Safety and Efficacy of AMG 592 in Subjects With Active Rheumatoid Arthritis

Inclusion Criteria:

- Subject has provided informed consent prior to initiation of any study specific
activities/procedures.

- Age ≥ 18 to ≤ 70 years of age at screening.

- A diagnosis of RA consistent with the 1987 or 2010 American College of Rheumatology
(ACR)/European League Against Rheumatism classification criteria.

- Active RA defined as: Phase 1b: DAS-28-CRP > 2.6 at screening. The 28-joint count
consists of the finger joints excluding the distal interphalangeal joints, the wrists,
elbows, shoulders, and knees. Phase 2a: ≥ 6 swollen joints (based on 66-joint count)
and ≥ 6 tender joints (based on 68-joint count) at screening and baseline. The distal
interphalangeal joint should be evaluated but not included in the total count to
determine eligibility. Additionally, C-reactive protein (CRP) must be greater than the
upper limit of normal (ULN) per the central laboratory at screening.

- Receiving treatment with methotrexate for ≥ 12 weeks and on a stable dose ≥ 15 mg
weekly for ≥ 8 weeks prior to day 1. A lower methotrexate dose is acceptable (but no
lower than 10 mg weekly) if it is the highest tolerated dose and gastrointestinal or
hematologic toxicity at doses ≥ 15 mg weekly is documented by the investigator.

- Receiving treatment with folic or folinic acid per investigator judgment or according
to local standard of care.

- Phase 1b only: Subject may be receiving a stable dose of leflunomide, sulfasalazine,
hydroxychloroquine, minocycline in combination with methotrexate and the dose must be
stable for ≥ 8 weeks prior to day 1.

- Subject may be receiving a stable dose of prednisone ≤ 10mg daily or other equivalent
corticosteroid dose and the dose must be stable for ≥ 2 weeks prior today 1.

- Phase 1b only. Normal or clinically acceptable ECG values (12-lead reporting
ventricular rate and PR, QRS, QT and QTc interval) at screening and baseline based on
opinion of the investigator.

- Immunizations (tetanus, diphtheria, pertussis, seasonal influenza [during flu season],
and pneumococcal [polysaccharide] vaccinations) up to date per local standards as
determined by the investigator.

Exclusion Criteria:

- Class IV RA according to ACR revised response criteria

- Diagnosis of Felty's Syndrome (RA, splenomegaly and granulocytopenia).

- Prosthetic joint infection within 3 years of screening or native joint infection
within 1 year prior to screening.

- Active infection (including chronic or localized infections) for which anti-infectives
were indicated within 4 weeks prior to day 1 OR presence of serious infection, defined
as requiring hospitalization or intravenous anti-infectives within 8 weeks prior to
day 1.

- Known history of active tuberculosis.

- Positive test for tuberculosis during screening defined as either: positive purified
protein derivative (PPD) (≥ 5 mm of induration at 48 to 72 hours after test is placed)
OR positive Quantiferon test: a positive PPD and a history of Bacillus Calmette-Guérin
vaccination are allowed with a negative Quantiferon test and negative chest x ray; a
positive PPD test (without a history of Bacillus Calmette-Guérin vaccination) or a
positive or indeterminate Quantiferon test are allowed if they have ALL of the
following at screening: no symptoms per tuberculosis or sheet provided by Amgen;
document history of a completed course of adequate prophylaxis(completed treatment for
latent tuberculosis per local standard of care prior to the start of investigational
product); no known exposure to a case of active tuberculosis after most recent
prophylaxis; negative chest X-ray.

- Positive for hepatitis B surface antigen, hepatitis B core antibody (confirmed by
hepatitis B DNA polymerase chain reaction [PCR] test) or detectable hepatitis C virus
RNA by PCR (screening is generally done by hepatitis C antibody [HepCAb], followed by
hepatitis C virus RNA by PCR if HepCAb is positive). A history of hepatitis B
vaccination without history of hepatitis B is allowed.

- Phase 1b only: Positive for Human Immunodeficiency Virus (HIV) at screening or known
to be HIV positive. Phase 2a only: Known history of HIV

- Positive drug or alcohol urine test at screening.

- Presence of one or more significant concurrent medical conditions per investigator
judgment, including but not limited to the following: poorly controlled diabetes or
hypertension; chronic kidney disease stage IIIb, IV, or V; symptomatic heart failure
(New York Heart Association class II, III, or IV); myocardial infarction or unstable
angina pectoris within the past 12 months prior to randomization; severe chronic
pulmonary disease (eg, requiring oxygen therapy); multiple sclerosis or any other
demyelinating disease; major chronic inflammatory disease or connective tissue disease
other than RA (eg, systemic lupus erythematosus with the exception of secondary
Sjögren's syndrome).

- Malignancy except non-melanoma skin cancers, cervical or breast ductal carcinoma in
situ within the last 5 years.

- History of alcohol or substance abuse within 6 months of screening

- Phase 1b only: Current smoker, and/or use of any nicotine or tobacco containing
products within the last 6 months prior to day 1. These types of products include but
are not limited to: snuff, chewing tobacco, cigars, electronic cigarettes, cigarettes,
pipes, or nicotine patches.

