   |        |         |       |
+-------------+-------+----------+-------+---+--------+---------+-------+
| Parameter   | Pla   | Eta      | P-    |   | Pl     | Etan    | P-    |
|             | cebo\ | nercept\ | value |   | acebo\ | ercept\ | value |
|             | N =   | N = 138  | ^c^   |   | N=139  | N=138   | ^c^   |
|             | 139   |          |       |   |        |         |       |
+-------------+-------+----------+-------+---+--------+---------+-------+
| ASAS 20     |       |          |       |   |        |         |       |
| (n/%)       |       |          |       |   |        |         |       |
+-------------+-------+----------+-------+---+--------+---------+-------+
| 12 weeks    | 38    | 83 (60)  | \<    |   | 39     | 82 (59) | \<0   |
|             | (27)  |          | 0     |   | (28)   |         | .0001 |
|             |       |          | .0001 |   |        |         |       |
+-------------+-------+----------+-------+---+--------+---------+-------+
| 24 weeks    | 32    | 80 (58)  | \<    |   | 31     | 78 (57) | \<0   |
|             | (23)  |          | 0     |   | (22)   |         | .0001 |
|             |       |          | .0001 |   |        |         |       |
+-------------+-------+----------+-------+---+--------+---------+-------+
| ^a^         |       |          |       |   |        |         |       |
| Proto       |       |          |       |   |        |         |       |
| col-defined |       |          |       |   |        |         |       |
| ASAS 20 is  |       |          |       |   |        |         |       |
| calculated  |       |          |       |   |        |         |       |
| with        |       |          |       |   |        |         |       |
| average of  |       |          |       |   |        |         |       |
| total and   |       |          |       |   |        |         |       |
| nocturnal   |       |          |       |   |        |         |       |
| back pain   |       |          |       |   |        |         |       |
|             |       |          |       |   |        |         |       |
| ^b^ ASAS 20 |       |          |       |   |        |         |       |
| is          |       |          |       |   |        |         |       |
| calculated  |       |          |       |   |        |         |       |
| using only  |       |          |       |   |        |         |       |
| total back  |       |          |       |   |        |         |       |
| pain        |       |          |       |   |        |         |       |
| (Anderson   |       |          |       |   |        |         |       |
| et al,      |       |          |       |   |        |         |       |
| 2001)       |       |          |       |   |        |         |       |
|             |       |          |       |   |        |         |       |
| ^c^         |       |          |       |   |        |         |       |
| C           |       |          |       |   |        |         |       |
| ochran-Mant |       |          |       |   |        |         |       |
| el-Haenszel |       |          |       |   |        |         |       |
| row means   |       |          |       |   |        |         |       |
| test        |       |          |       |   |        |         |       |
+-------------+-------+----------+-------+---+--------+---------+-------+

[]{#__RefHeading___Toc41869686 .anchor}Table 5‑6. Study 016.0037:
Secondary Endpoints:\
ASAS 50 and 70, and Partial Remission at Weeks 12 and 24

+-----------------------+-------------+-----------------+-------------+---+
|                       | Proto       |                 |             |   |
|                       | col-Defined |                 |             |   |
|                       | ASAS 20 ^a^ |                 |             |   |
+-----------------------+-------------+-----------------+-------------+---+
| Parameter             | Placebo\    | Etanercept\     | P-value ^b^ |   |
|                       | N = 139     | N = 138         |             |   |
+-----------------------+-------------+-----------------+-------------+---+
| ASAS 50 (n/%)         |             |                 |             |   |
+-----------------------+-------------+-----------------+-------------+---+
| 12 weeks              | 18 (13)     | 62 (45)         | \< 0.0001   |   |
+-----------------------+-------------+-----------------+-------------+---+
| 24 weeks              | 14 (10)     | 58 (42)         | \< 0.0001   |   |
+-----------------------+-------------+-----------------+-------------+---+
| ASAS 70 (n/%)         |             |                 |             |   |
+-----------------------+-------------+-----------------+-------------+---+
| 12 weeks              | 10 (7)      | 40 (29)         | \< 0.0001   |   |
+-----------------------+-------------+-----------------+-------------+---+
| 24 weeks              | 7 (5)       | 39 (28)         | \< 0.0001   |   |
+-----------------------+-------------+-----------------+-------------+---+
| Partial Remission     |             |                 |             |   |
| (n/%)                 |             |                 |             |   |
+-----------------------+-------------+-----------------+-------------+---+
| 12 weeks              | 11 (8)      | 29 (21)         | 0.0020      |   |
+-----------------------+-------------+-----------------+-------------+---+
| 24 weeks              | 5 (4)       | 24 (17)         | 0.0002      |   |
+-----------------------+-------------+-----------------+-------------+---+
| ^a^ Protocol-defined  |             |                 |             |   |
| ASAS 20 is calculated |             |                 |             |   |
| with average of total |             |                 |             |   |
| and nocturnal back    |             |                 |             |   |
| pain                  |             |                 |             |   |
|                       |             |                 |             |   |
| ^b^                   |             |                 |             |   |
| Co                    |             |                 |             |   |
| chran-Mantel-Haenszel |             |                 |             |   |
| row means test        |             |                 |             |   |
+-----------------------+-------------+-----------------+-------------+---+

[]{#__RefHeading___Toc41869680 .anchor}Figure 5‑1. Study 016.0037:
Percent of Subjects Achieving Protocol-Defined ASAS 20, 50, and 70 Over
Time

![](media/image2.wmf){width="3.747916666666667in"
height="6.877777777777778in"}

[]{#__RefHeading___Toc41869687 .anchor}Table 5‑7. Study 47687. Primary
and Secondary Endpoints:\
ASAS 20, 50, 70, and Partial Remission at Week 12

+---------------------------+--------------+--------------+-----------+
| Parameter                 | Placebo      | Etanercept   | P-value   |
|                           |              |              | ^a^       |
|                           | N = 39       | N = 45       |           |
+---------------------------+--------------+--------------+-----------+
| ASAS 20 (n/%)             | 9 (23)       | 27 (60)      | 0.0008    |
+---------------------------+--------------+--------------+-----------+
| ASAS 50 (n/%)             | 4 (10)       | 22 (49)      | 0.0002    |
+---------------------------+--------------+--------------+-----------+
| ASAS 70 (n/%)             | 4 (10)       | 11 (24)      | 0.0973    |
+---------------------------+--------------+--------------+-----------+
| Partial Remission (n/%)   | 4 (10)       | 8 (18)       | 0.3457    |
+---------------------------+--------------+--------------+-----------+
| ^a^                       |              |              |           |
| Cochran-Mantel-Haenszel   |              |              |           |
| row means test            |              |              |           |
+---------------------------+--------------+--------------+-----------+

### Individual Components of ASAS 20

All components of the ASAS 20 reflected substantial etanercept-related
improvement at both primary time points (Table 5-8) and at all other
time points measured (p \< 0.0005) in Study 016.0037, indicating that
etanercept acts on a broad range of disease symptoms. The median percent
improvement in pain was approximately 10-fold higher with etanercept
than with placebo, with an apparent advantage in the other component
scores. Comparable efficacy was observed in Study 47687 (Table 5-9).

