This will be a 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter study to evaluate the safety, efficacy, and PK of oral administration of PG-760564 in adult patients with active RA receiving treatment with MTX. Two oral doses of PG-760564 will be evaluated: 25 mg BID and 100 mg BID. The study will consist of a screening visit followed by a washout period for all disease modifying antirheumatic drugs (DMARDs) and anti-cytokine therapies except MTX. After the washout period, patients determined to be eligible will be randomized to receive either 25 mg BID or 100 mg BID of oral PG-760564, or placebo for 12 weeks. There will be 6 treatment visits and a follow-up visit 4 weeks after the last treatment visit. The primary efficacy endpoint will be the proportion of patients meeting the ACR 20 response criteria after 12 weeks of treatment.

The study will be conducted in North America and Europe at approximately 50 to 60 sites. Approximately 270 patients will be randomized, of which 189 are expected to complete the study.

The study will consist of a screening visit followed by a washout period for all disease modifying antirheumatic drugs (DMARDs) and anti-cytokine therapies except MTX. The washout period will be 4 weeks for sulfasalazine, hydroxychloroquine, azathioprine, D-penicillamine, etanercept, and anakinra, 8 weeks for gold, infliximab, and adalimumab, and 12 weeks for abatacept.

After the washout period, the patients determined to be eligible will be randomized to receive either 25 mg BID or 100 mg BID of oral PG-760564, or placebo for 12 weeks. There will be 6 treatment visits (Weeks 1, 2, 4, 6, 8, and 12) and a follow-up visit 4 weeks after the last treatment visit (Week 16). Patients will not initiate new therapies until after the 4-week follow-up is completed. Liver function tests will be evaluated at every visit.

The primary efficacy endpoint will be the proportion of patients meeting the ACR 20 response criteria after 12 weeks of treatment.

Inclusion Criteria:

• Meet American College of Rheumatology (ACR) criteria for Rheumatoid Arthritis
• Disease duration of at least 6 months
• Must be treated with Methotrexate for at least 24 weeks
• At least 6 swollen joints and 6 tender joints
• Washout required for other Disease Modifying Anti-rheumatic Drugs (DMARDs)
• Women of childbearing age and all males must use acceptable method of birth control

Exclusion Criteria:

• Tuberculosis
• Malignancies
• Abnormal electrocardiograms as described in the protocol
• Current infection or recurrent infections or immunodeficiency
• Liver diseases and abnormalities in liver function tests as described in the protocol
• Autoimmune diseases other than RA except Sjogren's syndrome secondary to RA;
• History of demyelization diseases
• Any condition that in the opinion of the investigator could be detrimental to patients enrolling in the study including clinically important changes in laboratory values and other diseases described in the protocol