• Proportion of Participants in Complete Remission (CR) at Week 52 and Week 156: By Treatment Group [ Time Frame: Week 52, Week 156 ]
  Defined as proteinuria of ≤ 0.3 g/day with a < 20% decrease in estimated glomerular filtration rate (eGFR) from baseline.
• Proportion of Participants in Partial Remission (PR) at Week 52, Week 104 and Week 156: By Treatment Group [ Time Frame: Week 52, Week 104, Week 156 ]
  Defined as a 50% or greater decrease in proteinuria compared to baseline and proteinuria <3.5 g/day with a < 20% decrease in eGFR from baseline.
• Proportion of Participants in Complete or Partial Remission at Week 52, Week 104, Week 156: By Treatment Group [ Time Frame: Week 52, Week 104, Week 156 ]
  Those who fulfill criteria for either complete or partial remission, as defined in prior outcome measures.
• Time to Relapse for Participants who Achieved Complete Remission (CR) or Partial Remission (PR): By Treatment Group [ Time Frame: Up to 156 Weeks (3 Years) ]
  Relapse is defined as a return of proteinuria ≥ 3.5 g/day after:

  • Achieving a CR, or
  • Achieving and maintaining a PR for at least 12 weeks.

  The first timepoint at which a participant achieves CR or PR will be taken defined as Time 0. Participants will be followed from Time 0 to the first evaluation at which the participant fulfills the definition for relapse.
• Level of Proteinuria at Week 52, Week 104 and Week 156: By Treatment Group [ Time Frame: Week 52, Week 104, Week 156 ]
  Method of assessment: 24 hour urine collection for quantitation of protein in the urine.
• Proportion of Participants in Complete Remission (CR) and Anti-PLA2R Negative: By Treatment Group [ Time Frame: Week 104 ]
  CR as defined per protocol. Antibodies to the phospholipase A2 receptor 1 (Anti-PLA2R antibodies) are a correlate ot primary MN disease activity.
• Proportion of Participants in Partial Remission (PR) and Anti-PLA2R Negative: By Treatment Group [ Time Frame: Week 104 ]
  PR as defined per protocol and in prior outcome measures. Antibodies to the phospholipase A2 receptor 1 (Anti-PLA2R antibodies) are a correlate ot primary MN disease activity.
• Proportion of Participants Who are Anti-PLA2R Negative: By Treatment Group [ Time Frame: Week 52, Week104, Week 156 ]
  Antibodies to the phospholipase A2 receptor 1 (Anti-PLA2R antibodies) are a correlate ot primary MN disease activity.
• Incidence of Adverse Events (AEs): By Treatment Group [ Time Frame: Week 0 to Week 52 ]
  An AE is any untoward or unfavorable medical occurrence associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research. For purposes of this study, neither B cell depletion nor proteinuria will be classified as an AE.
• Incidence of Grade 3 or Higher Infectious Adverse Events (AEs): By Treatment Group [ Time Frame: Week 0 to Week 52 ]
  Reference: NCI-CTCAE manual titled, National Cancer Institute (NCI)s Common Terminology Criteria for Adverse Events Version 5.0 (published November 27, 2017).
• Incidence of Arterial Thromboembolic Events: By Treatment Group [ Time Frame: Week 0 to Week 52 ]
  Peripheral vascular embolism, mesenteric infarct, or myocardial infarction.
• Incidence of Venous Thromboembolic Events: By Treatment Group [ Time Frame: Week 0 to Week 52 ]
  Venous thromboembolic event (VTE) is defined as a symptomatic deep vein thrombosis (DVT): the formation of a blood clot in a deep vein, detected by systematic compression ultrasonography, symptomatic DVT, or symptomatic fatal or non-fatal pulmonary embolism (PE). An embolism is a clot in the blood that forms and blocks a blood vessel. A pulmonary embolism is a blood clot that has travelled from elsewhere in the body through the blood stream to block the main artery of the lung or one of its branches.
• Kidney Disease Quality of Life (KDQOL-36) Mean Scale Scores at Baseline, Week 52, Week 104 and Week 156: By Treatment Group [ Time Frame: Week 52, Week 104, Week 156 ]
  A Quality of life (QOL) measure using the Kidney Disease Quality of Life-36 (KDQOL-36) survey, a kidney-disease-specific quality of life instrument that assesses five domains: general physical health, mental health, disease burden, disease symptoms, and disease effects. For all KDQOL scales, a higher score indicates better quality of life. All domain scales can range from 0-100.
• Belimumab Exposure After the First 4 Doses of Belimumab [ Time Frame: Week 0, Week 1, Week 2, Week 3 ]
  Pharmacokinetics (PK) Assay -Applicable to Part A of the Study. Belimumab exposure will be assessed using the observed belimumab trough levels (C_min) after 4 weeks (i.e., Week 0, Week 1, Week 2 and Week 3) of subcutaneous dosing. Analysis will be begin after all participants in Part A have reached week 4.