[]{#__RefHeading___Toc41869688 .anchor}Table 5‑8. Study 016.0037:
Results for Individual Components of Protocol‑Defined ASAS 20

+-------------------------------------+---+---+--------+---------+------------+
|                                     |   |   | Mean   |         |            |
|                                     |   |   | (m     |         |            |
|                                     |   |   | edian) |         |            |
|                                     |   |   |        |         |            |
|                                     |   |   | P      |         |            |
|                                     |   |   | ercent |         |            |
|                                     |   |   | Impro  |         |            |
|                                     |   |   | vement |         |            |
|                                     |   |   | from   |         |            |
|                                     |   |   | Ba     |         |            |
|                                     |   |   | seline |         |            |
+-------------------------------------+---+---+--------+---------+------------+
| Parameter                           |   | P |        | Eta     | P-value    |
|                                     |   | l |        | nercept | ^b^        |
|                                     |   | a |        |         |            |
|                                     |   | c |        | N = 138 |            |
|                                     |   | e |        |         |            |
|                                     |   | b |        |         |            |
|                                     |   | o |        |         |            |
|                                     |   |   |        |         |            |
|                                     |   | N |        |         |            |
|                                     |   | = |        |         |            |
|                                     |   | 1 |        |         |            |
|                                     |   | 3 |        |         |            |
|                                     |   | 9 |        |         |            |
+-------------------------------------+---+---+--------+---------+------------+
| Patient Global Assessment           |   |   |        |         |            |
+-------------------------------------+---+---+--------+---------+------------+
| 12 weeks                            |   |   | 9.8    | 40.2    | \< 0.0001  |
|                                     |   |   | (8.8)  | (50.8)  |            |
+-------------------------------------+---+---+--------+---------+------------+
| 24 weeks                            |   |   | 7.8    | 38.6    | \< 0.0001  |
|                                     |   |   | (6.5)  | (46.3)  |            |
+-------------------------------------+---+---+--------+---------+------------+
| Avg nocturnal back pain and total   |   |   |        |         |            |
| back pain^a^                        |   |   |        |         |            |
+-------------------------------------+---+---+--------+---------+------------+
| 12 weeks                            |   |   | 6.7    | 39.9    | \< 0.0001  |
|                                     |   |   | (5.4)  | (54.1)  |            |
+-------------------------------------+---+---+--------+---------+------------+
| 24 weeks                            |   |   | 5.1    | 34.8    | \< 0.0001  |
|                                     |   |   | (6.0)  | (51.1)  |            |
+-------------------------------------+---+---+--------+---------+------------+
| BASFI -- average of responses to 10 |   |   |        |         |            |
| questions                           |   |   |        |         |            |
+-------------------------------------+---+---+--------+---------+------------+
| 12 weeks                            |   |   | 4.9    | 33.1    | \< 0.0001  |
|                                     |   |   | (3.3)  | (32.3)  |            |
+-------------------------------------+---+---+--------+---------+------------+
| 24 weeks                            |   |   | 1.9    | 30.1    | \< 0.0001  |
|                                     |   |   | (-1.0) | (31.3)  |            |
+-------------------------------------+---+---+--------+---------+------------+
| Inflammation (BASDAI)               |   |   |        |         |            |
+-------------------------------------+---+---+--------+---------+------------+
| 12 weeks                            |   |   | 13.1   | 44.8    | \< 0.0001  |
|                                     |   |   | (9.5)  | (55.1)  |            |
+-------------------------------------+---+---+--------+---------+------------+
| 24 weeks                            |   |   | 5.7    | 43.9    | \< 0.0001  |
|                                     |   |   | (5.0)  | (45.0)  |            |
+-------------------------------------+---+---+--------+---------+------------+
| ^a^ One subject in the placebo      |   |   |        |         |            |
| group had a score of zero at        |   |   |        |         |            |
| baseline for the average nocturnal  |   |   |        |         |            |
| back pain and total back pain and   |   |   |        |         |            |
| was not included in the analysis of |   |   |        |         |            |
| percent improvement from baseline   |   |   |        |         |            |
| for that measure                    |   |   |        |         |            |
|                                     |   |   |        |         |            |
| ^b^ Cochran-Mantel-Haenszel row     |   |   |        |         |            |
| means test with Modridit option on  |   |   |        |         |            |
| percent improvement from baseline   |   |   |        |         |            |
+-------------------------------------+---+---+--------+---------+------------+

[]{#__RefHeading___Toc41869689 .anchor}Table 5‑9. Study 47687: Results
for Individual Components of the Protocol‑Defined ASAS 20 at Week 12

+----------------------------------------+---+---+---------+---------+--------+
|                                        |   |   | Mean    |         |        |
|                                        |   |   |         |         |        |
|                                        |   |   | Percent |         |        |
|                                        |   |   | Impr    |         |        |
|                                        |   |   | ovement |         |        |
|                                        |   |   | from    |         |        |
|                                        |   |   | B       |         |        |
|                                        |   |   | aseline |         |        |
+----------------------------------------+---+---+---------+---------+--------+
| Parameter                              |   | P |         | Eta     | P      |
|                                        |   | l |         | nercept | -value |
|                                        |   | a |         |         | ^a^    |
|                                        |   | c |         | N = 45  |        |
|                                        |   | e |         |         |        |
|                                        |   | b |         |         |        |
|                                        |   | o |         |         |        |
|                                        |   |   |         |         |        |
|                                        |   | N |         |         |        |
|                                        |   | = |         |         |        |
|                                        |   | 3 |         |         |        |
|                                        |   | 9 |         |         |        |
+----------------------------------------+---+---+---------+---------+--------+
| Patient Global Assessment              |   |   | 12.6    | 37.0    | 0.0107 |
+----------------------------------------+---+---+---------+---------+--------+
| Avg nocturnal back pain and total back |   |   | 6.2     | 43.1    | 0.0003 |
| pain                                   |   |   |         |         |        |
+----------------------------------------+---+---+---------+---------+--------+
| BASFI -- average of responses to 10    |   |   | 3.4     | 35.4    | 0.0003 |
| questions                              |   |   |         |         |        |
+----------------------------------------+---+---+---------+---------+--------+
| Inflammation (Average of last 2        |   |   | 15.9    | 43.3    | 0.0025 |
| questions on BASDAI related to morning |   |   |         |         |        |
| stiffness)                             |   |   |         |         |        |
+----------------------------------------+---+---+---------+---------+--------+
| ^a^ Cochran-Mantel-Haenszel row means  |   |   |         |         |        |
| test with Modridit option on percent   |   |   |         |         |        |
| improvement from baseline.             |   |   |         |         |        |
+----------------------------------------+---+---+---------+---------+--------+

### Additional Measures of Disease Activity

Etanercept therapy was associated with substantial improvement in a
number of endpoints not included in the ASAS 20. Measures of spinal
mobility were excluded from the composite criteria because they showed
no change in response to NSAID therapy. Etanercept treatment was
associated with significantly more improvement in all 3 measures of
spinal mobility than placebo in Study 016.0037 (Table 5-10), with median
percent improvement ranging from 10% to 25% across measures at week 24
compared with 0% in the placebo group.

Median percent improvement for the indicators of disease activity and
inflammation (BASDAI, acute phase reactants) ranged from 40% to 73% in
the etanercept group at weeks 12 and 24 and was superior to placebo at
every study visit (p \< 0.0001). In the etanercept group, the percent of
subjects with normal (nonelevated) acute phase reactants increased from
46% for both reactants at baseline to 83% ESR, 85% CRP at week 24, while
in the placebo group they remained unchanged.

Independent assessors judged global disease to be significantly improved
in the etanercept group vs placebo at every study visit (p \< 0.01),
with median percent improvement of 45% at weeks 12 and 24, more than
3-fold higher than with placebo (approximately 13% at both time points).

Tender joint counts improved with etanercept therapy but not swollen
joint counts. The lack of significant treatment effect on swollen joint
counts was likely due to the small number of subjects with peripheral
joints involved and the small number of joint counts involved in each
subject (median swollen joint count at baseline: placebo, 0;
etanercept, 1).

Similar improvement was seen in Study 47687 (Table 5-11 ), although mean
percent improvement in joint counts were not available.

[]{#__RefHeading___Toc41869690 .anchor}Table 5‑10. Study 016.0037:
Results for BASDAI, Spinal Mobility, Acute Phase Reactants, Assessor
Global, and Peripheral Joint Counts.

