povetacicept (ALPN-303) / Vertex, ZAI Lab, Ono Pharma - LARVOL DELTA

Management of Autoimmune Hemolytic Anemia (ASH 2025) - "For relapsed/refractory patients rituximab has become the preferred second line-therapy, comparing favorably with the traditional splenectomy, which has been progressively abandoned or moved to further lines along with classic immunosuppressors. Several novel treatments are in development for wAIHA, encompassing drugs targeting B-cells (parsaclisib, ibrutinib, rilzabrutinib, zanubrutinib, obexelimab, ianalumab, povetacicept), plasma cells (bortezomib, daratumumab), spleen tyrosine kinase (fostamatinib, sovleplenib), and the neonatal Fc receptor (nipocalimab)."

IO biomarker • Anemia • Autoimmune Hemolytic Anemia • Bone Marrow Transplantation • Hematological Disorders • Immunology • Infectious Disease • HP • SYK

Management of autoimmune hemolytic anemia. (PubMed, Hematology Am Soc Hematol Educ Program) - "Rituximab is now the preferred second-line option for relapsed/refractory patients, comparing favorably with the traditional splenectomy. The latter is increasingly reserved for later lines together with classic immunosuppressants. Several novel treatments are in development for refractory wAIHA, encompassing drugs targeting B-cells (parsaclisib, ibrutinib, rilzabrutinib, zanubrutinib, obexelimab, ianalumab, povetacicept), plasma cells (bortezomib, daratumumab), spleen tyrosine kinase (fostamatinib, sovleplenib), and the neonatal Fc receptor (nipocalimab)."

Journal • Review • Anemia • Autoimmune Hemolytic Anemia • Bone Marrow Transplantation • Complement-mediated Rare Disorders • Hematological Disorders • Immunology • Infectious Disease • Oncology • Paroxysmal Nocturnal Hemoglobinuria • Transplantation • SYK

Evaluation of Efficacy of Povetacicept in Adults With Immunoglobulin A Nephropathy (IgAN) (clinicaltrials.gov) - P3 | N=605 | Active, not recruiting | Sponsor: Alpine Immune Sciences Inc, A Subsidiary of Vertex | Recruiting ➔ Active, not recruiting

Enrollment closed • Glomerulonephritis • IgA Nephropathy • Renal Disease

Initial Report of Povetacicept, an Enhanced Dual BAFF/APRIL Antagonist, in Autoimmune Cytopenias: The RUBY-4 Study (ASH 2023) - P1/2 | "Patients with ITP or AIHA have elevated serum BAFF and APRIL levels and belimumab, a BAFF inhibitor, has exhibited encouraging efficacy in the treatment of lupus-associated ITP as well as alone or in combination with rituximab for the treatment of primary ITP. To our knowledge, povetacicept is the first dual BAFF/APRIL inhibitor to be evaluated for the treatment of autoimmune cytopenias. Previous preclinical and healthy volunteer studies suggest the potential of povetacicept for suppression of the pathogenic autoimmunity that mediates platelet/erythrocyte destruction in ITP, wAIHA, and CAD, which may lead to more durable responses and improved outcomes for patients."

Anemia • Autoimmune Hemolytic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Immune Thrombocytopenic Purpura • Immunology • Inflammatory Arthritis • Lupus • Thrombocytopenia • Thrombocytopenic Purpura

Povetacicept (ALPN-303), a Potent Dual BAFF/APRIL Antagonist in Development for the Treatment of Autoimmune Cytopenias, Suppresses Disease in a Mouse Model of Autoimmune Hemolytic Anemia (ASH 2023) - P1/2 | "Belimumab, an anti-BAFF antibody, has demonstrated encouraging efficacy in the treatment of ITP associated with systemic lupus erythematosus [De Marchi, et al. , Clin Exp Rheumatol, 2017] and in combination with rituximab in patients with ITP [Mahévas, et al... Povetacicept effectively reduced pathogenic autoantibodies and key B cell populations (e. g. , ASC) and limited serum LDH elevations in this mouse model of erythrocyte autoimmunity."

