Approximately 108 subjects will be randomized in 2 arms in 2:1 ratio to receive weekly subcutaneous injections of either 400mg Natrunix + MTX weekly or placebo + MTX weekly for 14 weeks. At the week 14 visit subjects in both arms will undergo a safety follow up visit OR begin receiving biweekly subcutaneous injections of 400mg Natrunix for 14 weeks as part of an Open Label Extension (OLE).

The study will last for a maximum of 33 weeks, including: a screening period of up to 4 weeks, a 14-week double-blinded treatment phase followed by a 14-week open label extension phase and one-week follow-up.

Number of Planned Subjects: Approximately 108 subjects within 2 arms randomized 2:1 [400 mg Natrunix + MTX weekly (n=72) or placebo + MTX weekly arms (n=36)].

Study Duration: The study will last for a maximum of 33 weeks, including: a screening period of up to 4 weeks, a 14-week double-blinded treatment phase followed by a 14-week open label extension phase and one-week follow-up.

Study Design: Subjects will be randomized into the study in a 2:1 ratio to receive weekly subcutaneous injections of either 400mg Natrunix + MTX weekly or placebo + MTX weekly for 14 weeks. At the week 14 visit subjects in both arms will undergo a safety follow up visit OR begin receiving biweekly subcutaneous injections of 400mg Natrunix for 14 weeks as part of an Open Label Extension (OLE).

Subjects will undergo a preliminary assessment for study eligibility. Subjects who meet pre-screening requirements may then provide informed consent to acknowledge understanding of and accept enrollment into the clinical study. Subjects enrolled in the study will be taking concomitant methotrexate, have a diagnosis of moderate to severe RA according to 2010 ACR/EULAR classification criteria and have ≥6 swollen joints (based on DAS28), ≥6 tender joints (based on DAS28) and DAS-ESR > 3.2.

Inclusion Criteria:

1. Weight > 40 kg

2. Diagnosis of moderate to severe RA according to 2010 ACR/EULAR classification criteria.

3. Patients must be methotrexate-inadequate responders.

   a. Persistent moderate to severe RA disease activity (i.e., criteria #2 above) despite ongoing treatment with MTX.

4. Meets the following minimum disease activity criteria at screening: ≥6 swollen joints (based on DAS28) and ≥6 tender joints (based on DAS28) and DAS-ESR (Erythrocyte Sedimentation Rate) > 3.2.

5. Subject must be receiving MTX treatment at a dosage of 10-25 mg/week for a minimum of 12 weeks; and be receiving a stable dose of MTX for >4 weeks preceding randomization. Subjects must also be in principle agreement to remain at the pre-randomization stable dose of MTX for the entire duration of the study. Subjects must also be willing to take a minimum of 5 mg folic acid/folinic acid per week for the duration of the study.

6. Subjects must have discontinued all csDMARDs (excluding MTX) for at least 4 weeks or 5 half-lives prior to enrollment, whichever is longer.

7. Subjects taking regular NSAIDs, Acetaminophen, oral corticosteroids (<10mg/day prednisone equivalent), and inhaled corticosteroids must be on a stable dose for 2 weeks prior to enrollment.

8. Subjects must have discontinued high potency opioids (oxycodone, fentanyl, etc.) for at least 4 weeks prior to enrollment.

9. Male or female, at least 18 years of age, willing to provide informed consent, able to attend all clinic visits, comply with study-related procedures and able to understand and complete study-related questionnaires.

10. Patients must provide at least 7 consecutive days of NRS-pain data in the subject's diary prior to the baseline visit. The NRS pain diary should ideally be completed for the 7 days immediately prior to Visit 1 (when the first dose of test drug is administered). Subjects may record more than 7 days of pain records in the diary for their baseline. At least seven consecutive days of pain diary are necessary to be eligible for enrollment in the study.

11. Peripheral blood CD19+ cell count recovery to >10 cells/uL or >1% of total lymphocyte count (Required only for subjects who have received a Rituximab (or anti-CD20 biosimilar) infusion within 12 months prior to enrollment).

