The goal of this clinical study is to evaluate multiple dose levels of povetacicept in adults with immunoglobulin A (IgA) nephropathy (IgAN), primary membranous nephropathy (pMN), lupus-related kidney disease (lupus nephritis - LN), or anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) to determine if povetacicept is safe and potentially beneficial in treating these diseases.

During the study treatment period, participants will receive povetacicept approximately every 4 weeks for 6 months, with the possibility of participating in a 6-month treatment extension period and an optional 52-week treatment extension period. Participants with IgAN and pMN may also receive povetacicept for an additional 52 weeks, if eligible.

Key Inclusion Criteria Summary:

Part A:

• Biopsy-confirmed autoantibody-associated glomerular disease: immunoglobulin A nephropathy (IgAN), primary membranous nephropathy (pMN), or lupus nephritis (LN)

• On maximal dose or the maximally tolerated dose ACEis/ARBs for ≥12 weeks prior to study Day 1

• Indication-specific criteria:

  1. IgAN

     • Biopsy-confirmed diagnosis less than or equal to (≤)10 years prior to the start of screening AND Screening UPCR greater than or equal to (≥)0.5 g/g.
     • No background immunosuppression therapies.

  2. pMN

     • A historical biopsy-confirmed diagnosis with positive anti-PLA2R1 antibodies or anti-THSD7A antibodies at screening AND Screening UPCR ≥1 g/g
     • Inadequate reduction of proteinuria determined by the Principal Investigator (PI) despite optimal supportive care for at least 12 weeks.
     • No background immunosuppression therapies except for optional calcineurin inhibitors.

  3. LN

     • A Biopsy-confirmed diagnosis of active, proliferative Class III, IV, (with or without Class V) LN ≤6 months prior to the start of screening AND Screening UPCR ≥1 g/g,
     • Anti-dsDNA at screening. Anti-dsDNA testing is required but the result need not be positive.
     • On stable background immunosuppression ≥ 8 weeks prior to Day 1

  4. AAV

     • Past diagnosis of renal AAV, defined as either of the following:
     • History of renal biopsy consistent with renal AAV.
     • History of clinically diagnosed renal AAV.
     • Myeloperoxidase (MPO)-ANCA or proteinase 3 (PR3)-ANCA positive by enzyme-linked immunosorbent assay at screening.
     • At least 4 weeks since initiation of AAV induction therapy, if applicable.

     Part B:

• Participants meet at least 1 of the following criteria:

  • Completed investigational product (IP) treatment and 24 weeks of follow-up in Part A, or
  • Had IP interruption(s) in Part A, but did not permanently discontinue IP, and completed study visits up to the last scheduled visit of the follow-up period of Part A.

Key Exclusion Criteria Summary:

Part A:

• Prior diagnosis of, or fulfills diagnostic criteria for, another renal disease
• eGFR <30 milliliter per minute per square meter (mL/min/1.73m^2) or rapidly progressive glomerulonephritis
• Recent serious or ongoing infection; risk or history of serious infection
• Receipt of B cell depleting therapies or anti-BAFF and/or APRIL therapies within protocol specified timeframes

Part B:

• History of poor compliance with IP and/or procedures in Part A, as deemed by the investigator or Sponsor
• History of any AEs or clinical conditions during Part A or emerging thereafter that may pose a safety concern for participation in Part B as deemed by investigator or Sponsor.

Other protocol defined Inclusion/Exclusion criteria will apply

Details on Vertex data sharing criteria and process for requesting access can be found at: https://www.vrtx.com/independent-research/clinical-trial-data-sharing