VIBRANT: VIB4920 for Active Lupus Nephritis (VIBRANT)

A Phase 2a Randomized Placebo-Controlled Double-Blind Multicenter Trial of VIB4920 for Active Lupus Nephritis (ITN091AI)

This is a multi-center double-blind placebo controlled clinical trial evaluating the efficacy of VIB4920 combined with mycophenolate mofetil (MMF) and prednisone in achieving a renal response in participants with active lupus nephritis (LN).

Seventy-four eligible participants with active lupus nephritis (LN) will be randomized to receive VIB4920 1500 mg or placebo intravenously at Weeks 0, 2, 4, 8, 12, 16, 20, and 24. Participants will also receive methylprednisolone 1000 mg at Week 0 and will begin MMF 2-3 g per day and prednisone 25 mg per day, tapered to ≤ 5 mg per day from Week 8. The primary endpoint will be assessed at Week 36, and participants followed until Week 60.

Participants will receive VIB4920 1500 mg intravenously at Weeks 0, 2, 4, 8, 12, 16, 20, and 24. Participants will also receive methylprednisolone 1000 mg at Week 0 and will begin MMF 2-3 g per day and prednisone 25 mg per day, tapered to ≤ 5 mg per day from Week 8.

Participants will receive VIB4920 placebo intravenously at Weeks 0, 2, 4, 8, 12, 16, 20, and 24. Participants will also receive methylprednisolone 1000 mg at Week 0 and will begin MMF 2-3 g per day and prednisone 25 mg per day, tapered to ≤ 5 mg per day from Week 8.

Participants will receive 1500 mg of VIB4920 at Weeks 0, 2, 4, 8, 12, 16, 20, and 24 while continuing on MMF and prednisone

Participants will receive placebo for VIB4920 at Weeks 0, 2, 4, 8, 12, 16, 20, and 24 while continuing on MMF and prednisone

Complete renal response is defined as all of the following: Urine protein-to-creatinine ratio (UPCR) <= 0.5, based on a 24-hour urine collection Estimated glomerular filtration rate (eGFR) >= 120 ml/min/1.73 m^2 or, if < 120 ml/min/1.73 m^2, then > 80 percent of the eGFR at baseline Prednisone <= 5 mg/day from Week 8, according to the prednisone dosing restrictions

Complete renal response is defined as all of the following: Urine protein-to-creatinine ratio (UPCR) <= 0.5, based on a 24-hour urine collection Estimated glomerular filtration rate (eGFR) >= 120 ml/min/1.73 m^2 or, if < 120 ml/min/1.73 m^2, then > 80 percent of the eGFR at Week 0 Prednisone tapered to <= 5 mg/day by Week 8, and adherence to the prednisone dosing restrictions

Overall renal response is defined as all of the following: >= 50 percent improvement in the urine protein-to-creatinine ratio (UPCR) compared to baseline, based on a 24-hour urine collection Estimated glomerular filtration rate (eGFR) >= 120 ml/min/1.73 m^2, or if < 120 ml/min/1.73 m^2, then > 80 percent of the eGFR at baseline, and Prednisone <= 5 mg/day from Week 8, according to the prednisone dosing restrictions

Change in proportion of participants who have negative Anti-dsDNA antibodies post treatment initiation

The change in the proportion of participants who had a negative anti-dsDNA test after initiation of VIB4920 or placebo will be summarized by arm, and will be analyzed using an exact conditional logistic regression model

The change in the proportion of participants who were hypocomplementemic for C3 after initiation of VIB4920 or placebo will be summarized by arm, and analyzed using an exact conditional logistic regression model with the binary response variable for the test result (C3)

The change in the proportion of participants who were hypocomplementemic for C4 after initiation of VIB4920 or placebo will be summarized by arm, and analyzed using an exact conditional logistic regression model with the binary response variable for the test result (C4)

Renal treatment failure is defined as any one of the following: Worsening proteinuria, defined as both of the following: Urine protein-to-creatinine ratio (UPCR) > 1.0 >= 50 percent increase in UPCR compared to the lowest previous value Progressive deterioration in renal function, defined as both of the following: Serum creatinine >1.5 >= 50 percent increase in serum creatinine compared to the lowest previous value Nephritis that worsens or fails to sufficiently improve, according to the judgment of the investigator Receipt of a prohibited immunosuppressive medication, including but not limited to cyclophosphamide, azathioprine, solumedrol, rituximab, belimumab, and calcineurin inhibitors

The change in SLEDAI-2K scores after initiation of VIB4920 or placebo will be summarized by arm, and analyzed using an analysis of covariance (ANCOVA) model with the SLEDAI-2K score at the timepoint as the dependent variable

Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for Systemic Lupus Erythematosus (SLICC/ACR-DI) post treatment

The change in SLICC/ACR-DI scores after initiation of VIB4920 or placebo will be summarized by arm, and analyzed using an ANCOVA model with the SLICC/ACR-DI score at the time point as the dependent variable

The number of participants who experienced at least one SAE and the number of participants who experienced at least one AESI will be analyzed using a Fisher's exact test.

