A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Subcutaneous AMG 108 in Subjects with Rheumatoid Arthritis

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 and premature death.
Current treatments for RA include palliative, nonspecific anti-inflammatory
agents (eg, NSAIDs and corticosteroids) and DMARDs such as MTX.
Current anti-cytokine therapies show promising results, but some patients
respond subs optimally develop intolerance to the drugs or become refractory to
therapy. Because IL-I may not be sufficiently antagonized by ankinra, anti-Il1
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.

The primary objective for this study is to determine whether AMG 108 at a
monthly dose of 250 mg SC or less in combination with MTX demonstrates a higher
frequency in clinical response (ACR20) than that observed with placebo (MTX
alone) in RA subjects at Week 16 of therapy.

The study will be a double-blind, placebo-controlled, and parallel dosing trial
of AMG 108 at 3 doses (50, 125 and 250 mg sub coetaneous) administered Q4W X 4
in RA subjects with active disease continuing on stable MTX therapy 10 to 25 mg
weekly, and of all other DMARDs prior to randomization. All subjects will be
biologic-naïve meaning they cannot have ever been on a commercial or
experimental biologic therapy for RA. Randomization will be equal across all
4-treatment arms.

After completing all screening procedures and meeting all eligibility criteria,
subjects will be randomized equally to receive either AMG 108 (50mg, 125 mg, or
250 mg) or placebo SC administration once every 4 weeks for a total of 4 doses.
Randomization assignment to the treatment arms will be based on a
computer-generated randomization schedule prepared by Amgen before the start of
the study

AMG 108 is an antibody that inhibits Interleukin-one (IL-1), a naturally
occurring substance in the body. In theory, a decrease in IL-1 levels may
reduce the body*s inflammatory response. Since studies in humans with AMG108
began, approximately 417 subjects have been enrolled in Amgen sponsored trials,
a limited number, and therefore the potential adverse effects are not
completely known. In an AMG 108 clinical study, subjects with osteoarthritis
have reported the following commonly (1% to 10%) occurring adverse events:
arthralgia, headache, painful joints and back pain.
Lower than normal levels, or counts, of a certain type of white blood cells
(neutrophils) have been observed in a subset of patients in AMG 108 studies.
The significance of this decrease in neutrophils is currently unknown. Changes
in neutrophil counts can be due to multiple causes. When neutrophil counts
become very low the body*s ability to fight certain infections may be weakened.
Infection leading to death could result. This decrease in neutrophils was
temporary and subjects* levels returned to normal ranges, generally within a
few weeks.