+-----------------------------------+---+---+---------+----------+------------+
|                                   |   |   | Mean    |          |            |
|                                   |   |   | (       |          |            |
|                                   |   |   | median) |          |            |
|                                   |   |   |         |          |            |
|                                   |   |   | Percent |          |            |
|                                   |   |   | Impr    |          |            |
|                                   |   |   | ovement |          |            |
|                                   |   |   | from    |          |            |
|                                   |   |   | B       |          |            |
|                                   |   |   | aseline |          |            |
|                                   |   |   | ^a^     |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| Parameter                         |   | P |         | Et       | P-value    |
|                                   |   | l |         | anercept | ^b^        |
|                                   |   | a |         |          |            |
|                                   |   | c |         | N = 138  |            |
|                                   |   | e |         |          |            |
|                                   |   | b |         |          |            |
|                                   |   | o |         |          |            |
|                                   |   |   |         |          |            |
|                                   |   | N |         |          |            |
|                                   |   | = |         |          |            |
|                                   |   | 1 |         |          |            |
|                                   |   | 3 |         |          |            |
|                                   |   | 9 |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| BASDAI                            |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| 12 weeks                          |   |   | 11.3    | 42.2     | \< 0.0001  |
|                                   |   |   | (9.9)   | (44.6)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| 24 weeks                          |   |   | 5.8     | 39.5     | \< 0.0001  |
|                                   |   |   | (3.1)   | (40.4)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| Spinal Mobility Measures          |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| Schober's Test                    |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| 12 weeks                          |   |   | 21.4    | 25.6     | 0.0359     |
|                                   |   |   | (0)     | (8.6)    |            |
+-----------------------------------+---+---+---------+----------+------------+
| 24 weeks                          |   |   | 7.8 (0) | 25.1     | 0.0014     |
|                                   |   |   |         | (9.7)    |            |
+-----------------------------------+---+---+---------+----------+------------+
| Chest Expansion                   |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| 12 weeks                          |   |   | 11.2    | 57.8     | 0.0026     |
|                                   |   |   | (0)     | (4.8)    |            |
+-----------------------------------+---+---+---------+----------+------------+
| 24 weeks                          |   |   | -0.6    | 56.5     | \< 0.0001  |
|                                   |   |   | (0)     | (16.7)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| Occiput-to-Wall Measurements      |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| 12 weeks                          |   |   | -80.9   | 18.3     | 0.0034     |
|                                   |   |   | (0)     | (15.7)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| 24 weeks                          |   |   | -98.7   | 26.0     | \< 0.0001  |
|                                   |   |   | (0)     | (25.0)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| Acute Phase Reactants             |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| ESR (mm/hr)                       |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| 12 weeks                          |   |   | -19.2   | 17.7     | \< 0.0001  |
|                                   |   |   | (0)     | (60.0)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| 24 weeks                          |   |   | -23.0   | 42.1     | \< 0.0001  |
|                                   |   |   | (0)     | (60.0)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| C-reactive Protein (mg/dL)        |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| 12 weeks                          |   |   | -142.5  | 10.1     | \< 0.0001  |
|                                   |   |   | (-5.4)  | (68.5)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| 24 weeks                          |   |   | -95.9   | 38.0     | \< 0.0001  |
|                                   |   |   | (0)     | (72.7)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| Assessor Global                   |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| 12 weeks                          |   |   | 10.3    | 34.2     | \< 0.0001  |
|                                   |   |   | (13.5)  | (45.0)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| 24 weeks                          |   |   | 5.9     | 29.5     | \< 0.0001  |
|                                   |   |   | (13.2)  | (45.2)   |            |
+-----------------------------------+---+---+---------+----------+------------+
|                                   |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| Tender Joint Count                |   |   | n=114   | n=101    |            |
+-----------------------------------+---+---+---------+----------+------------+
| 12 weeks                          |   |   | -1.0    | 36.8     | 0.0061     |
|                                   |   |   | (20.6)  | (50.0)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| 24 weeks                          |   |   | 1.4     | 35.5     | 0.0014     |
|                                   |   |   | (31.4)  | (61.5)   |            |
+-----------------------------------+---+---+---------+----------+------------+
|                                   |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+
| Swollen Joint Count               |   |   | n=65    | n=73     |            |
+-----------------------------------+---+---+---------+----------+------------+
| 12 weeks                          |   |   | -14.6   | 35.7     | 0.1263     |
|                                   |   |   | (50.0)  | (66.7)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| 24 weeks                          |   |   | -10.5   | 3.7      | 0.8384     |
|                                   |   |   | (50.0)  | (60.0)   |            |
+-----------------------------------+---+---+---------+----------+------------+
| ^a^ Subjects with a score of zero |   |   |         |          |            |
| at baseline were not included in  |   |   |         |          |            |
| the analysis of percent           |   |   |         |          |            |
| improvement from baseline for     |   |   |         |          |            |
| that measure                      |   |   |         |          |            |
|                                   |   |   |         |          |            |
| ^b^ Cochran-Mantel-Haenszel row   |   |   |         |          |            |
| means test with Modridit option   |   |   |         |          |            |
| on percent improvement from       |   |   |         |          |            |
| baseline.                         |   |   |         |          |            |
+-----------------------------------+---+---+---------+----------+------------+

[]{#__RefHeading___Toc41869691 .anchor}Table 5‑11. Study 47687: Results
for BASDAI, Spinal Mobility, Acute Phase Reactants, and Assessor Global
at Week 12

+-------------------------------------+---+---+----------+----------+---------+
|                                     |   |   | Mean     |          |         |
|                                     |   |   |          |          |         |
|                                     |   |   | Percent  |          |         |
|                                     |   |   | Imp      |          |         |
|                                     |   |   | rovement |          |         |
|                                     |   |   | from     |          |         |
|                                     |   |   | Baseline |          |         |
|                                     |   |   | ^a^      |          |         |
+-------------------------------------+---+---+----------+----------+---------+
| Parameter                           |   | P |          | Et       | P-value |
|                                     |   | l |          | anercept | ^b^     |
|                                     |   | a |          |          |         |
|                                     |   | c |          | N = 45   |         |
|                                     |   | e |          |          |         |
|                                     |   | b |          |          |         |
|                                     |   | o |          |          |         |
|                                     |   |   |          |          |         |
|                                     |   | N |          |          |         |
|                                     |   | = |          |          |         |
|                                     |   | 3 |          |          |         |
|                                     |   | 9 |          |          |         |
+-------------------------------------+---+---+----------+----------+---------+
| BASDAI                              |   |   | 13.6     | 43.6     | 0.0014  |
+-------------------------------------+---+---+----------+----------+---------+
| Spinal Mobility Measures            |   |   |          |          |         |
+-------------------------------------+---+---+----------+----------+---------+
| Schober's Test                      |   |   | -1.3     | 36.0     | 0.0085  |
+-------------------------------------+---+---+----------+----------+---------+
| Chest Expansion                     |   |   | 9.0      | 29.9     | 0.8695  |
+-------------------------------------+---+---+----------+----------+---------+
| Occiput to Wall Measurements        |   |   | 7.2      | 12.5     | 0.0650  |
+-------------------------------------+---+---+----------+----------+---------+
| Acute Phase Reactants               |   |   |          |          |         |
+-------------------------------------+---+---+----------+----------+---------+
| ESR (mm/hr)                         |   |   | 0.0      | 79.6     | 0.0000  |
+-------------------------------------+---+---+----------+----------+---------+
| C-reactive Protein (mg/dL)          |   |   | 0.0      | 69.5     | 0.0000  |
+-------------------------------------+---+---+----------+----------+---------+
| Assessor Global                     |   |   | 19.8     | 39.3     | 0.0321  |
+-------------------------------------+---+---+----------+----------+---------+
| ^a^ Subjects with a score of zero   |   |   |          |          |         |
| at baseline were not included in    |   |   |          |          |         |
| the analysis of percent improvement |   |   |          |          |         |
| from baseline for that measure      |   |   |          |          |         |
|                                     |   |   |          |          |         |
| ^b^ Cochran-Mantel-Haenszel row     |   |   |          |          |         |
| means test with Modridit option on  |   |   |          |          |         |
| percent improvement from baseline.  |   |   |          |          |         |
+-------------------------------------+---+---+----------+----------+---------+

### Disease-Controlling Anti-Rheumatic Therapy Response

The DCART 20 and DCART 40 response criteria are discussed in Section 3.2
and are defined in Appendix 1.

The proportion of subjects who attained the DCART responses was more
than 3-fold higher with etanercept therapy than with placebo at week 24
(Table 5-12). Statistically significant improvements were evident at all
time points during the study compared with the placebo group (data on
file).