The primary objective of this study is to evaluate the effectiveness of belimumab and intravenous rituximab co-administration at inducing a complete remission (CR) compared to rituximab alone in participants with PM.

Background:

Primary membranous nephropathy (MN) is among the most common causes of nephrotic syndrome in adults. MN affects individuals of all ages and races. The peak incidence of MN is in the fifth decade of life.

Primary MN is recognized to be an autoimmune disease, a disease where the body's own immune system causes damage to kidneys. This damage can cause the loss of too much protein in the urine.

Drugs used to treat MN aim to reduce the attack by one's own immune system on the kidneys by blocking inflammation and reducing the immune system's function. These drugs can have serious side effects and often do not cure the disease. There is a need for new treatments for MN that are better at improving the disease while reducing fewer treatment associated side effects.

In this study, researchers will evaluate if treatment with a combination of two different drugs, belimumab and rituximab, is effective at blocking the immune attacks on the kidney compared to rituximab alone. Rituximab works by decreasing a type of immune cell, called B cells. B cells are known to have a role in MN. Once these cells are removed, disease may become less active or even inactive. However, after stopping treatment, the body will make new B cells which may cause disease to become active again.

Belimumab works by decreasing the new B cells produced by the body and, may even change the type of new B cells subsequently produced. Belimumab is approved by the US Food and Drug Administration (FDA) to treat systemic lupus erythematosus (also referred to as lupus or SLE). Rituximab is approved by the FDA to treat some types of cancer, rheumatoid arthritis, and vasculitis. Neither rituximab nor belimumab is approved by the FDA to treat MN. Treatment with a combination of belimumab and rituximab has not been studied in individuals with MN, but it is currently being tested in other autoimmune diseases, including lupus nephritis and Sjögren's syndrome.

This trial is a two-part study (Part A and Part B) of adults with primary membranous nephropathy (MN), ages 18-75 inclusive. The study will be conducted at multiple sites in the United States and Canada.

Part A: Open-label Phase

Part A is an open-label, pharmacokinetics (PK) phase to compare belimumab exposure between participants who have "low" proteinuria (≥ 4 to < 8 g/day) and "high" proteinuria (≥ 8 g/day) at the Screening Visit, Visit-1.

Part A will enroll 20 individuals with primary MN: 10 individuals with low proteinuria and 10 individuals with high proteinuria. All Part A participants will receive 200 mg subcutaneous belimumab weekly for 52 doses (weeks 0-51), unless a dose increase is warranted by the PK analysis. Trough serum belimumab levels will be obtained weekly following the first 4 doses of belimumab. Participants will receive rituximab 1000 mg intravenously (IV) at weeks 4 and 6.

All participants will be followed after the 52 week treatment period on no study medication until week 156.

Belimumab serum trough levels will be analyzed after all participants receive the first 4 belimumab doses to compare belimumab exposure between the low and high proteinuria groups. Belimumab serum trough levels will also be analyzed to determine if a different proteinuria level (instead of 8 g/day) warrants increased belimumab dosing and should be used to define "high" proteinuria.

Dose determinations for participants with high proteinuria in Parts A and B will be made by an adjudication committee.

The study participation phase is 156 weeks (3 years), which includes a treatment phase of 52 weeks and a post-treatment observation phase of 104 weeks.

Part B: Randomized Phase

Part B is a prospective, randomized, phase II, double-blind, placebo-controlled, multicenter clinical trial in adults with primary MN. Part B will commence after the analysis of the PK data in Part A.

