A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the
Safety, Pharmacokinetics, and Efficacy of VX-509 using Magnetic Resonance Imaging and Arthroscopic Biopsies in Subjects with Active Rheumatoid Arthritis on Stable Disease-Modifying
Antirheumatic Drugs

• Male and female subjects 18 to 65 years of age (inclusive)
• Diagnosis of RA
• Subject must have a swollen joint count of >=6 out of 66 assessed joints and a tender joint count of >=8 out of 68 assessed joints
• Seropositivity based on either a positive rheumatoid factor or anti-cyclic citrullinated peptide antibody at screening OR known erosive disease based on previous X-ray report (available and filed) or erosions detected on baseline hand and foot X-ray
• Baseline CRP level >=1.2 x ULN or Westergren erythrocyte sedimentation rate >=1.2 x upper limit of normal at screening
• Subjects must be receiving stable therapy with 1 of the following DMARDs: methotrexate, sulfasalazine, leflunomide, anti-malarial drug, or penicillamine.
• Subjects must have palpable 2+ synovitis of the wrist or >=2 MCPs, defined as loss of bony contours with palpable joint effusion and/or swelling, in the MRI-designated hand (the hand being used in MRI assessments).

A complete list of the exclusion criteria can also be found in the protocol Section 10.2 Exclusion Criteria.;Subjects who meet any of the following exclusion criteria will not be eligible for this study:
1. Inflammatory and rheumatological disorders other than RA, where arthritis may be a prominent feature, such as systemic lupus erythematosus, mixed connective tissue disease, scleroderma, poly/dermatomyositis, or gout; secondary Sjogren*s syndrome or interstitial lung disease are allowed.
2. History of any illness that might confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This may include, but is not limited to, history of cardiovascular or central nervous system disease, history or presence of clinically significant abnormalities on physical exam, ECG or laboratory examination, or history of clinically significant psychiatric or mental disease.
3. History of cancer, except squamous or basal cell cancers of the skin or in situ cancer of the cervix.
4. History of hematologic disorders including neutropenia and thrombocytopenia other than Felty*s syndrome.
5. History of tuberculosis (TB), regardless of history of anti-mycobacterial treatment; or active TB as determined by X-ray, TB skin test and QuantiFeron® TB Gold Assay (QuantiFeron assay). If the subject has a hypersensitivity to skin test preparation associated with the TB skin test then the QuantiFeron alone is acceptable.
6. Acute or chronic active infection requiring systemic antimicrobial treatment with the exception of onychomycosis receiving antifungal medication, or acne and rosacea receiving low-dose antibiotics.
7. History of febrile illness within 5 days before the first dose of study drug.
8. History of previous osteomyelitis, infected joint or joint prosthesis.
9. Subjects who are at high risk of developing an infection due to a compromised immune system including poorly controlled diabetes.
10. Weight <45 kg at screening.
11. A 12-lead ECG demonstrating QT interval corrected (QTc) >450 msec at the screening Visit. If QTc exceeds 450 msec, the ECG should be repeated 2 more times, and the average of the 3 QTc values used to determine the subject*s eligibility. Subjects should also be excluded if any other clinically significant interval (e.g., PR prolongation), morphologic (e.g., T-wave inversion), or conduction abnormalities are observed.
12. Planned surgery during the study.
13. Metal implant or other contra-indication to MRI scanning.
14. History of alcohol or drug abuse, or excessive alcohol consumption as determined by the investigator, during the previous 12 months before screening.
15. For female subjects: Pregnant or nursing; or planning to become pregnant during the study or within 90 days following the last VX-509 dose; or female subjects of childbearing potential who are unwilling or unable to use an acceptable method of contraception as outlined in this protocol from at least 14 days before the first dose of study drug and for 90 days following the last dose of study drug.
16. For male subjects: Subject has a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days following the last VX-509 dose; or male subjects who are unwilling or unable to use an acceptable method of contraception as outlined in this protocol from at least 14 days before the first dose of study drug and for 90 days following the last dose of study drug.
17. Subject is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, other staff, or a relative of study personnel directly involved with the conduct of the study.
18. Requirement for more than 1 NSAID after signing informed consent at screening (additional aspirin [second NSAID] <=325 mg/day is allowed). The dose of any ongoing NSAID must be stable for at least 28 days before Day 1.
19. Systemic corticosteroid treatment (prednisone or equivalent) >10 mg/day. The dose of any ongoing systemic corticosteroid must be stable for at least 28 days before Day 1 (Section 16.13).
20. Allergy to gadolinium.
21. Prior treatment with a JAK inhibitor.
22. Other DMARDs (biologic/non-biologic) beyond the required DMARD for study entry must have been discontinued for specified minimum periods before screening (see Section 16.2). Subjects with prior treatment with rituximab/ocrelizumab (or other depleting monoclonal antibody) must show demonstrated recovery of any cytopenia(s).
23. Intraarticular corticosteroids in any joint within 4 weeks before screening, or within 12 weeks before screening for the MRI-designated hand or joint planned for arthroscopy.
24. Treatment with an investigational drug within 60 days or 5 half-lives preceding the first dose of study drug, whichever is longer.
25. Subjects who require concomitant use of any moderate or strong inhibitors or inducers of CYP3A or P-gp or who require CYP3A substrates with serious associated side effects at high exposure (Section 10.3; partial lists in Section 16.3).
26. Have received a live or live attenuated vaccination in the 4 weeks before study Day 1.
27. Positive urine or serum pregnancy test.
28. Hemoglobin <11 g/dL for females or <12 g/dL for males at screening.
29. Absolute neutrophil count <1.5 K/µL at screening.
30. Platelet count <120 K/µL at screening.
31. ALT or AST >=1.5 × the ULN at screening.
32. Creatinine clearance <30 mL/min at screening
33. Positive hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus 1 and 2 antibodies at screening.
34. Other clinically significant out-of-range laboratory results in hematology, serum chemistry, coagulation studies, or urinalysis at the screening as judged by the investigator.