- Phase 1b only: Subject unwilling to limit alcohol consumption to ≤ 1 drink of alcohol
per day and ≤ 3 drinks per week for the duration of the study, where a drink is
equivalent to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of
wine, or 1.5 ounces of 80 proof distilled spirits. Phase 1b only: Unwilling or unable
to abstain from alcohol consumption within 48 hours prior to each visit (including
screening).

- Subjects who have received intra-articular or systemic corticosteroid injections for
treatment of acute RA flare (not being part of a regular therapeutic regimen) within 4
weeks prior to screening.

- Currently receiving or had treatment with cyclophosphamide, chlorambucil, nitrogen
mustard, or any other alkylating agent ≤ 6 months prior to day 1.

- Prior treatment with more than a total of 3 therapies that include biologic DMARDs or
oral synthetic DMARDs (such as tofacinitib, baricitinib). Prior treatment consists of
at least 4 doses of a given therapy where the doses were given solely for treatment of
RA disease. Prior therapies must not have been used within the following time periods:

- ≤ 4 weeks prior to day 1 for etanercept and anakinra

- ≤ 6 months for rituximab

- ≤ 2 weeks for oral janus kinase inhibitors

- ≤ 9 weeks prior to day 1 for all therapies not listed above

- Currently receiving or had treatment with any of the following ≤ 12 weeks prior to day
1:

- azathioprine

- cyclosporine

- gold

- mycophenolate mofetil

- Prosorba column

- Tacrolimus

- Phase 2a only: Currently receiving or had treatment with leflunomide ≤ 12 weeks prior
to day 1 unless an active washout with cholestyramine has been performed.

- Phase 2a only: Currently receiving or had treatment with any of the following ≤ 4
weeks prior to day 1:

- hydroxychloroquine

- sulfasalazine

- minocycline

- oral janus kinase inhibitor (eg, tofacitinib, baricitinib)

- intra-articular, intramuscular or intravenous corticosteroids, including
adrenocorticotropic hormone

- intra-articular hyaluronic acid injections

- live vaccines

- Unstable dose of non-steroidal anti-inflammatory drugs (NSAID), acetaminophen, and/or
analgesics which is taken on an unscheduled basis (ie, not daily or scheduled every
certain number of hours) and/or initiated <4 weeks prior to day 1.

- Received the following within 12 hours prior to screening or day 1:

acetaminophen, NSAIDs, tramadol, and/or any narcotic analgesics such as but not limited to
hydrocodone, codeine, tramadol, propoxyphene and/or oxycodone (unless in the form of
oxycontin). Subject has taken oxycontin within 24 hours prior to screening or day 1.

- Phase 1b only: Received any herbal medicines (eg St John's wort),or non-vitamin
dietary supplements (eg, magnesium) with the exception of calcium within 4 weeks prior
to day 1.

- Currently receiving treatment in another investigational device or drug study, or less
than 30 days since ending treatment on another investigational device or drug
study(ies). Other investigational procedures while participating in this study are
excluded.

- Presence of laboratory abnormalities at screening including the following:

- Aspartate aminotransferase (AST) or alanine amino transferase (ALT) at screening
> 1.5X upper limit of normal (ULN)

- Serum total bilirubin (TBL) ≥ 1.5 mg/dL (≥ 26 μmol/L)

- Hemoglobin ≤ 10.5 g/dL(≤105 g/L)

- Platelet count < 100,000/mm3 (<100 x 109/L)

- White blood cell count < 3,000 cells/mm3 (3.0 x 109/L)

- Absolute neutrophil count (ANC) < 1,500/mm3 (1.5 x 109/L)

- Calculated glomerular filtration rate of ≤ 50 mL/min/1.73 m2 using the
Modification of Diet in Renal Disease (MDRD) formula

- Any other laboratory abnormality, which, in the opinion of the investigator, poses a
safety risk, will prevent the subject from completing the study, will interfere with
the interpretation of the study results, or might cause the study to be detrimental to
the subject.

- Female subject is pregnant or breastfeeding or planning to become pregnant or
breastfeed during treatment and for an additional 6 weeks after the last dose of
investigational product.

- Females of child-bearing potential with a positive pregnancy test (assessed by a serum
pregnancy test at screening and a urine pregnancy test at baseline).

- Female subjects of childbearing potential unwilling to use 1 highly effective method
of contraception during treatment and for an additional 6 weeks after the last dose of
investigational product. Refer to Appendix 5 for additional contraceptive information.

- Subject has known sensitivity to any of the products or components to be administered
during dosing.

- Subject likely to not be available to complete all protocol-required study visits or
procedures, and/or to comply with all required study procedures (eg, Clinical Outcome
Assessments [COAs]) to the best of the subject and investigator's knowledge.

- History or evidence of any other clinically significant disorder, condition or disease
(with the exception of those outlined above) that, in the opinion of the investigator
or Amgen physician, if consulted, would pose a risk to subject safety or interfere
with the study evaluation, procedures or completion