[]{#__RefHeading___Toc41869692 .anchor}Table 5‑12. Study 016.0037: DCART
20 and DCART 40 Responses

+-------------------------------+------------+------------+----------+---+
|                               | Placebo    | Etanercept | P        |   |
|                               |            |            | -value\* |   |
|                               | N = 139    | N = 138    |          |   |
+-------------------------------+------------+------------+----------+---+
| DCART 20 (n/%)                |            |            |          |   |
+-------------------------------+------------+------------+----------+---+
| 12 weeks                      | 11 (8)     | 51 (37)    | \<       |   |
|                               |            |            | 0.0001   |   |
+-------------------------------+------------+------------+----------+---+
| 24 weeks                      | 10 (7)     | 46 (33)    | \<       |   |
|                               |            |            | 0.0001   |   |
+-------------------------------+------------+------------+----------+---+
| DCART 40 (n/%)                |            |            |          |   |
+-------------------------------+------------+------------+----------+---+
| 12 weeks                      | 21 (15)    | 59 (43)    | \<       |   |
|                               |            |            | 0.0001   |   |
+-------------------------------+------------+------------+----------+---+
| 24 weeks                      | 18 (13)    | 57 (41)    | \<       |   |
|                               |            |            | 0.0001   |   |
+-------------------------------+------------+------------+----------+---+
| \* P-value determined by      |            |            |          |   |
| Cochran-Mantel-Haenszel row   |            |            |          |   |
| means test.                   |            |            |          |   |
+-------------------------------+------------+------------+----------+---+

### Subgroup Analyses for Study 016.0037

Exploratory analyses were conducted to evaluate the primary endpoint
within subgroups defined by baseline demographics (including age, sex,
weight, race, HLA-B27, study site, prior use of NSAIDS or
corticosteroids, or concomitant DMARD use), baseline disease status
(patient global score; average of nocturnal back pain and total back
pain; inflammation; BASFI; BASDAI; disease duration; history of
extraspinal and extra-articular involvement; hip disease), and
occurrence of injection site reactions during the study. These analyses
should be interpreted with caution. No adjustments for multiple analyses
were performed.

The following subgroup variables had significant treatment-by-subgroup
interaction p‑values (p\<0.05): HLA-B27 status, baseline average of
nocturnal back pain and total back pain (above and below median), and
baseline BASDAI (above and below median).

In subjects with a positive HLA-B27 test (etanercept, n=108; placebo,
n=109), ASAS 20 responses (etanercept, 65%; placebo, 27%) were
comparable to the overall study results. In subjects with a negative
HLA-B27 test (etanercept, n=21; placebo, n=20), the week-12 results
showed that ASAS 20 was achieved by a similar percentage of subjects in
both the etanercept group (38%) and the placebo group (35%). By week 24,
however, a treatment advantage was apparent in ASAS 20 response for
etanercept (48% of subjects) vs placebo (20%) among HLA-B27-negative
subjects. The relevance of this finding is unclear, but the relatively
small number of HLA-B27-negative subjects may have contributed to this
outcome.

For average back pain at week 12, the ASAS 20 responses for the
etanercept subgroup compared with the placebo subgroup were 54% vs 34%
for subjects with ≤ median back pain and were 67% vs 22% for subjects
with \> median back pain. In both subgroups, the etanercept subjects had
significantly higher responses than the placebo subjects. Similarly,
ASAS 20 responses for etanercept compared with placebo were
significantly higher in both BASDAI subgroups (56% vs 36% and 65% vs 19%
grouped as ≤ median and \> median for BASDAI, respectively). Neither of
the subgroup analyses for back pain or BASDAI suggests a different
conclusion regarding the efficacy of etanercept compared with placebo
with respect to the primary endpoint.

## Summary of Efficacy Results

Three randomized, double-blind, placebo-controlled clinical trials
demonstrated marked efficacy of etanercept in the treatment of AS. A
proof-of-principle trial demonstrated clinical response in its
prespecified clinical composite measure as well as in most of the
individual response measures used. Two additional studies, a 277-subject
study performed by Amgen (Study 016.0037) and an 84-subject study
performed by Wyeth (Study 47687), confirmed the effectiveness of
etanercept in treatment of AS. The primary endpoint in both studies was
the proportion of subjects achieving a composite endpoint, the
protocol-defined ASAS 20, at 12 weeks.

In study 016.0037, a significantly greater proportion of
etanercept-treated subjects (60%) than placebo subjects (27%) met the
protocol-defined ASAS 20 at 12 weeks (p \< 0.0001). Since the primary
endpoint was significantly greater in the etanercept group, a
conditional primary endpoint (protocol-defined ASAS 20 at 24 weeks) was
to be evaluated. The results at 24 weeks were similar to those at 12
weeks with 58% and 23% of subjects achieving the protocol-defined ASAS
20 in the etanercept and placebo groups, respectively. Additional
composite measures were also evaluated: protocol-defined ASAS 50 and
ASAS 70, partial remission, DCART 20, and DCART 40. Each one of these
endpoints was achieved by a significantly greater proportion of subjects
in the etanercept group compared with the placebo group at all time
points measured (weeks 2, 4, 8, 12, and 24).

The results of the Study 016.0037 are supported by the results of Study
47687. A significantly greater proportion of etanercept-treated subjects
(60%) achieved a protocol-defined ASAS 20 compared with 23% of placebo
subjects. Response rates for higher levels of protocol-defined ASAS 20
were also supportive of Study 016.0037.

Study 47687 supports the conclusions of Study 016.0037 with comparable
results. Etanercept provides clinically and statistically meaningful
benefit to subjects with AS.

# Safety Results

## Overview of Safety Results

The adverse events profiles seen in Studies 016.0037 and 47687 are
summarized in Table 6-13. The overall incidence of adverse events was
not increased by etanercept in any study, and no deaths were seen.
Etanercept was associated with a higher incidence of injection site
reactions. These findings are further described in the sections that
follow.

[]{#__RefHeading___Toc41869693 .anchor}Table 6‑13. Overall Summary of
Adverse Events in Studies 016.0037 and 47687: Number (%) of Subjects
Reporting Adverse Events

+-----------------------+-----------+-----------+---+--------+----------+
|                       | Study     |           |   | Study  |          |
|                       | 016.0037  |           |   | 47687  |          |
+-----------------------+-----------+-----------+---+--------+----------+
|                       | Placebo\  | Et        |   | Pl     | Eta      |
|                       | N = 139   | anercept\ |   | acebo\ | nercept\ |
|                       |           | N = 138   |   | N = 39 | N = 45   |
+-----------------------+-----------+-----------+---+--------+----------+
| Serious adverse       | 5 (3.6)   | 9 (6.5)   |   | 0 (0)  | 1 (2.2)  |
| events                |           |           |   |        |          |
+-----------------------+-----------+-----------+---+--------+----------+
| Medically important   | 1 (0.7)   | 2 (1.4)   |   | 0 (0)  | 0 (0)    |
| infections^a^         |           |           |   |        |          |
+-----------------------+-----------+-----------+---+--------+----------+
| Events leading to     | 1 (0.7)   | 7 (5.1)   |   | 0 (0)  | 0 (0)    |
| withdrawal            |           |           |   |        |          |
+-----------------------+-----------+-----------+---+--------+----------+
| Non-infectious        | 105 (76)  | 99 (72)   |   | 23     | 25       |
| adverse events^b^     |           |           |   | (59.0) | (55.6)   |
+-----------------------+-----------+-----------+---+--------+----------+
| Injection site        | 13 (9)    | 41 (30)   |   | 6 (15) | 15 (33)  |
| reactions             |           | ^c^       |   |        | ^d^      |
+-----------------------+-----------+-----------+---+--------+----------+
| Infections            | 42 (30)   | 57 (41)   |   | 13     | 16       |
|                       |           |           |   | (33.3) | (35.6)   |
+-----------------------+-----------+-----------+---+--------+----------+
| ISR = injection site  |           |           |   |        |          |
| reaction              |           |           |   |        |          |
|                       |           |           |   |        |          |
| ^a^ Infections        |           |           |   |        |          |
| requiring             |           |           |   |        |          |
| hospitalization or    |           |           |   |        |          |
| parenteral            |           |           |   |        |          |
| antibiotics           |           |           |   |        |          |
|                       |           |           |   |        |          |
| ^b^ Excluding         |           |           |   |        |          |
| infections and        |           |           |   |        |          |
| injection site        |           |           |   |        |          |
| reactions             |           |           |   |        |          |
|                       |           |           |   |        |          |
| ^c^ P \< 0.0001,      |           |           |   |        |          |
| Fisher\'s exact test  |           |           |   |        |          |
|                       |           |           |   |        |          |
| ^d^ P = 0.0283,       |           |           |   |        |          |
| Co                    |           |           |   |        |          |
| chran-Mantel-Haenszel |           |           |   |        |          |
| row means test        |           |           |   |        |          |
+-----------------------+-----------+-----------+---+--------+----------+

## Serious Adverse Events

No deaths were reported in any of the studies of etanercept in subjects
with AS. A total of 10 of 183 etanercept-treated subjects (5%) had
serious adverse events.

