CD40L Antagonism in Rheumatoid Arthritis (RA)

Inclusion Criteria:

1. Participant or legally authorized representative must be able to understand andprovide informed consent

2. Adults ≥ 18 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 citrullinatedpeptide antibody (ACPA)

5. SDAI ≥ 17

6. At least 4 tender and 4 swollen joints by a 44 joint count (Appendix 5)

7. Receiving treatment with an FDA-approved TNFi (including biosimilars) that is dosedsubcutaneously at an FDA-approved dosing regimen for at least 12 weeks.

8. Willing to continue or discontinue treatment with their current TNFi at the samedose depending upon study arm assignment

9. If treated with leflunomide, sulfasalazine, or hydroxychloroquine, must be taking astable 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:

11. Holding methotrexate after COVID-19 vaccination as per American College ofRheumatology guidance (https://rheumatology.org/)

12. Holding methotrexate for 1 or 2 weeks after influenza vaccination

13. All participants who engage in sexual activity that could lead to pregnancy mustagree to use abstinence or an FDA-approved contraception for the duration of thestudy to prevent pregnancy

Exclusion Criteria:

1. Inability or unwillingness to give written informed consent or comply with the studyprotocol

2. Prior or ongoing systemic inflammatory or autoimmune disease (other than RA andsecondary Sjögren's syndrome) requiring or potentially requiring other systemicimmunomodulatory therapy during the 40-week study period

3. Use of glucocorticoid and/or disease-modifying therapies as specified below:

4. Prior treatment with any B cell depleting therapy (e.g., rituximab)

5. Treatment with other biologic therapy (i.e., not targeting TNF-α), includingabatacept, tocilizumab, or sarilumab within the previous 12 weeks

6. Treatment with a JAK inhibitor within the previous 12 weeks

7. Concurrent use of methotrexate and leflunomide in combination

8. Prednisone > 10 mg a day or equivalent glucocorticoid use within the previous 4weeks

9. Intramuscular, intra-articular, or intravenous glucocorticoids within theprevious 4 weeks

10. Other immunomodulatory medications within the previous 12 weeks except formethotrexate, leflunomide, sulfasalazine, or hydroxychloroquine

11. Lack of any subjective or objective clinical response (i.e., complete non-responder)to treatment with the current TNFi, in the opinion of the study investigator basedon available documentation in the medical record and/or history provided by thepatient and/or referring rheumatologist

12. Use of an investigational agent including VIB4920 in the past 30 days or 5half-lives, whichever is longer

13. History of a severe allergy, hypersensitivity reaction, or infusion reaction to anycomponent of the VIB4920 formulation

14. History of Felty's syndrome

15. History of interstitial lung disease with FVC < 70% predicted, DLCO < 70% predicted,or requiring supplemental oxygen

16. Arterial or deep venous thromboembolism including pulmonary embolism in the priortwo years

17. Infection: a. Evidence of current or prior infection with hepatitis B, as indicated by apositive test for the hepatitis B surface antigen (HBsAg) or a positive test for thehepatitis B core antibody (HBcAb) b. Positive HCV serology unless treated with ananti-viral regimen resulting in a sustained virologic response (undetectable viralload 24 weeks after cessation of therapy) c. Evidence of HIV infection d. Evidenceof active tuberculosis, untreated or incompletely treated latent tuberculosis, orrecent close contact with a person who has active tuberculosis e. PositiveQuantiFERON-TB Gold, QuantiFERON-TB Gold Plus, or T-SPOT-TB test without history ofprevious treatment for active or latent TB f. Indeterminate QuantiFERON-TB Gold,QuantiFERON-TB Gold Plus, or T-SPOT.TB test which remains indeterminate on repeattesting, and any of the following additional required screening which indicates anincreased risk of TB infection: i. History of tuberculosis exposure ii. History oftravel to an area where tuberculosis is endemic iii. Findings on chest radiographsuggestive of prior exposure to tuberculosis (e.g., granulomas or apical scarring)obtained at screening or within the past 3 months iv. Positive purified proteinderivative (PPD) skin test for tuberculosis obtained in the past 3 months, eitherobtained at screening or within the past 3 months v. Prior history of a positiveQuantiFERON-TB Gold, QuantiFERON-TB Gold Plus, T- SPOT.TB, or purified proteinderivative (PPD) test without history of previous treatment for latent TB g.Symptoms of presumed or documented SARS-CoV-2 infection in the past 30 days h. Morethan one episode of herpes zoster in the past 12 months i. An opportunistic infection in the past 12 months j. Acute or chronic infection,including current use of suppressive systemic anti-microbial therapy for chronic orrecurrent bacterial or fungal infection, hospitalization for treatment of infectionin the past 60 days, or parenteral anti-microbial (including anti-bacterial,anti-viral, or anti-fungal agents) use in the past 60 days for infection k. Historyof bronchiectasis with recurrent pulmonary infections

18. History of a primary immunodeficiency disorder

19. Vaccination with a live vaccine within the past 30 days

20. Women who are pregnant or breast-feeding

21. White Blood Cell (WBC) count < 3.0 x 103/μl

22. Absolute neutrophil count < 1.5 x 103/μl

23. Hemoglobin < 9 g/dL

24. Platelet count < 100 x 103/μl

25. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2x the upperlimit of normal (ULN)

26. History of malignant neoplasm within the last 5 years, except for basal cell orsquamous cell carcinoma of the skin treated with local resection only or carcinomain situ of the uterine cervix treated locally

27. Current, diagnosed mental illness or current, diagnosed or self-reported drug oralcohol abuse that, in the opinion of the investigator, would interfere with theparticipant's ability to comply with study requirements

28. Any new or uncontrolled condition occurring within the past 12 weeks which, in thejudgment of the investigator, could interfere with participation in the trial (e.g.,diabetes mellitus with HbA1c ≥ 9.0%, myocardial infarction, or stroke)

29. Past or current medical problems or findings from physical examination or laboratorytesting that are not listed above, which, in the opinion of the investigator, maypose additional risks from participation in the study, may interfere with theparticipant's ability to comply with study requirements, or that may impact thequality or interpretation of the data obtained from the study

30. Inability to comply with study and follow-up procedures