A total of 104 participants will be randomized in a 1:1 fashion into two treatment arms.

Randomization will be stratified by low and high proteinuria as determined by the identified threshold in Part A.

Participants in both arms will receive rituximab 1000 mg IV at weeks 4 and 6. Participants randomized to the experimental arm will receive subcutaneous belimumab 200 mg weekly for 52 doses (weeks 0-51), unless the results from Part A indicate that participants with high proteinuria should receive belimumab 400 mg weekly. If the participant's proteinuria subsequently decreases to below the high proteinuria threshold, the belimumab dose will be decreased to 200 mg weekly for the remainder of the treatment phase.

Participants randomized to the comparator arm will receive subcutaneous belimumab placebo according to the same dose and schedule.

The study participation phase is 156 weeks (3 years), which includes a treatment phase of 52 weeks and a post-treatment observation phase of 104 weeks.

• Membranous Nephropathy
• MN

• Drug: Belimumab

  Belimumab is a recombinant, human, IgG1λ monoclonal antibody.

  Belimumab will be provided as a 200 mg sterile, liquid product in a prefilled syringe. Each syringe contains 1.0 mL of 200 mg/mL belimumab. Each syringe will be a single use.

  Standard Weekly dose: 200 mg. administered subcutaneously. A higher weekly dose, 400 mg weekly, per protocol and based on PK analysis, may be indicated for participants with high proteinuria.

  Other Name: Benlysta®
• Drug: Placebo for Belimumab

  The placebo control will be provided as a sterile liquid product in a prefilled syringe. Each syringe will be of a single use.

  Standard weekly dose: 200 mg. administered subcutaneously. A higher weekly dose, 400 mg weekly, per protocol, may be indicated for participants with high proteinuria.

  Other Name: Belimumab placebo
• Drug: Rituximab

  Rituximab is a monoclonal antibody with specificity for CD20, a transmembrane protein expressed on B cells from the pre-B to memory cell development stages.

  Rituximab is supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-use vials for infusion. It is a clear, colorless liquid.

  Dose: 1000 mg intravenously (IV), Week 4 and -6.

  Other Name: Rituxan®

• Experimental: Part A: Low Proteinuria Group - Belimumab and Rituximab

  Open-label pharmacokinetics (PK) phase.

  Ten participants with low proteinuria classification will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.

  Low proteinuria classification: The excretion of ≥4 to <8 g/day of protein by the kidneys in adults. (Normal in adults: 0.15 g/day).

  Interventions:

  • Drug: Belimumab
  • Drug: Rituximab
• Experimental: Part A :High Proteinuria Group - Belimumab and Rituximab

  Open-label pharmacokinetics (PK) phase.

  Ten participants with high proteinuria classification will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.

  An adjustment (increase) in prescribed weekly dose may occur, per protocol, if indicated by pharmacokinetics (PK) assay results.

  High proteinuria classification: The excretion of ≥8 g/day of protein by the kidneys in adults. (Normal in adults: 0.15 g/day).

  Interventions:

  • Drug: Belimumab
  • Drug: Rituximab
• Experimental: Part B: Low Proteinuria Group - Belimumab and Rituximab
  Participants in the low proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.
  Interventions:

  • Drug: Belimumab
  • Drug: Rituximab
• Placebo Comparator: Part B: Low Proteinuria Group - Placebo and Rituximab
  Participants in the low proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive will receive belimumab placebo weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.
  Interventions:

  • Drug: Placebo for Belimumab
  • Drug: Rituximab
• Experimental: Part B :High Proteinuria Group - Belimumab and Rituximab

  Participants in the high proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.

  A higher dose of belimumab, per protocol, will be prescribed in high proteinuria participants, if indicated in Part A.

  Interventions:

  • Drug: Belimumab
  • Drug: Rituximab
• Placebo Comparator: Part A :High Proteinuria Group - Placebo and Rituximab

  Participants in the high proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive will receive belimumab placebo weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.

  A higher dose of belimumab placebo, per protocol, will be prescribed in high proteinuria participants, if indicated in Part A.