> In Study 016.0037, the incidence of serious adverse events was not
> significantly different in the etanercept (9 subjects) and placebo (5
> subjects) groups (Table 6-14). The only serious event ocurring in more
> than a single subject in the etanercept group was bone fracture. Three
> subjects sustained bone fracture secondary to trauma. All cases were
> considered unrelated to etanercept.

[]{#__RefHeading___Toc41869694 .anchor}Table 6‑14. Study 016.0037:
Summary of Serious Adverse Events

  -------------------------------- ------------------ -------------------
                                   Placebo\           Etanercept\
                                   N = 139            N = 138

  Any (n/%)                        5 (3.6)            9 (6.5)

                                                      

  Bone fracture (n/%)              0 (0.0)            3 (2.2)

  Accidental injury (n/%)          2 (1.4)            0 (0.0)

  Cellulitis (n/%)                 0 (0.0)            1 (0.7)

  Colitis (n/%)                    0 (0.0)            1 (0.7)

  Fever (n/%)                      0 (0.0)            1 (0.7)

  Infection (n/%)                  0 (0.0)            1 (0.7)

  Viral infection (n/%)            1 (0.7)            0 (0.0)

  Lymphadenopathy (n/%)            0 (0.0)            1 (0.7)

  Intestinal obstruction (n/%)     0 (0.0)            1 (0.7)

  Chest pain (n/%)                 1 (0.7)            0 (0.0)

  Rash (n/%)                       0 (0.0)            1 (0.7)

  Suicide attempt (n/%)            1 (0.7)            0 (0.0)
  -------------------------------- ------------------ -------------------

In Study 47687, the only serious event was a myocardial infarction in
the etanercept group. The event was considered unrelated to etanercept,
therapy was continued, and the subject completed study.

## Medically Important Infections

Medically important infections were those requiring hospitalization or
treatment with intravenous (IV) antibiotics. Three events occurred in
Study 016.0037. Two occurred in the etanercept group: an infection
secondary to a cat bite and cellulitis secondary to an insect bite. In
the placebo group, one subject experienced a viral infection. No
life-threatening infections occurred in Study 016.0037. No medically
important infections occurred in Study 47687.

## Withdrawals Because of Adverse Events

Withdrawals because of adverse events in Study 016.0037 are summarized
in Table 6-15.

[]{#__RefHeading___Toc41869695 .anchor}Table 6‑15. Study 016.0037:
Summary of Adverse Events Causing Withdrawal

  ------------------------------- ------------------- --------------------
                                  Placebo\            Etanercept\
                                  N = 139             N = 138

  All (n/%)                       1 (0.7)             7 (5.1)

                                                      

  Bone fracture (n/%)             0 (0.0)             2 (1.4)

  Fever (n/%)                     0 (0.0)             1 (0.7)

  Hemorrhoidal bleeding (n/%)     0 (0.0)             1 (0.7)

  Ileitis (n/%)                   0 (0.0)             1 (0.7)

  Obstruction intestinal (n/%)    0 (0.0)             1 (0.7)

  Ulcerative colitis (n/%)        0 (0.0)             1 (0.7)

  Suicide attempt (n/%)           1 (0.7)             0 (0.0)
  ------------------------------- ------------------- --------------------

No withdrawals because of adverse events occurred in Study 47687.

## Noninfectious Adverse Events

The incidence of the most common adverse events in each of the AS
studies is shown in the following table by study. The overall incidence
of adverse events was comparable in both etanercept and placebo groups
in both studies, with the exception of injection site reactions and
injury accidents.

Other than injection site reactions, discussed in Section 6.1, the only
noninfectious adverse event that occurred significantly more frequently
in the etanercept group was accidental injury in Study 016.0037 (Table
6-16). Most adverse events were of mild or moderate intensity. The only
life-threatening event was an attempted suicide in the placebo group.

Eight subjects in the placebo group and 3 subjects in the etanercept
group had flares of uveitis during the Study 016.0037. One subject in
the placebo group and no subject in the etanercept group had flares of
uveitis in Study 47687.

Three subjects experienced adverse events related to inflammatory bowel
disease during Study 016.037. A subject in the etanercept group with a
history of recurrent flares of ulcerative colitis requiring treatment
with steroids had 2 flares during the study. Two subjects were diagnosed
with Crohn's disease during the study, one in the placebo group and one
in the etanercept group.

[]{#__RefHeading___Toc41869696 .anchor}Table 6‑16. Noninfectious Adverse
Events in ≥ 5% of Subjects in Either Study or Treatment Group

  ------------------------ ---------- ------------- -- ---------- -------------
                           Study                       Study      
                           016.0037                    47687      

                           Placebo\   Etanercept\      Placebo\   Etanercept\
                           N = 139    N = 138          N = 39     N = 45

  Any (n/%)                105 (76)   99 (72)          23 (59)    25 (56)

                                                                  

  Injection site           23 (17)    29 (21)          4 (10)     8 (18)
  ecchymosis (n/%)                                                

  Headache (n/%)           16 (12)    19 (14)          4 (10)     6 (13)

  Accidental injury (n/%)  6 (4)      17 (12)^a^       2 (5)      0

  Diarrhea (n/%)           13 (9)     11 (8)           2 (5)      2 (4)

  Rash (n/%)               9 (7)      11 (8)           0          2 (4)

  Dizziness (n/%)          3 (2)      8 (6)            1 (3)      1 (2)

  Rhinitis (n/%)           9 (7)      8 (6)            0          1 (2)

  Abdominal pain (n/%)     7 (5)      8 (6)            2 (5)      1 (2)

  Nausea (n/%)             7 (5)      7 (5)            4 (10)     3 (7)

  Asthenia (n/%)           7 (5)      5 (4)            1 (3)      5 (11)

  ^a^ P \< 0.05 (Fisher's                                         
  exact test)                                                     
  ------------------------ ---------- ------------- -- ---------- -------------

## Infections 

Infections are summarized in Table 6-17. In Study 016.0037, upper
respiratory infections were more common in the etanercept group than in
the placebo group (20% vs 12%). This increase was not evident in Study
47687 (9% vs 8%). Most infections in Study 016.0037 were of mild or
moderate intensity, and no life-threatening infections occurred. No
opportunistic infections were observed in any study.

[]{#__RefHeading___Toc41869697 .anchor}Table 6‑17. Infections in ≥ 5% of
Subjects in Either Study or Treatment Group

+---------------------+---------+-----------+---+--------+---------------+
|                     | Study   |           |   | Study  |               |
|                     | 0       |           |   | 47687  |               |
|                     | 16.0037 |           |   |        |               |
+---------------------+---------+-----------+---+--------+---------------+
|                     | P       | Et        |   | Pl     | Etanercept\   |
|                     | lacebo\ | anercept\ |   | acebo\ | N = 45        |
|                     | N = 139 | N = 138   |   | N = 39 |               |
+---------------------+---------+-----------+---+--------+---------------+
| Any (n/%)           | 42 (30) | 57 (41)   |   | 13     | 16 (35.6)     |
|                     |         |           |   | (33.3) |               |
+---------------------+---------+-----------+---+--------+---------------+
| Any infection       | 28 (20) | 33 (24)   |   | NA     | NA            |
| except URI (n/%)    |         |           |   |        |               |
+---------------------+---------+-----------+---+--------+---------------+
| Upper respiratory   | 16 (12) | 28 (20)   |   | 3      | 4 (8.9)       |
| infection (n/%)     |         | ^a^       |   | (7.7)  |               |
+---------------------+---------+-----------+---+--------+---------------+
| Flu syndrome (n/%)  | 10 (7)  | 5 (4)     |   | 2      | 1 (2.2)       |
|                     |         |           |   | (5.1)  |               |
+---------------------+---------+-----------+---+--------+---------------+
| NA = not available; |         |           |   |        |               |
| URI = upper         |         |           |   |        |               |
| respiratory         |         |           |   |        |               |
| infection           |         |           |   |        |               |
|                     |         |           |   |        |               |
| ^a^ P \< 0.05       |         |           |   |        |               |
| (Fisher's exact     |         |           |   |        |               |
| test)               |         |           |   |        |               |
+---------------------+---------+-----------+---+--------+---------------+

## Malignancies

No malignancies were reported in any of the studies.

