A Long-term Assessment of Safety and Efficacy of AMG 827 Treatment in Subjects With Crohn's Disease

Crohn*s disease is a chronic relapsing, remitting inflammatory disease of the
gastrointestinal tract although some patients may have continuously active
disease. The cause of Crohn*s disease remains unknown.
Crohn*s disease affects the gastrointestinal tract discontinuously from mouth
to anus, but most commonly the disease is located both in the ileum and colon,
small bowel only, or colon only. Crohn*s disease occurs in all age groups with
a higher incidence in the younger population; there is no marked sex
difference. The incidence of Crohn*s disease in adults has been reported as up
to approximately 8 per 100,000 person-years, with the highest reported
adult-onset incidences in Spain (Saro Gismera et al, 2000), Sweden (Lapidus et
al, 2006), and the United Kingdom (García Rodríguez et al, 2005).
Studies have found increased mortality in patients with Crohn*s disease
(Duricova et al, 2009), as well as a negative impact to their daily life.
Medical therapy used in clinical practice includes aminosalicylates,
corticosteroids, immunomodulators, antibiotics, and biologic therapies;
nutritional support also has a role (Lichtenstein et al, 2009). When medical
treatment is unsuccessful or with certain complications, surgery is indicated.
Due to therapeutic failures and serious side effects of present therapies,
alternatives are needed.
The clinical hypothesis in this study is that AMG 827 is well tolerated with
extended dosing for up to 132 weeks (approximately 2.5 years).

1.1 Safety
To evaluate the safety of long-term exposure with AMG 827 in subjects with
Crohn*s disease
1.2 Efficacy
* To evaluate the efficacy of AMG 827 as measured by the Harvey-Bradshaw Index
(HBI) and the Crohn*s Disease Activity Index (CDAI)
* To evaluate the maintenance of effect as measured by the HBI and CDAI
Efficacy analyses will use study 20090072 baseline for primary analyses but
will also examine changes from the baseline values of 20100008.
1.3 Other
* To evaluate the change of EQ-5D from baseline at all measured timepoints
* To determine the proportion of subjects who develop anti-AMG 827 antibodies
* To evaluate the effect of treatment on inflammatory markers (C-reactive
protein [CRP]) at post-baseline measured timepoints
* To evaluate the pharmacokinetics of AMG 827 with long-term administration

This study is an open-label extension of phase 2 study 20090072 in subjects
with Crohn*s disease. All subjects will receive 350 mg AMG 827 intravenously
every 4 weeks. Overall, subjects will participate in the study for
approximately 132 weeks or until the investigator*s recommendation of
discontinuation, Amgen*s recommendation of discontinuation, the subject*s
decision to discontinue for any reason, or an administrative decision is made
to close the study for any reason, including, but not limited to, no proven or
insufficient efficacy demonstrated in study 20090072.

350 Mg AMG 827 is administered intravenously at day 1 and every 4 weeks
thereafter (week 4, 8, 12, etc). Each dose will require 5 vails of AMG 827.

Subjects do need to visit the clinic every 2 weeks during the first 10 weeks,
thereafter eveery 4 weeks. Some subjecst do need to do an PPD test. A sc
injection is required for the PPD test. There are additional blood collections
if a subject is positive for antibodies against AMG 827 (until the result is
negative). If ANC < 1500 cells/uL, additional blood collections may be
necessary. Study medication is administered via an infusion of at least 30 min.
Possible, a quantiferon test is required, which means an extra blood
collection. The discomforft and risks for teh subjects are minimal.
Administration of the study medication, the injection for the PPD test and
quantiferon test (if applicable) and the blood collections will only be done by
experienced and trained staff. Administration of the study medication will
always be done under the supervision of the principal investigator or a sub
investigator. If a subjec thas a positive blood test for antibodies against AMG
827 duirng the study ,the subject might be asked to return to the clinic at
different occasions until the result of the blood test is negative. This will
mean additional blood collections.

If at week 2, 6 or 10 ANC < 1500 cells/uL, a new CBC is required in week 3, 7
or 11: this means an dditional blood collection of 2 mL.

AMG 827 is administered o nday 1 (baseline), week 4 and every 4 weeks
thereafter. The dosis of AMG 827 (70 mg per mL packaged in 1 mL single use
vials) will be administered as an IV infusion. Each dose will require 5 vials
of AMG 827. Subjects will receive 350 mg of AMG 827 per infusion.

If the subject will participate until and including the last visit, there are
37 visits of on average 2 hours each and 38 blood collections (13 mL per
collection).

The infusions with AMG 827 and the blood collections will involve risks.
However, administration of study medication and collection of blood will only
be done by trained and experieneced staff, by which the risks will be reduced
to minimal. Adminitsration of every study medication has a general risk on side
effects. Because AMG 827 is a investigational productm not all side effects in
humans are known. There is always a possibility of an allergic reaction on a
medicine.

Side effects reported to be related to AMG 827: Injection site redness, itching
or general reaction, headache. Neutropenia has been seen in lab tests for some
subjects in AMG 827 studies. It is possible subjects may produce antibodies
agianst AMG 827 after having received AMG 827.

The subjects are asked to complete questionnaires (HBI and EQ-5D) and a diary,
according the flowchart on page 54 of the protocol. The CDAI will be completed
by involved site staff by interviewing the subjects.

All subjects will be treated with AMG 827 and may benefit from the treament.