An Open-label Study of Povetacicept in Autoantibody-Associated Glomerular Diseases (RUBY-3)

An Open-Label, Multiple-Ascending Dose Study to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Different Dose Levels of Povetacicept in Subjects With Autoantibody-Associated Glomerular Diseases (RUBY-3)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Lupus Nephritis; Immunoglobulin A Nephropathy; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Membranous Nephropathy
• Intervention / Treatment: Drug: Povetacicept

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Investigational Site (519)
  • Victoria
    • Saint Albans, Victoria, Australia, 3021
      • Investigational Site (515)
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Investigational Site (102)
• Puerto Rico
  • Caguas, Puerto Rico, 00725
    • Investigational Site (191)
• South Korea
  • Chungcheongnam-do
    • Cheonan, Chungcheongnam-do, South Korea, 31151
      • Investigational Site (507)
  • Gyeonggi-do
    • Anyang-si, Gyeonggi-do, South Korea, 14068
      • Investigational Site (505)
    • Goyang-si, Gyeonggi-do, South Korea, 10444
      • Investigational Site (504)
    • Guri-si, Gyeonggi-do, South Korea, 11923
      • Investigational Site (510)
    • Seoul, Gyeonggi-do, South Korea, 03080
      • Investigational Site (125)
    • Seoul, Gyeonggi-do, South Korea, 03181
      • Investigational Site (520)
    • Seoul, Gyeonggi-do, South Korea, 05278
      • Investigational Site (521)
    • Suwon, Gyeonggi-do, South Korea, 16499
      • Investigational Site (116)
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Investigational Site (523)
    • Phoenix, Arizona, United States, 85302
      • Investigational Site (501)
    • Tucson, Arizona, United States, 85712
      • Investigational Site (524)
  • California
    • Valencia, California, United States, 91335
      • Investigational Site (506)
  • Colorado
    • Arvada, Colorado, United States, 80002
      • Investigational Site (513)
  • Florida
    • Orlando, Florida, United States, 32806
      • Investigational Site (512)
    • Tamarac, Florida, United States, 33321
      • Investigational Site (525)
  • Georgia
    • Lawrenceville, Georgia, United States, 30046
      • Investigational Site (502)
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • The Johns Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Investigational Site (503)
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine in St. Louis
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Investigational Site (509)
  • New York
    • Albany, New York, United States, 12209
      • Investigational Site (511)
    • Brooklyn, New York, United States, 11203
      • Investigational Site (508)
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Investigational Site (518)
  • Texas
    • Colleyville, Texas, United States, 76034
      • Investigational Site (118)
    • Houston, Texas, United States, 77054
      • Investigational Site (516)
    • Irving, Texas, United States, 75061
      • Investigational Site (526)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Povetacicept; Part A: Participants will receive povetacicept for 24 weeks with the possibility of participating in treatment extensions through 104 weeks of treatment. Part B: Participants with IgAN and pMN will receive povetacicept for an additional 52 weeks.	Drug: Povetacicept; Administered by subcutaneous injection every 4 weeks; Other Names: ALPN-303

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Safety as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Study Day 1 Through 24 Weeks After Last Dose Of Study Drug
Part B: Safety as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Study Day 1 Through 12 Weeks After Last Dose Of Study Drug