12. Female patients of childbearing potential must consent to undergo a serum pregnancy test at enrollment, and urine pregnancy tests at each visit after screening. Women of non-childbearing potential include those considered to have a medical history that indicates that pregnancy is not a reasonable risk, including post-menopausal women and those with a history of hysterectomy or surgically sterilized.

13. In case of female patients of childbearing potential, willingness to use one method of contraception of high efficacy during the entire study period. These methods can include but not limited to hormonal contraceptives, intrauterine devices, condoms, diaphragms, etc.

14. Males participating in this clinical research study should not get a sexual partner pregnant during their participation in this research study as the effect of the study drug on sperm is not known. Male contraception methods can include but are not limited to mechanical methods (e.g., abstinence, non-vaginal intercourse), contemporary methods comprising barrier methods (e.g., spermicide, condom, sponge, diaphragm and cervical cap) and vasectomy.

Exclusion Criteria:

1. History of treatment with Natrunix for any reason.

2. Any active, chronic, or recurrent infections. (e.g., ongoing bacterial, viral, or fungal infection).

3. Comorbid severe psychiatric illness and/or complicated social situations that would limit compliance with study requirements.

4. Patients with a positive result of TB test (QuantiFERON-TB Gold (QFT) at screening unless the patients can present a documentation of completion of TB treatment course by the local Health Department and a clear chest x-ray at enrollment.

5. Patients who have failed more than 1 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) regimen (excluding Methotrexate monotherapy) due to inefficacy at any point prior to enrollment.

6. Patients who have received any biological therapy including anakinra, rilonacept, canakinumab, adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept, tocilizumab, sarilumab, and biosimilars at any point prior to enrollment.

7. Treatment with JAK inhibitors at any point prior to enrollment.

8. Patients who have received treatment with Injectable corticosteroids within 8 weeks prior to enrollment.

9. Investigational therapy administered within a time interval less than at least 5 half-lives of the investigational agent prior to the first scheduled day of dosing in this study.

10. Pregnant or breastfeeding patients.

11. Patients with current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within a year prior to enrollment.

12. Uncontrolled heart disease, including NYHA Class III or IV congestive heart failure, ventricular arrhythmia, uncontrolled blood pressure (defined as ≥ 160/100 mm Hg), or unstable angina.

13. Clinically significant laboratory abnormalities, including:

    1. Hemoglobin <9.0 g/dL
    2. White blood cell counts < 4000/mm3
    3. Absolute neutrophil count (ANC) <1500/mm3
    4. Platelet count <100,000/mm3
    5. Absolute lymphocyte count (ALC) <500/mm3
    6. eGFR <45 mL/min
    7. Alanine Aminotransferase (ALT) >1.5x lab upper limit of normal (ULN)
    8. Aspartate Aminotransferase (AST) >1.5x lab upper limit of normal (ULN)
    9. Bilirubin >1.5x lab upper limit of normal (ULN)

14. Major surgery (including joint surgery) within 3 months of baseline.

15. Patients who have suffered severe trauma or fracture within 4 weeks of baseline.

16. Evidence of active hepatitis B, hepatitis C, or HIV infection.

    1. Patients positive for HBsAg and/or positive for anti-HBc antibody (regardless of anti-HBs antibody status) are excluded.
    2. Patients who are positive for Hepatitis C antibody and negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample will be eligible to participate. Patients who are positive for Hepatitis C antibody and have a positive result for the HCV when the Hepatitis C RNA-PCR assay is performed on the subsequent sample will not be eligible to participate.

17. Any other concomitant disease, disorder, or condition that could interfere with the interpretation of study endpoints, or the patient's ability to participate in and complete the study, including but not limited to:

    1. Coexisting diseases which are contraindicated for MTX treatment.
    2. Cardiovascular, renal, pulmonary, gastrointestinal, or nervous system disorders that, in the opinion of the principal investigator and/or study medical monitor, make the patient not suitable for enrollment.
    3. Concurrent autoimmune disease excluding Sjogren's syndrome secondary to rheumatoid arthritis.