## Clinical Laboratory Results

In Study 016.0037 and Study 47687, clinical laboratory results were
categorized using a modified National Cancer Institute (NCI) common
toxicity scale and the central laboratory's normal ranges for each
parameter. Baseline clinical laboratory values for each subject was
determined from blood and urine samples obtained before administration
of study drug.

In Study 016.0037, 3 subjects in the etanercept group had transient
grade 3 or 4 low absolute neutrophil counts (ANC) or lymphocyte counts.
One subject, whose ANC at screening was normal, had grade 3
(0.5x10^9^/L) low ANC at week 12. A repeat sample 6 days later was
normal, although the subject had grade 1 ANC at the end-of-study
evaluation. A second subject had persistent grade 2 low lymphocytes from
screening through end-of-treatment, with a transient grade 3 result
noted at the week-12 visit. Neither of these subjects experienced an
infection during the study. One subject who had normal ANC at screening,
had grade 4 low ANC at baseline and grade 1 low ANC for the duration of
the study.

In Study 47687, 1 subject in the etanercept group had grade 3 abnormal
values for aspartate aminotransferase, alanine aminotransferase, and
bilirubin during therapy. This subject had increased transaminases and
bilirubin serum values at the week-12 visit. The subject continued on
open-label etanercept, and after 4 weeks liver function tests had
normalized. No subjects in the placebo group had clinically important
laboratory abnormalities.

No subject discontinued either study due to abnormal laboratory values.

## Antibody Results

Testing for anti-etanercept antibodies was conducted in Studies 016.0037
and 47687.

In Study 016.0037, antibodies to etanercept were detected in samples
from 3 subjects (2.2%) in the etanercept group. Serum samples from all
3 subjects were negative in a binding assay for neutralizing antibodies.
All other serum samples were negative for anti-etanercept antibodies.

In Study 47687, all serum samples were negative for anti-etanercept
antibodies.

## Safety Summary and Conclusions

Etanercept was safe when administered to subjects with AS at a dose of
25 mg BIW for 24 weeks. No deaths occurred in any study. Most adverse
events were of mild or moderate intensity. Nine subjects had 10 serious
adverse events receiving etanercept, and 5 serious events occurred in 5
subjects receiving placebo. Seven subjects receiving etanercept and one
receiving placebo discontinued study drug due to adverse events.

No life-threatening infections occurred during either study. Three
infections occurred that required hospitalization or IV antibiotics, 2
in subjects receiving etanercept and 1 in a subject receiving placebo.
In Study 016.0037, upper respiratory infections were significantly more
frequent in subjects receiving etanercept. This difference was not
observed in Study 47687. No opportunistic infections were observed.

Few abnormal laboratory results exceeded grade 2 intensity, and no
subject was discontinued from study due to an abnormal laboratory
result. Antibodies to etanercept were detected by ELISA in serum samples
from 3 subjects; all samples were negative for neutralizing antibodies.

## Safety Profile in Ankylosing Spondylitis is Comparable to Established Etanercept Safety Profile in Rheumatic Diseases

Etanercept has been the subject of extensive investigation and safety
evaluations. The FDA and the Arthritis Advisory Committee have evaluated
etanercept extensively on multiple occasions:

  ---------- -------------------------------------- --------------------------
  **Year**   **Indication**                         **Reviewed by:**

  1998       Approval for RA (alone or with MTX)    FDA, Arthritis Advisory
                                                    Committee

  1999       Approval for JRA                       FDA

  2000       Approval as initial therapy for RA/    FDA, Arthritis Advisory
             Approval for inhibition of             Committee
             radiographic progression               

  2001       FDA Arthritis Advisory re: TNF         FDA, Arthritis Advisory
             Antagonists Safety                     Committee

  2002       Approval for psoriatic arthritis       FDA
             (alone or with MTX)                    

  2002       Approval of 3-year efficacy and safety FDA
             data in RA                             

  2003       FDA Arthritis Advisory re: TNF         FDA, Arthritis Advisory
             Antagonists Safety                     Committee

  2003       50-mg Dosing Regimen Once Weekly in RA FDA review ongoing
  ---------- -------------------------------------- --------------------------

MTX = methotrexate; RA = rheumatoid arthritis; TNF = tumor necrosis
factor

### Clinical Trials in Subjects with Rheumatoid Arthritis and Psoriatic Arthritis

The etanercept clinical trial database through 2002 includes 3389
subjects who have received etanercept in Amgen- and Wyeth-sponsored
rheumatic disease clinical trials for currently approved indications. In
open-label extension studies, the efficacy and the safety profile
associated with longer-term administration of etanercept (up to 6 years)
remain stable over time.

In 3- to 6-month controlled clinical trials in rheumatic diseases, the
only adverse event occurring more frequently in etanercept-treated
subjects relative to placebo-treated subjects was injection site
reactions.

Results from long-term, open-label studies show that adverse event rates
do not increase with prolonged exposure to etanercept.

### Comparison of Etanercept Safety Results in Ankylosing Spondylitis with Rheumatoid Arthritis and Psoriatic Arthritis Populations

The safety profile of etanercept in subjects with AS is compared with
the profile observed in subjects with RA and PsA in Table 6-6 using
adverse event rates adjusted for total exposure to etanercept. Overall,
the safety profile of etanercept in subjects with AS is comparable to
that observed in subjects with RA and PsA.

Table 6‑6. Exposure-adjusted Incidence (Events/Subject-Year) of Adverse
Events and Infections in Controlled Studies of Etanercept in Subjects
with RA, PsA, or AS

+----------------+---------+---------+---------+---+--------+---+--------+
|                | Rhe     |         |         |   | PsA    |   | AS     |
|                | umatoid |         |         |   |        |   |        |
|                | Ar      |         |         |   |        |   |        |
|                | thritis |         |         |   |        |   |        |
+----------------+---------+---------+---------+---+--------+---+--------+
| Event          | P       | P       | P       |   | Pr     |   | Pr     |
|                | rotocol | rotocol | rotocol |   | otocol |   | otocol |
|                | 0       | 0       | 0       |   | 01     |   | 01     |
|                | 16.0009 | 16.0014 | 16.0012 |   | 6.0030 |   | 6.0037 |
|                | ^a^     | ^b^     | ^c^     |   | ^d^    |   |        |
+----------------+---------+---------+---------+---+--------+---+--------+
| Any adverse    | 4.58    | 5.02    | 5.94    |   | 3.28   |   | 6.10   |
| event          |         |         |         |   |        |   |        |
+----------------+---------+---------+---------+---+--------+---+--------+
| Serious        | 0.15    | 0.11    | 0.09    |   | 0.14   |   | 0.17   |
| adverse event  |         |         |         |   |        |   |        |
+----------------+---------+---------+---------+---+--------+---+--------+
| Any infection  | 2.55    | 2.07    | 1.54    |   | 1.24   |   | 1.20   |
+----------------+---------+---------+---------+---+--------+---+--------+
| Upper          | 1.08    | 0.57    | 0.54    |   | 0.50   |   | 0.54   |
| respiratory    |         |         |         |   |        |   |        |
| infection      |         |         |         |   |        |   |        |
+----------------+---------+---------+---------+---+--------+---+--------+
| Infection      | 0.03    | 0.08    | 0.02    |   | 0      |   | 0.03   |
| requiring      |         |         |         |   |        |   |        |
| h              |         |         |         |   |        |   |        |
| ospitalization |         |         |         |   |        |   |        |
| or IV          |         |         |         |   |        |   |        |
| antibiotics    |         |         |         |   |        |   |        |
+----------------+---------+---------+---------+---+--------+---+--------+
| ^a^ 6 months   |         |         |         |   |        |   |        |
| of etanercept  |         |         |         |   |        |   |        |
| as monotherapy |         |         |         |   |        |   |        |
| in subjects    |         |         |         |   |        |   |        |
| with           |         |         |         |   |        |   |        |
| late-stage RA  |         |         |         |   |        |   |        |
|                |         |         |         |   |        |   |        |
| ^b^ 6 months   |         |         |         |   |        |   |        |
| of etanercept  |         |         |         |   |        |   |        |
| added to       |         |         |         |   |        |   |        |
| background MTX |         |         |         |   |        |   |        |
| in subjects    |         |         |         |   |        |   |        |
| with           |         |         |         |   |        |   |        |
| late-stage RA  |         |         |         |   |        |   |        |
|                |         |         |         |   |        |   |        |
| ^c^ 1 year of  |         |         |         |   |        |   |        |
| etanercept as  |         |         |         |   |        |   |        |
| monotherapy in |         |         |         |   |        |   |        |
| early RA       |         |         |         |   |        |   |        |
|                |         |         |         |   |        |   |        |
| ^d^ 6 months   |         |         |         |   |        |   |        |
| of etanercept  |         |         |         |   |        |   |        |
| as monotherapy |         |         |         |   |        |   |        |
+----------------+---------+---------+---------+---+--------+---+--------+

