CD40L Antagonism in Rheumatoid Arthritis (RA)

Eligibility Criteria

• 1. Participant or legally authorized representative must be able to understand and provide informed consent
• 2. Adult 18-75 years of age
• 3. Diagnosed with RA by fulfilling the ACR/EULAR 2010 Classification Criteria for RA ≥ 6 months prior to screening (Appendix 9)
• 4. Documented positive test for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibody (ACPA)
• 5. SDAI ≥ 17
• 6. At least 4 tender and 4 swollen joints by a 44 joint count (Appendix 5)
• 7. On one of the followingTNFi therapy regimens:
• 1. Etanercept 50 mg SC (or its respective biosimilar) weekly for at least 12 weeks, with or without methotrexate
• 2. Adalimumab 40 mg SC (or its respective biosimilar) every other week for at least 12 weeks, with or without methotrexate
• 3. Adalimumab 40 mg SC weekly (or its respective biosimilar) for at least 12 weeks, without methotrexate
• 8. Willing to continue or discontinue treatment with their current TNFi at the same dose depending upon study arm assignment
• 9. If treated with leflunomide, sulfasalazine, or hydroxychloroquine, must be taking a stable dose for at least 12 weeks
• 10. If treated with methotrexate, must be taking a stable dose for at least 12 weeks. The following exceptions are permitted within the 12 weeks prior to screening:
• 1. Holding methotrexate after COVID-19 vaccination as per American College of Rheumatology guidance (https://rheumatology.org/)
• 2. Holding methotrexate for 1 or 2 weeks after influenza vaccination
• 11. COVID-19 vaccination according to the current Centers for Disease Control and Prevention (CDC) vaccination recommendations for individuals who are moderately to severely immunocompromised, with the last COVID-19 vaccine dose administered at least 14 days prior to the initiation of the study drug (Visit 0)
• 12. All participants who engage in sexual activity that could lead to pregnancy must agree to use abstinence or an FDA-approved contraception for the duration of the study to prevent pregnancy (Section 7.5)
• 1. Inability or unwillingness to give written informed consent or comply with the study protocol
• 2. Prior or ongoing systemic inflammatory or autoimmune disease (other than RA and secondary Sjögren's syndrome) requiring or potentially requiring other systemic immunomodulatory therapy during the 40-week study period
• 3. Use of glucocorticoid and/or disease-modifying therapies as specified below:
• 1. Prior treatment with any B cell depleting therapy (e.g., rituximab)
• 2. History of treatment with more than two different TNFi, including the current treatment with etanercept, adalimumab, or their respective biosimilars. Treatment with a brand name TNFi (e.g., Enbrel or Humira) and its respective biosimilar would count as a single TNFi if treatment has been continuous and without interruption by more than 90 days when switching between the brand name and biosimilar TNFi.
• 3. Treatment with other biologic therapy (i.e., not targeting TNF-α), including abatacept, tocilizumab, or sarilumab within the previous 12 weeks
• 4. Treatment with a JAK inhibitor within the previous 12 weeks
• 5. Concurrent use of methotrexate and leflunomide in combination
• 6. Prednisone \> 10 mg a day or equivalent glucocorticoid use within the previous 4 weeks
• 7. Intramuscular, intra-articular, or intravenous glucocorticoids within the previous 4 weeks
• 8. Other immunomodulatory medications within the previous 12 weeks except for methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine
• 4. Lack of any subjective or objective clinical response (i.e., complete non-responder) to current TNFi use, in the opinion of the study investigator based on information provided by the patient and referring rheumatologist
• 5. Use of an investigational agent including VIB4920 in the past 30 days or 5 half-lives, whichever is longer
• 6. History of a severe allergy, hypersensitivity reaction, or infusion reaction to any component of the VIB4920 formulation
• 7. History of Felty's syndrome
• 8. History of interstitial lung disease with FVC \< 70% predicted, DLCO \< 70% predicted, or requiring supplemental oxygen
• 9. Deep venous thrombosis or thromboembolism including pulmonary embolism in the prior two years
• 10. Infection:
• 11. History of a primary immunodeficiency disorder
• 12. Vaccination with a live vaccine within the past 30 days
• 13. Women who are pregnant or breast-feeding
• 14. WBC count \< 3.0 x 103/μl
• 15. Absolute neutrophil count \< 1.5 x 103/μl
• 16. Hemoglobin \< 9 g/dL
• 17. Platelet count \< 100 x 103/μl
• 18. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2x the upper limit of normal (ULN)
• 19. History of malignant neoplasm within the last 5 years, except for basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally
• 20. Current, diagnosed mental illness or current, diagnosed or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements
• 21. Any new or uncontrolled condition occurring within the past 12 weeks which, in the judgment of the investigator, could interfere with participation in the trial (e.g., diabetes mellitus with HbA1c ≥ 9.0%, myocardial infarction, or stroke)
• 22. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study
• 23. Inability to comply with study and follow-up procedures