Secondary Outcome Measures

Outcome Measure	Time Frame
Part A: Incidence and Titer of Anti-drug Antibodies (ADA) Against Povetacicept	Study Day 1 Through 24 Weeks After Last Dose Of Study Drug
Part B: Incidence and Titer of Anti-drug Antibodies (ADA) Against Povetacicept	Study Day 1 Through 12 Weeks After Last Dose Of Study Drug
Part A: Time Required for Povetacicept To Reach Half its Concentration (t1/2)	Study Day 1 Through 24 Weeks After Last Dose Of Study Drug
Part B: Time Required for Povetacicept To Reach Half its Concentration (t1/2)	Study Day 1 Through 12 Weeks After Last Dose Of Study Drug
Part A: Change from Baseline in Serum Ig Isotypes (IgM, total IgA, IgA1, IgA2, total IgG, IgG1, IgG2, IgG3, IgG4, IgE).	Study Day 1 Through 24 Weeks After Last Dose Of Study Drug
Part B: Change from Baseline in Serum Ig Isotypes (IgM, total IgA, IgA1, IgA2, total IgG, IgG1, IgG2, IgG3, IgG4, IgE)	Study Day 1 Through 12 Weeks After Last Dose Of Study Drug
Part A: Change from Baseline in Peripheral Blood Lymphocytes and Subsets	Study Day 1 Through 24 Weeks After Last Dose Of Study Drug
Part B: Change from Baseline in Peripheral Blood Lymphocytes and Subsets	Study Day 1 Through 12 Weeks After Last Dose Of Study Drug
Part A:Change from Baseline Over Time In Circulating Levels Of anti-dsDNA in LN; galactose deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 in IgAN; anti-PLA2R1 or anti THSD7A in pMN and anti-PR3 or anti-MPO in AAV	Study Day 1 Through 24 Weeks After Last Dose Of Study Drug
Part B: Change from Baseline Over Time In Circulating Levels Of galactose deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 in IgAN; anti-PLA2R1 or anti THSD7A in pMN	Study Day 1 Through 12 Weeks After Last Dose Of Study Drug
Part A: Change From Baseline Over Time In Complement Components (C3, C4, CH50)	Study Day 1 Through 24 Weeks After Last Dose Of Study Drug
Part B: Change From Baseline Over Time In Complement Components (C3, C4, CH50)	Study Day 1 Through 12 Weeks After Last Dose Of Study Drug
Part A: Immunological Remission (pMN only)	Study Day 1 Through Week 24 After Dose of Study Drug
Part B: Immunological Remission (pMN only)	Study Day 1 Through Week 12 After Dose of Study Drug
Part A: Change from Baseline at Week 24 in UPCR (Urine protein/creatinine ratio) (based on assessment of 24-hour urine)	Baseline and at Week 24
Part A: Change from Baseline at Week 24 in Estimated Glomerular Filtration Rate (eGFR)	Baseline and at Week 24
Part B: Change from Baseline at Week 24 in Estimated Glomerular Filtration Rate (eGFR)	Baseline and at Week 24
Part A: Renal Response	At Week 24
Part A: Remission of Vasculitis (Birmingham Vasculitis Activity Score (BVAS = 0)) (for AAV cohorts only)	At Week 24
Part A: Changes in Biomarkers Including Cytokines and Autoantibodies After Treatment with Povetacicept	Study Day 1 Through 24 Weeks After Last Dose Of Study Drug
Part B: Changes in Biomarkers Including Cytokines and Autoantibodies After Treatment with Povetacicept	Study Day 1 Through 12 Weeks After Last Dose Of Study Drug

Collaborators and Investigators

• Sponsor: Alpine Immune Sciences, Inc.
• Investigators: Study Director: Jiahua Li, M.D., Alpine Immune Sciences, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2023
• Primary Completion (Estimated): March 2, 2028
• Study Completion (Estimated): March 2, 2028

Study Registration Dates

• First Submitted: February 8, 2023
• First Submitted That Met QC Criteria: February 8, 2023
• First Posted (Actual): February 17, 2023

Study Record Updates

• Last Update Posted (Estimated): October 14, 2025
• Last Update Submitted That Met QC Criteria: October 10, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Granulomatosis with polyangiitis; AAV; lupus nephritis; IgA nephropathy; Wegener's granulomatosis; membranous nephropathy; Immunoglobulin A nephropathy; Eosinophilic granulomatosis with polyangiitis; Gd-IgA1; Microscopic polyangiitis; glomerulonephritis, IgA; Berger disease; lupus glomerulonephritides; primary membranous nephropathy; glomerulonephritis, membranous; PLA2R; THSD7A; ALPN-303; povetacicept; RUBY-3; RUBY3; GdIgA1; anti-neutrophil cytoplasmic antibody associated vasculitis; Churg-Strauss Disease; Myeloperoxidase (MPO); Proteinase 3 (PR3); ANCA Vasculitis
• Additional Relevant MeSH Terms: Urogenital Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Skin Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Skin Diseases, Vascular; Lung Diseases, Interstitial; Vasculitis; Glomerulonephritis; Lupus Erythematosus, Systemic; Nephritis; Granuloma; Cerebral Small Vessel Diseases; Systemic Vasculitis; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; Lupus Nephritis; Glomerulonephritis, IGA; Granulomatosis with Polyangiitis; Churg-Strauss Syndrome; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Glomerulonephritis, Membranous; Microscopic Polyangiitis
• Other Study ID Numbers: AIS-D03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No