A Long-term Assessment of Safety and Physical Function with AMG 108 Subcutaneous Monthly Treatment in Subjects with Rheumatoid Arthritis

RA is a chronic, systemic, autoimmune, inflammatory arthropathy of unknown
etiology. RA is characterized by progressive destruction of the affected
joints, deformity, disability. Symptoms include joint stiffness, pain and
swelling, fatigue, weakness, and psychologic depression. RA occurs worldwide in
approximately 1% of adults of all races. Disease onset occurs most often
between the ages 20 and 60 years, with peak occurrences at 35 to 40 years. RA
has a higher prevalence in women than men. Current treatments for RA include
NSAIDs and corticosteroids and DMARDs such as MTX. In addition, improved safety
and efficacy profiles have been achieved with biologic response modifiers
(BRMs) that selectively inhibit cytokines that are thought to be central to the
pathogenesis of RA, including tumor necrosis factor (TNF) antagonists such as
etanercept and infliximab, and interleukin-1 (IL-1) antagonists such as
anakinra. Current anti-cytokine therapies show promising results, but some
patients respond suboptimally, develop intolerance to the drugs, or become
refractory to therapy. Because IL-1 may not be sufficiently antagonized by
anakinra, anti-IL-1 therapy remains an incompletely explored treatment option
for inflammatory diseases. Results for anakinra show clear indications of
efficacy with an excellent safety profile, but higher levels of IL-1 blockage
may result in benefits over existing therapies.
AMG 108 is a fully human immunoglobulin type G2 (IgG2) monoclonal antibody and
inhibits IL-1 signaling by targeting the IL-1 type I receptor (IL-1RI).
The primary aim of this study is longterm safety of AMG 108 in RA in the
highest doses tested in the preceeding study 20050168. It is expected that
these doses will give sufficient IL-1 suppression at the end of the 1 month
dosage interval. AMG 108 was sofar well tolerated and seems to have a wide
safety margin. All eligible patients have participated in the study 20050168.

Primary Objective: The primary objective of the study is to assess long-term
safety of AMG 108 (125 mg, 250 mg) SC in subjects with RA previously enrolled
in study 20050168.

Secondary Objective(s): The secondary objectives of the study are:
* To assess impact of concomitant immunosuppressives on long-term safety
profile of AMG 108
* To assess impact of comorbidity on adverse event (AE) profile of AMG 108
* To determine whether long-term use of AMG 108 improves function in subjects
with RA
* To assess the change in mental and physical component summaries (MCS & PCS)
and each of the 8 domain scores of SF-36 from baseline to weeks 24, 48, 96, 144
and EOS
* To determine effect of long- term use of AMG 108 on work productivity
* To evaluate long-term pharmacokinetics (trough levels) of AMG 108
* To assess the clinical effect of AMG 108 as determined by ACR20 response at
week 24, 48, 96, 144 and EOS
* To determine whether immunogenicity of AMG 108 affects efficacy and safety as
determined by frequency, subject incidence and time-to-onset of cardiovascular
safety events and changes in biomarkers related to cardiovascular disease

Exploratory Objective(s):
* To assess the clinical effect of AMG 108 as determined by American College of
* Rheumatology (ACR) 50 and 70 response, ACRn and AUC ACRn, individual
components of ACR response, morning stiffness and change in DAS28 from baseline
(EULAR response) at weeks 24, 48, 96, 144 and EOS
* To assess cardiovascular outcomes in RA subjects treated with AMG 108 as
determined by frequency, subject incidence and time-to-onset of cardiovascular
safety events and changes in biomarkers related to cardiovascular disease

This is a long-term extension study to evaluate the safety of AMG 108 at 125 mg
and 250 mg SC monthly in subjects with RA who were eligible for and completed
24 weeks of participation in study 20050168. The study will be blinded to
treatment doses until the study 20050168 is unblinded. An interim analysis for
this study will be performed following the unblinding of study 20050168. All
subjects will be on weekly MTX SC or PO at entry into this study unless
discontinued for toxicity reasons in study 20050168. Subjects who met LOE
criteria at or after week 12 in study 20050168 may be on additional therapies
for RA at baseline in this study.
An external data monitoring committee (DMC) will monitor the safety of study
participants throughout the study duration.

Administration of AMG 108.

Written informed consent must be obtained from all subjects before screening.
Upon completing all screening assessments and meeting all eligibility criteria,
subjects will be enrolled and receive either 125mg or 250 mg AMG 108 Q4W for
approximately 48 months or until an administrative decision is made to end the
study.
The following procedures will be performed per the schedule outlined in
Appendix A: pregnancy test (at screening only), physical exam, vital signs,
blood draw for serum chemistry, hematology, PK, AMG 108 antibody assay,
concomitant medication and AE recording, HAQ, EQ-5D, SF-36, SGA, Pain VAS,
Morning Stiffness, WPAI questionnaires, CRP, ESR, PGA and joint assessments
(tender and swollen joint counts). Once all procedures are completed, the
subject will receive the dose of IP.