R-2487 in Patients with Rheumatoid Arthritis

Inclusion Criteria:

• Ages 18-75 years (Inclusive).

• Able to provide written informed consent.

• Men or women (not nursing or pregnant) who have active RA, defined as symptoms of RAprior to screening and have satisfied the ACR/EULAR 2010 criteria for theclassification of RA prior to signing the informed consent.

• Subjects must have a CDAI > 10.0 at screening and have at least 3 tender and atleast 3 swollen joints (excluding distal interphalangeal) at screening and at Day 1,based on the DAS28 joint count.

• Subjects may be able to be on hydroxychloroquine, methotrexate, and leflunomide.Sulfasalazine use is not permitted.

• Subjects may have received targeted synthetic DMARDs such as tofacitinib,baricitinib, and investigational therapies for RA if they have been washed out for 1month prior to screening.

• Subjects receiving oral corticosteroids must be on a stable dose and at theequivalent of ≤10 mg prednisone daily for at least 4 weeks. Subjects may not receivean IM, IV or IA administration of a corticosteroid within 4 weeks prior to screeningvisit or initiation of therapy.

• All male and female subjects who are biologically capable of having children mustagree to use a medically acceptable method of birth control for the duration of thestudy. All female subjects who are biologically capable of having children must havea negative pregnancy test result before administration of study drug. Any pregnancythat occurs in the female partner of a male subject in the trial must be reported ifit occurs at any time during the study.

• Refrain from receiving any type of vaccinations during the study period (to includebut not limited to influenza, COVID, shingles, tetanus, hepatitis, pneumonia, HPV,DPT, MMR, and polio).

Exclusion Criteria:

• Pregnancy (females, unless surgically sterile or at least two years post- menopausalmust have a negative serum pregnancy test within 14 days prior to receiving thestudy drug and a negative urine pregnancy test on Study Day 0 before receiving thestudy drug).

• Nursing mothers.

• Subjects with autoimmune disease other than RA [e.g., psoriasis, systemic lupuserythematosus (SLE), vasculitis, seronegative spondylarthritis, Inflammatory BowelDisease, Sjogren's syndrome] or currently active fibromyalgia.

• Subjects should not receive any of the following medications:

• Rituximab within 12 months prior to Day 1,

• Abatacept within 3 months prior to Day 1,

• Infliximab, Adalimumab, Certolizumab, Tocilizumab, Cyclosporine, or

• Mycophenolate mofetil within 2 months prior to Day 1, or

• Etanercept, Anakinra, Immunoglobulin, or blood products within 28 days prior to Day 1

• Prior immunotherapy, including systemic corticosteroids, such prednisone, biologics,Janus kinase (JAK) inhibitors (such as tofacitinib, baricitinib or upadacitinib),ozanimod, or investigational therapy must have completed at least 5 half-lives or 30days, whichever is longer, prior to Day 0, unless otherwise specified. In the caseof cell-depleting therapies, such as B or T cell depletion, cell counts must haverecovered to acceptable or baseline levels (use of licensed agents for indicationsnot listed in the package insert is permitted).

• Prior history of or current inflammatory joint disease other than RA (such aspsoriatic arthritis, gout, reactive arthritis, Lyme disease).

• Subjects at risk for tuberculosis (TB) defined as follows: Current clinical,radiographic or laboratory evidence of active TB. Chest x-rays (posterior, anteriorand lateral) obtained within the 3 months prior to obtaining written informedconsent will be permitted but the images must be available and reviewed by theinvestigator. TB testing (IFN-gamma release assay or PPD) performed in the pastmonth prior to Screening will be accepted; however, a copy of the report must beplaced in the subject binder.

• A history of active TB.

• Subjects with a positive TB screening test indicative of latent TB includingsubjects currently being treated for latent tuberculosis infection (LTBI) will notbe eligible for the study.

• Subjects with recent acute infection defined as:

• Any acute infection within 60 days prior to randomization that requiredhospitalization or treatment with parenteral antibiotics,

• Any acute infection within 30 days prior to randomization that required oralantimicrobial or antiviral therapy,

• Subjects with history of chronic or recurrent bacterial infection (such as chronicpyelonephritis, osteomyelitis, and bronchiectasis etc.),

• Subjects with any history of infection of a joint prosthesis or artificial joint,

• Subjects who have a history of systemic fungal infections (such as histoplasmosis,blastomycosis, or coccidiomycosis),

• Subjects with history of recurrent herpes zoster (more than 1 episode) ordisseminated (more than 1 dermatome) herpes zoster or disseminated herpes simplex,or ophthalmic zoster will be excluded,

• Symptoms of herpes zoster or herpes simplex must have resolved more than 60 daysprior to screening,

• Subjects with history of primary immunodeficiency.

• Subjects with history of Human Immunodeficiency Virus (HIV) infection or who testedpositive for HIV.

• Evidence of infection with hepatitis B virus (HBV), hepatitis C virus (C), humanimmunodeficiency virus (HIV)-1 or HIV-2, or active infection with hepatitis A, asdetermined by results of testing at screening.

• Subjects who have a present malignancy or previous malignancy within the last 5years prior to screening (except documented history of cured non- metastaticsquamous or basal cell skin carcinoma or cervical carcinoma in situ). Subjects whohad a screening procedure that is suspicious for malignancy, and in whom thepossibility of malignancy cannot be reasonably excluded following additionalclinical, laboratory or other diagnostic evaluations.

• Current clinical findings of a history of a demyelinating disorder.

• New York Heart Association (NYHA) Class III or IV heart failure.

• Subjects who have undergone a major surgical procedure within the 60 days prior toenrollment.

• Subjects for whom 5 or more joints cannot be assessed for tenderness or swelling (i.e. due to surgery, fusion, amputation, etc.).

• Current clinical findings of severe, progressive, or uncontrolled renal, hepatic,hematological, gastrointestinal, pulmonary, cardiac, endocrine, neurological, orcerebral disease with laboratory values as following:

• Hemoglobin level < 9.0 g/dL,

• Absolute white blood cell (WBC) count of <3.0×109/L (<3000/mm3), or absoluteneutrophil count of <1.2×109/L (<1200/mm3), or absolute lymphocyte count of <0.8×109/L (<800/mm3),

• Thrombocytopenia, defined by platelet count <100×109/L (<100,000/mm3),

• Chronic kidney disease defined as Estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2, based on the age-appropriate calculation,

• Proteinuria ≥3+,

• Total bilirubin (T-bili), aspartate aminotransferase (AST), alanine aminotransferase (ALT) more than 1.5 times upper limit of normal (ULN)

• Previously diagnosed hepatic cirrhosis (Child Pugh A or higher) or previouslydiagnosed significant liver fibrosis (> F3).

• Any form of vaccination in the last 30 days, to include but not limited toinfluenza, COVID, shingles, tetanus, hepatitis, pneumonia, HPV, DPT, MMR, and polio.