  Interventions:

  • Drug: Placebo for Belimumab
  • Drug: Rituximab

Inclusion Criteria:

Subjects must meet all of the following criteria to be eligible for this study-

• Primary membranous nephropathy (MN), confirmed by kidney biopsy obtained in the past 36 months;
• Anti-PLA2R positive;
• Estimated Glomerular Filtration Rate (eGFR) ≥ 40 ml/min/1.73m^2 while on maximally tolerated renin-angiotensin system (RAS) blockade;

• Proteinuria:

  • ≥4 and < 8 g/day that has been present for ≥ 3 months while on while on maximally tolerated RAS blockade, or
  • ≥8 g/day while on maximally tolerated RAS blockade.

• Blood pressure while on maximally tolerated RAS blockade:

  • Systolic blood pressure ≤ 140 mmHg, and
  • Diastolic blood pressure ≤ 90 mmHg

Exclusion Criteria:

Subjects meeting any of the following criteria will not be eligible for this study-

• Secondary cause of membranous nephropathy (MN) (e.g., systemic lupus erythematosus (SLE), drug, infection, malignancy) suggested by review of the subject's medical history and/or clinical presentation;
• Rituximab use within the previous 12 months;

• Rituximab use > 12 months ago:

  • With an undetectable CD19 B cell count, or
  • Did not result in a complete remission (CR) or partial remission (PR) with rituximab treatment alone (e.g., without other immunosuppressive or immunomodulatory therapy).
• Use of anti-B cell therapy other than rituximab within the previous 12 months (or 5 half-lives, whichever is greater);
• Cyclophosphamide use within the past 3 months;
• Use of other immunosuppressive medications, such as cyclosporine or tacrolimus, within the past 30 days;
• Use of corticosteroids within the past 30 days;
• Use of any biologic investigational agent, defined as any drug not approved for sale in the country it is used, in the previous 12 months;
• Use of any non-biologic investigational agent in the past 30 days (or 5 half-lives, which ever is greater);
• Unstable kidney function defined as > 15% decrease in the Estimated Glomerular Filtration Rate (eGFR) during the previous 3 months;
• Decrease in proteinuria by 50% or more during the previous 12 months;
• White blood cell (WBC) count < 3.0 x 10^3/µl;
• Absolute neutrophil count < 1.5 x 10^3/µl;
• Moderately severe anemia (hemoglobin <9mg/dL);
• History of primary immunodeficiency;
• Serum immunoglobulin A (IgA) < 10 mg/dL;
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = ≥2 times the upper limit of normal (ULN);
• Positive human immunodeficiency virus (HIV) serology;
• Positive hepatitis C virus (HCV) serology, unless treated with anti-viral therapy with achievement of a sustained virologic response (undetectable viral load 24 weeks after cessation of therapy);
• Evidence of current or prior infection with hepatitis B, as indicated by a positive HBsAg, positive HBcAb, or positive HBsAb serology without history of vaccination;

• Positive QuantiFERON - tuberculosis (TB) Gold test results,

  --Note: Tuberculin Purified Protein Derivative (PPD) test may be substituted for QuantiFERON - TB Gold test.

• History of malignant neoplasm within the last 5 years,

  --Exception: basal cell or squamous cell carcinoma of the skin treated with local resection only, or carcinoma in situ of the uterine cervix treated locally and with no evidence of metastatic disease for 3 years.

• Absence of individualized, age-appropriate cancer screening;
• Women of child-bearing potential who are pregnant, nursing, or unwilling to be sexually inactive or use FDA-approved contraception until study week 104;

• Acute or chronic infection, including:

  • current use of suppressive therapy for chronic infection,
  • hospitalization for treatment of infection in 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.

• History of anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies, including:

  • rituximab, or
  • belimumab.

• Evidence of serious suicide risk, including:

  • any history of suicidal behavior in the last 6 months,
  • any suicidal ideation in the last 2 months, or
  • who, in the investigator's judgment, pose a significant suicide risk.
• Evidence of current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence in the past 12 months;
• Vaccination with a live vaccine within the past 30 days;
• Other diseases or conditions which, in the opinion of the investigator, would put the subject at risk or confound the results of the study; or
• Inability to comply with study and follow-up procedures.

• Immune Tolerance Network (ITN)
• GlaxoSmithKline