Examining Distinct Immunophenotypes to Validate and Enhance Rational Treatment in Systemic Lupus

Inclusion Criteria Participants must meet all of the following criteria to be eligible for randomization as study participants. 1. Aged ≥ 18 and ≤ 60 years at the time of informed consent. 2. Meets EULAR/ACR 2019 criteria for SLE. 3. Moderately severe, active, but non-organ threatening disease. Specifically, signs or symptoms meeting criteria for a minimum of: 1. 1 BILAG A (severe) score in the constitutional, musculoskeletal or mucocutaneous system at the time of screening. See Exclusion Criteria number 2 for additional detail. 2. 2 BILAG B (moderate) activity scores in any organ systems; or 3. 1 BILAG B (moderate) activity score in any organ systems and a SELENA-SLEDAI score of ≥ 6. * If there is only 1 BILAG B score: * If a musculoskeletal BILAG B is scored due to moderate arthritis, where some loss off functional range of movements was present on several days over the last 4 weeks, there must also be a minimum of at least 3 joints that are both tender and swollen due to lupus disease activity in wrists, MCPs or PIPs for the participant to qualify. * If a mucocutaneous BILAG B is scored due to acute or subacute cutaneous skin eruption, the rash must cover at least 4% of the body surface area for the participant to qualify. Any active discoid lesion or other form of chronic cutaneous lupus would be qualifying. 4. Approval, by an adjudication committee of a brief entry packet describing the type, severity and duration of symptoms meeting the minimal criteria for entry. The participant will meet this criterion if the committee is confident of all of the following: 1. Convincing diagnosis of SLE, 2. Active disease, due to SLE, warranting the potential of dual therapy with potent immune modulators, 3. No medical or other condition to contraindicate participation in a placebo-controlled, outpatient study of this design. 5. Women of childbearing potential must have a negative serum pregnancy test at screening. 6. Able or willing to use reliable methods of contraception, as outlined in the Mycophenolate REMS brochure for health care providers, from 4 weeks prior to first randomization to 6 weeks after completion of the study. This criterion applies to females of reproductive potential. Inclusion Criteria Required Prior to Randomization Participants who meet the following criterion at the Stage 2 Randomization Visit may proceed to randomization in Stage 2: 7. After completion of corticosteroid injection(s) and prior to randomization in Stage 2, the participant and his/her physician must agree that disease activity has improved sufficiently from screening such that randomization is acceptable. 1. The physician must score the CGI-C as "moderately better" or "much better" prior to randomization. • The reference value for the CGI-C should be the investigator's determination of the participant's condition at the Screening Visit. 2. The participant must agree that his/her symptoms have improved (yes/no). Exclusion Criteria Participants who meet any of the following criteria are not eligible for randomization as study participants: 1. Inability or unwillingness of a participant to understand and provide written informed consent or comply with the study protocol. 2. BILAG A (severe) disease in the Cardiorespiratory, Neuropsychiatric, Gastrointestinal, Ophthalmic, Renal, or Hematological Systems. 3. Severe or unstable nephritis defined as any of the following: 1. History of confirmed Class 3-5 nephritis within the last 2 years, 2. History of confirmed Class 3-5 nephritis \> 2 years ago in the absence of documented treatment including both induction and maintenance therapy, 3. UPCR \> 1 g/g at screening, • If UPCR is \> 0.5 g/g and ≤ 1 g/g at screening, then a second assessment must be completed with at least 1 week between assessments. If the second assessment is \> 1 g/g or has increased by ≥ 0.3 g/g, then the participant is excluded. 4. Evidence of chronic kidney disease defined as eGFR \< 45 mL/min per 1.73 m2 at screening, where 175 x (Creatinine/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if of African descent). 5. History of cirrhosis or chronic liver disease unrelated to SLE other than fatty liver disease. 