# Risk-Benefit Assessment

Currently, no disease-modifying therapies or biologic therapies are
approved in the US for patients with AS. Many patients have unacceptable
pain, stiffness, progressive immobility, and disability despite
treatment with NSAIDS and other therapies.

The data from the 3 studies described in this briefing document
demonstrate that etanercept acts rapidly and remarkably effectively in
reducing signs and symptoms, increasing mobility, and improving
laboratory markers of inflammation in patients with AS.

The etanercept safety profile in AS is favorable and comparable to the
well-established safety profile observed in the treatment of other
rheumatic diseases. This pattern of compelling efficacy with excellent
tolerability constitutes a highly favorable risk-benefit profile, and
establishes etanercept as a significant advance in therapy for patients
afflicted by AS.

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**Appendix 1: Efficacy and Safety Definitions and Instruments for
Assessment of AS in Clinical Trials**

**1. Efficacy Definitions**

Studies 016.0037 and 47687 used the following definitions for composite
response criteria.

**ASAS 20**

An improvement of at least 20% and absolute improvement of at least 10
units on a 0 to 100-mm VAS scale in at least 3 of the following 4
domains:

> [Inflammation:]{.underline} represented by the average of the last 2
> questions on the 6-question BASDAI (Garrett et al, 1994) regarding
> morning stiffness as measured by VAS: one (No. 5) with extremes
> labeled "none" and "very severe"; the other (No. 6) marking duration
> of morning stiffness between "0" and "2 or more hours."
>
> [Pain:]{.underline} represented by the average of total and nocturnal
> pain scores, both measured on a VAS scale with extremes labeled "no
> pain" and "most severe pain".
>
> [Function:]{.underline} represented by the BASFI (Calin et al, 1994):
> average of 10 questions regarding ability to perform specific tasks as
> measured by VAS with extremes labeled "easy" and "impossible."
>
> [Patient global assessment:]{.underline} measured on a VAS scale with
> extremes labeled "none" and "severe."

For a patient to be considered a responder, there could not be
deterioration in the potential fourth domain. Deterioration was defined
as a worsening of at least 20% and absolute change of at least 10 units
(on a 0 to 100-mm VAS scale).

**ASAS 50**

For Study 016.0037, the ASAS 50 required an improvement of at least 50%
and absolute improvement of at least 10 units on a 0 to 100-mm scale in
at least 3 of the 4 domains with an absence of deterioration in the
remaining domain. Absence of deterioration was defined as for the ASAS
20. For Study 47687 the ASAS 50 did not require an absolute change of 10
or more units. Absence of deterioration was defined as for the ASAS 20.

**ASAS 70**

The ASAS 70 was defined for each study in a similar manner as the ASAS
50 except requiring improvement of at least 70% in at least 3 of the 4
domains.

**Partial Remission of AS**

Partial remission is defined as a value of \< 20 units (scale 0 to 100)
in each of 4 domains of the ASAS 20.

**DCART 20**

The DCART 20 response was defined as a composite score that combines the
4 criteria of the ASAS 20 with 2 additional criteria: improvement in a
measure of spinal mobility and improvement in acute phase reactants. The
prespecified measures of spinal mobility and acute phase reactant were
chest expansion and CRP, respectively. The DCART 20 response requires a
20% improvement in 5 of the 6 criteria, with no worsening in the
remaining criterion. Improvement and worsening for the 4 criteria of the
ASAS 20 are defined above. Improvement and worsening for the measures of
spinal mobility and acute phase reactant were based strictly on a 20%
improvement or worsening relative to baseline, with no requirement of
absolute change.

**DCART 40**

The DCART 40 requires a 40% improvement relative to baseline plus
absolute improvement of at least 20 units in 3 of the 4 ASAS 20
criteria, with no worsening in the remaining criterion. Worsening was
defined as for the ASAS 20.

**2. Safety Definitions**

**Adverse Events**

The types and intensities (grades) of adverse events (infectious and
non-infectious) were tabulated. Injection site reactions and infections
were collected on separate forms than the non-infectious adverse events.
Events were graded (1 = mild, 2 = moderate, 3 = severe, or 4 =
life-threatening) using a modified NCI Common Toxicity Criteria Scale.
Events were classified using a modified Coding Symbols for a Thesaurus
of Adverse Reaction Terms dictionary (COSTART 1990) and summarized at
the term level. Studies 016.0037 and 47687 used the same COSTART
dictionary. For each patient, the most severe intensity of all
occurrences of an event was tabulated in the summaries.

**Serious Adverse Events**

21 CFR 312.32 defines an adverse event as serious (SAE) if it results in
death, is life‑threatening, results in permanent or significant
disability, results in drug dependency or abuse, requires patient
hospitalization or prolongs hospitalization, is a congenital anomaly, or
is a symptomatic overdose. An SAE also includes any important medical
event that jeopardizes the patient or requires medical or surgical
intervention to prevent one of the outcomes listed.

**Laboratory Results**

Laboratory results were categorized using a modified NCI Common Toxicity
Criteria Scale and the laboratory's normal ranges. Toxicities noted
before and during the study were summarized.

**Anti-etanercept antibodies**

Serum samples were analyzed by ELISA for the detection of antibody to
etanercept. Test samples that were positive in the ELISA were tested for
the presence of neutralizing antibodies to etanercept. Neutralizing
antibodies are those that interfere with the binding of TNF to the
receptor portion of etanercept.

**3. Instruments for Assessment of AS in Clinical Trials**

**Physical Function - Bath AS Functional Index (BASFI)**

The BASFI is a series of 8 questions regarding function in AS and 2
questions regarding the patient's ability to cope with everyday life
(see Appendix Table 1 below). Each question is measured on a 100-mm VAS,
the mean of which gives the BASFI. Subjects are asked about their
ability to perform activities of daily living, including reaching up to
shelves, putting on socks, standing unsupported, etc., and given a
choice to answer between the extremes of "easy" or "impossible". The
index was developed to address shortcomings in other functional indices,
including the Dougados Functional Index and Stanford Health Assessment
Questionnaire (Calin et al, 1994).