Adverse events of special interest include: Anaphylaxis Grade 3 or greater infusion reaction Grade 3 or greater hypersensitivity reaction Grade 3 or greater infection Thromboembolic event

Serum IgM levels will be analyzed using a longitudinal mixed effects model with the test results at the time points as the dependent variable

Serum IgG levels will be analyzed using a longitudinal mixed effects model with the test results at the time points as the dependent variable

defined as all of the following: UPCR ≤ 0.7, and eGFR ≥ 60 ml/min/1.73m2, or if < 60 ml/min/1.73m2, then ≥ 80% of the eGFR at baseline, and no receipt of a prohibited immunosuppressive or immunomodulatory medication.

Inclusion Criteria: Individuals who meet all of the following criteria are eligible for enrollment as study participants: Age 18 years or older. Classification of Systemic Lupus Erythematosus (SLE) by any of the following criteria: the 1997 update of the 1982 American College of Rheumatology (ACR) criteria (1, 2), the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria (3), or the 2019 European League Against Rheumatism (EULAR)/ACR criteria (4). UPCR ≥ 1.0 based on a 24-hour urine collection at Visit -1. Renal biopsy within 24 weeks prior to Visit -1 of ISN/RPS LN (5, 6) with both of the following: Class III, Class IV, or Class V in combination with Class III or IV, and Modified NIH Activity Index ≥ 1. COVID-19 vaccination according to the current Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommendations (36). Exclusion Criteria: Individuals who meet any of these criteria are not eligible for enrollment as study participants: Inability or unwillingness to give written informed consent or comply with study protocol. Contraindication to treatment with MMF or mycophenolate sodium; or treatment with MMF or mycophenolate sodium is inappropriate in the opinion of the investigator. Treatment with a biologic agent, except belimumab, or investigational agent within 90 days or 5 half-lives prior to Visit 0, whichever is longer. Agents authorized by the FDA for prevention or treatment of COVID-19 are not considered investigational and are not exclusionary. Rituximab or other B cell depleting agent within 6 months prior to Visit 0. Prior treatment with VIB4920. Receipt of a live attenuated vaccine within 4 weeks prior to Visit 0. Comorbidities requiring treatment with systemic corticosteroids, including those that have required 3 or more courses of systemic corticosteroids within 12 months prior to Visit 0. Current malignancy or history of malignancy, except for adequately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ > 12 months prior to Visit 0. End stage renal disease, defined as eGFR < 20 ml/min/1.73m2. History of transplantation. The following risks for thromboembolic events: Recent or recurrent deep venous thrombosis or arterial thromboembolism. Immobilization or major surgery within 12 weeks prior to Visit 0. History of congenital or inherited deficiency of antithrombin III, protein S, or protein C. History of anti-phospholipid syndrome, according to the 2006 Sapporo classification criteria (37). History of a severe allergy or hypersensitivity reaction to any component of the VIB4920 formulation. Any one of the following laboratory abnormalities: Peripheral B cell count < 5/μl. Neutropenia (absolute neutrophil count < 1000/mm3). Anemia (hemoglobin < 8 g/dL). Thrombocytopenia (platelets < 50,000/mm3). Aspartate aminiotransferase or alanine aminotransferase ≥ 2x upper limit of normal. Evidence of current or prior tuberculosis infection, including any of the following: Positive QuantiFERON-TB Gold or TB Gold Plus test. Positive T-SPOT.TB test. Positive purified protein derivation (PPD) tuberculin test, defined as > 5mm induration. Human immunodeficiency virus (HIV) infection. Current or past hepatitis B (HBV) infection. Current or past hepatitis C virus (HCV) infection, except adequately treated HCV with documented sustained virologic response. Active bacterial, viral, fungal, or opportunistic infection. History of significant, recurrent, or chronic infection that may pose additional risks from participating in the study, in the opinion of the investigator. History of severe psychiatric condition that would interfere with the participant's ability to comply with the study protocol, in the opinion of the investigator. Current substance abuse, or history of substance abuse within 12 months of Visit 0. Lack of peripheral venous access. Pregnancy. Breastfeeding. Unwillingness to use a medically acceptable form of contraception for the duration of the study if female of child-bearing potential or if male with a partner of childbearing potential. 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.

University of California San Francisco School of Medicine: Lupus Clinic and Rheumatology Clinical Research Center

University of California San Francisco School of Medicine: Lupus Clinic and Rheumatology Clinical Research Center

University of California San Diego School of Medicine: Division of Rheumatology, Allergy and Immunology

University of California San Francisco School of Medicine: Lupus Clinic and Rheumatology Clinical Research Center

Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical mechanistic data from NIAID/DAIT-funded grants and contracts