6. History, within 1 year of the Screening Visit, of uncontrolled SLE that would have warranted a BILAG A (except mucocutaneous, constitutional, musculoskeletal) including, but not limited to, hemolytic anemia, neuropsychiatric lupus, or interstitial lung disease. 7. Uncontrolled HTN at the Screening or Randomization Visits defined as a blood pressure \> 150/100 with or without treatment, not to exceed 3 complementary antihypertensive treatments. 8. Any of the following laboratory values during screening: 1. Hemoglobin (Hg) \< 8.0 g/dL, 2. WBC \< 2.0 x 10\^9 cells/L, 3. ANC \< 1.0 x 10\^9 cells/L, 4. Platelets \< 60 x 10\^9 cells/L at screening, • If platelets \< 70 x 10\^9 cells/L at screening, platelet count should be retested 2 weeks later. If platelets are \< 60 x 10\^9 cells/L at retest, participant will be excluded 5. AST or ALT \> 2.5 times the ULN, 6. Serum IgG levels \< 5 g/L 9. Use of ≥ 40 mg/day of prednisone within 4 weeks prior to the Screening Visit or use of \> 20 mg/day of prednisone at screening. 10. Unwilling or unable to taper to ≤ 10 mg/day of prednisone or equivalent by the day of randomization. 11. Use of hydroxychloroquine, chloroquine, or quinacrine, if taking, at a prescribed dose that has not been stable for at least 2 months prior to randomization. 12. Use of MMF within 1 year of randomization. 13. Use of CNIs within 3 months of randomization. Topical formulations applied stably for at least one month are allowed. 14. Use of rituximab, obinutuzumab, ocrelizumab, or long-acting B cell depletion agents within 1 year of randomization. Use of agents ≥ 6 months and within 1 year of randomization is permitted if there is evidence of B cell reconstitution as defined as CD19+ counts of ≥ 50 cells/µL. 15. History of intolerance or allergy to MMF, voclosporin, or long-acting corticosteroid preparations. 16. Individuals with known hypersensitivity to Polysorbate 80 (Tween). 17. A woman who is pregnant, breastfeeding, or planning pregnancy from the time of consent until 6 weeks after completion of the study. 18. Any participant with plans for major surgery during the time of the trial. 19. Active infections requiring hospitalization or intravenous antibiotics within 1 month prior to the Screening Visit. 20. Any grade 2 infection or higher from 14 days prior to the Screening Visit and through the screening period that has not resolved by randomization. 21. Acute herpes zoster within 4 months of the Screening Visit. 22. Positive results from a SARS-CoV-2 antigen test administered 2 days prior to and on the day of first randomization. 23. Positive Quantiferon Gold (or equivalent) assay. Indeterminate Quantiferon Gold (or equivalent) assays must be repeated (with same or other interferon gamma release assay per local policy) and shown to be negative. Alternatively, if the Quantiferon Gold (or equivalent) assay remains indeterminate, a participant must have a negative PPD. Finally, if the participant has had the BCG vaccine or has some other condition complicating the interpretation of TB testing, consultation with infection disease specialist must be obtained. • Participants diagnosed with latent TB are eligible but must have received appropriate prophylaxis for 30 days prior to initiation of Stage 2 treatment. 24. Serologic evidence at screening of chronic infections including: 1. HIV infection. 2. Hepatitis B as indicated by surface antigen or hepatitis B core antibody positivity; if a participant has an isolated positive hepatitis B core antibody, they will be eligible to participate in the study if they are negative for reflex viral load at Screening. 3. Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody positive, they will be eligible to participate in the study if they are negative for viral load at Screening. 25. Current, diagnosed, or self-reported drug or alcohol abuse within the last 6 months that, in the opinion of the investigator, would interfere with the ability to comply with study protocol. 26. Recipient of live attenuated vaccine(s) within 8 weeks of the Screening Visit. 27. Use of investigational drugs (excluding SARS-CoV-2 vaccinations or SARS-CoV2 therapeutics) within 8 weeks of the Screening Visit or 5 half-lives, whichever is longer. 28. Past or current mental or physical 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 may impact the quality or interpretation of the data obtained from the study.