Appendix Table 1. The Bath Ankylosing Spondylitis Functional Index

+-----------------------------------------------------------------------+
| PLEASE DRAW A MARK ON EACH LINE BELOW TO INDICATE YOUR ABILITY WITH   |
| EACH OF THE FOLLOWING ACTIVITIES DURING THE [PAST WEEK]{.underline}:  |
| (AN AID IS A PIECE OF EQUIPMENT WHICH HELPS YOU TO PERFORM AN ACTION  |
| OF MOVEMENT)                                                          |
|                                                                       |
| Putting on your socks or tights without help or aids (e.g sock aid)   |
|                                                                       |
| EASY­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
|                                                                       |
| Bending forward from the waist to pick up a pen from the floor        |
| without an aid                                                        |
|                                                                       |
| EASY­­­­­­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
|                                                                       |
| Reaching up to a high shelf without help or aids (eg, helping hand)   |
|                                                                       |
| EASY­­­­­­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
|                                                                       |
| Getting up out of an armless dining room chair without using your     |
| hands or any other help                                               |
|                                                                       |
| EASY­­­­­­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
|                                                                       |
| Getting up off the floor without help from lying on your back         |
|                                                                       |
| EASY­­­­­­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
|                                                                       |
| Standing unsupported for 10 minutes without discomfort                |
|                                                                       |
| EASY­­­­­­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
|                                                                       |
| Climbing 12-15 steps without using a handrail or walking aid. **One   |
| foot on each step**                                                   |
|                                                                       |
| EASY­­­­­­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
|                                                                       |
| Looking over your shoulder without turning your body                  |
|                                                                       |
| EASY­­­­­­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
|                                                                       |
| Doing physically demanding activities (eg, physiotherapy exercises,   |
| gardening or sports)                                                  |
|                                                                       |
| EASY­­­­­­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
|                                                                       |
| Doing a full days activities whether it be at home or at work         |
|                                                                       |
| EASY­­­­­­­­­­­­­­­­­­\-\-\-\-\                                                         |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--IMPOSSIBLE |
+-----------------------------------------------------------------------+

**Physical Function - Dougados Functional Index (DFI)**

The DFI is a 20-item patient questionnaire is used to assess patient
function.

**Pain - Nocturnal Pain**

Amount of pain each patient experienced at night, as measured on a
100-mm VAS (with extremes of the scale from "no pain" to "most severe
pain")

**Pain - Total Back Pain**

Amount of total back pain patient experienced, as measured on a 100-mm
VAS (with extremes of the scale from "no pain" to "most severe pain")

**Spinal Mobility - Modified Schober's Test**

The Modified Schober's Test is measured by marking, with the patient
standing fully erect, the midpoint of a line between the superior iliac
spines and a point 10 cm above this point. The distance in cm between
the 2 points is then measured after the patient is asked to bend
maximally forward with knees locked.

**Spinal Mobility - Chest Expansion Score**

The chest expansion score is a measure of the difference in chest
circumference in cm at the nipple line between maximal inspiration and
maximal expiration.

**Spinal Mobility -- Occiput-To-Wall Measurement**

The occiput-to-wall measurement is the distance in cm between the wall
and the occiput with the patient standing with his/her back against the
wall.

**Patient Global Assessment**

In each study the patient global assessment was measured using a VAS
with a range of 0 to 100, or by using a 5-point scale (with "none" and
"very severe"). In Study 0016.0037 and Study 47687, the 100-mm VAS was
used.

**Inflammation - BASDAI morning stiffness duration/intensity**

The last 2 of the 6 questions of the BASDAI have been incorporated into
the overall ASAS Working Group Definition of Short-Term Improvement as a
measure of inflammation. These questions are related to the duration and
intensity of morning stiffness and are measured on a 100-mm VAS. The
first asks "How would you describe the overall level of morning
stiffness you had from the time you wake up?" and allows a range of
choices on a VAS from "none" to "very severe". The second asks on a VAS
(on a scale from 0 to 2 hours) "How long does your morning stiffness
last from the time you wake up?"

**Inflammation - CRP**

C-reactive protein is an acute phase reactant plasma protein that rises
rapidly in response to infection or tissue injury.

**Inflammation - Westergren sedimentation rate (ESR)**

The erythrocyte sedimentation rate is an acute phase reactant that rises
in response to infection or tissue injury.

**The Bath Ankylosing Spondylitis Disease Activity Index**

The (BASDAI) is a self-administered series of questions regarding
fatigue, spinal and peripheral joint pain, and localized tenderness and
morning stiffness (both qualitative and quantitative) measured on 6
horizontal, 100-mm VAS (see Appendix Table 2 below). It has been found
to be useful, reliable, sensitive-to-change, and comprehensive measure
of disease activity for subjects with ankylosing spondylitis (Garrett et
al, 1994).

Appendix Table 2. The BASDAI

+-----------------------------------------------------------------------+
| PLEASE PLACE A MARK ON EACH LINE BELOW TO INDICATE YOUR ANSWER TO     |
| EACH QUESTION, RELATING TO THE [PAST WEEK]{.underline}                |
|                                                                       |
| How would you describe the overall level of fatigue/tiredness you     |
| have experienced?                                                     |
|                                                                       |
| NONE­­­­­­­­­­­­­­­­­­\-\                                                               |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--VERY |
| SEVERE                                                                |
|                                                                       |
| How would you describe the overall of AS [neck, back or               |
| hip]{.underline} pain you have had                                    |
|                                                                       |
| NONE­­­­­­­­­­­­­­­­­­\-\                                                               |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--VERY |
| SEVERE                                                                |
|                                                                       |
| How would you describe the overall level of pain/swelling in joints   |
| [other than]{.underline} neck, back or hips you have had?             |
|                                                                       |
| NONE­­­­­­­­­­­­­­­­­­\-\                                                               |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--VERY |
| SEVERE                                                                |
|                                                                       |
| How would you describe the overall level of discomfort you have had   |
| from any areas tender to touch or pressure?                           |
|                                                                       |
| NONE­­­­­­­­­­­­­­­­­­\-\                                                               |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--VERY |
| SEVERE                                                                |
|                                                                       |
| How would you describe the overall of level of morning stiffness you  |
| have had from the time you wake up?                                   |
|                                                                       |
| NONE­­­­­­­­­­­­­­­­­­\-\                                                               |
| -\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\- |
| \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--VERY |
| SEVERE                                                                |
|                                                                       |
| How long does your morning stiffness last from the time you wake up   |
|                                                                       |
| 0                                                                     |
| hours\-\-\-                                                           |
| \-\-\-\-\--I\-\-\-\-\-\-\-\--I­­­­­­­­­­­\-\-\-\-\-\-\-\--I\-\-\-\-\-\-\-\--I­­­­­­­­­­­\-\ |
| -\-\-\-\-\-\--I\-\-\-\-\-\-\-\--I­­­­­­­­­­­\-\-\-\-\-\-\-\--I\-\-\-\-\-\-\-\--I­­­­­­­­­­­ |
| 2 or more hours                                                       |
|                                                                       |
| ½ hour 1 hour 1 and ½ hour                                            |
+-----------------------------------------------------------------------+

**Physician/Assessor Assessment**

This instrument measures on a 100-mm VAS with extremes labeled "none"
and "severe".

**Peripheral Tender and Swollen Joint Count**

Symptoms of peripheral joint synovitis/enthesitis are hallmarks of
active inflammation in patients with AS and were considered by the ASAS
Working Group to be important parameters for assessment of short-term
outcomes in patients with this disease, although these measures
individually were not ultimately included in the ASAS core composite
response criteria for measurement of short-term symptomatic improvement
(they were, however, included in measures of "disease-controlling"
therapies) (Van der Heijde et al, 1998).

**Modified Enthesopathy Index**

Performed by applying uniform manual pressure to vertebral processes
C1-C2, C7-T1, T12-L1, L5-S1, the symphysis pubis, both greater
trochanters, pelvis abductor origin, anterior superior border of the
iliac crests, ischial tuberosities, insertions of Achilles tendons, and
plantar fascia; tenderness scored on a 4-point scale (0=no pain, 1= mild
tenderness, 2=moderate tenderness, 3= wince or withdrawal); total score
subjected to analysis.

**Krupp's Fatigue Severity Scale**

This instrument is comprised of 9 statements relating to fatigue that
subjects rate from 1 (indicating strong disagreement with the statement)
to 7 (indicating strong agreement); the average of the 9 components
subjected to analysis.

**Quality-of-Life as measured by Short-Form Health Survey (SF-36)**

A 36-item questionnaire comprising 8 scales: physical functioning, role
limitations attributable to physical or emotional problems, social
functioning, general health, vitality, bodily pain, and mental health.
The SF-36 can be converted into 2 summary scores: a physical component
summary (PCS) and a mental component summary (MCS), which are linear
combinations of the 8 scales.