Preclinical • Anemia • Autoimmune Hemolytic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Immune Thrombocytopenic Purpura • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • Thrombocytopenia • Thrombocytopenic Purpura

Povetacicept for IgAN: Design of a Phase 3 Randomized, Placebo-Controlled Study (KIDNEY WEEK 2025) - "Conclusion Povetacicept demonstrated significant efficacy in reducing proteinuria and stabilizing renal function in Phase 1/2. The RAINIER Phase 3 study will confirm the clinical benefits previously observed and support the potential of povetacicept as a treatment for IgAN."

Clinical • P3 data • Fatigue • Glomerulonephritis • IgA Nephropathy • Lupus Nephritis • Nephrology • Renal Disease

povetacicept Phase 3 IgAN trial full enrollment complete; on track to submit first module of povetacicept IgAN BLA to FDA by end of 2025 (Vertex Press Release)

Enrollment closed • FDA filing • IgA Nephropathy

Efficacy and Safety of Povetacicept in Patients with IgAN and Primary Membranous Nephropathy (pMN) at 48 Weeks of Treatment: The RUBY-3 Study (KIDNEY WEEK 2025) - "Similar results were seen in pMN. By directly targeting both BAFF and APRIL, povetacicept interdicts the causal biology of IgAN and pMN, with potential to be a best-in-class, transformative, disease-modifying treatment; ph3 studies in IgAN and pMN are underway."

Clinical • Late-breaking abstract • Glomerulonephritis • IgA Nephropathy • Immunology • Lupus Nephritis • Renal Disease

OLYMPUS: A Study to Evaluate Efficacy, Safety, and Tolerability of Povetacicept in Participants With Primary Membranous Nephropathy (pMN) (clinicaltrials.gov) - P2/3 | N=176 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Not yet recruiting ➔ Recruiting

Enrollment open • Glomerulonephritis • Renal Disease

RUBY-3: An Open-label Study of Povetacicept in Autoantibody-Associated Glomerular Diseases (clinicaltrials.gov) - P1/2 | N=72 | Active, not recruiting | Sponsor: Alpine Immune Sciences, Inc. | Trial completion date: Jan 2026 ➔ Mar 2028 | Trial primary completion date: Jan 2026 ➔ Mar 2028

Trial completion date • Trial primary completion date • ANCA Vasculitis • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Vasculitis

LBL-047, A First-In-Class Anti-BDCA2/TACI Fusion Protein, Inhibits the Function of Both pDCs and B cells [WITHDRAWN] (ACR Convergence 2025) - "Litifilimab, an anti-BDCA2 antibody, has demonstrated promising preliminary efficacy and excellent safety profile in patients with cutaneous lupus erythematosus...Targeting this pathway, two TACI based recombinant fusion proteins, such as Povetacicept and Telitacicept, have shown clinical benefits and favorable safety profile in autoimmune disease trials... LBL-047 has shown dual immunosuppressive effects, inhibiting simultaneously the function of pDCs and B cells both in vitro and in vivo. In addition, it has demonstrated excellent PK and PD profile, coupled with good safety profile and tolerability in cynomolgus monkeys. Taken together, these findings support the clinical development of LBL-047 and highlight its promise as a therapeutic candidate for autoimmune diseases."

Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • CD34 • IFNA1 • IL6 • TNFA

OLYMPUS: A Study to Evaluate Efficacy, Safety, and Tolerability of Povetacicept in Participants With Primary Membranous Nephropathy (pMN) (clinicaltrials.gov) - P2/3 | N=176 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

New P2/3 trial • Glomerulonephritis • Renal Disease

Povetacicept in IgAN (Businesswire) - "Vertex announced today that the Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) to povetacicept (pove) for the treatment of IgAN. Pove is an investigational recombinant fusion protein therapeutic and dual antagonist of the BAFF (B cell activating factor) and APRIL (a proliferation inducing ligand) cytokines with best-in-class potential in IgAN and other B cell-driven diseases....The IA cohort has been fully enrolled, and Vertex remains on track to file for accelerated approval in the U.S. in H1 2026 if results are supportive."

Breakthrough therapy • Enrollment status • FDA filing • IgA Nephropathy

A Study to Evaluate the Relative Bioavailability of Povetacicept Formulations and Bioequivalence of Povetacicept Presentations (clinicaltrials.gov) - P1 | N=136 | Completed | Sponsor: Vertex Pharmaceuticals Incorporated | Active, not recruiting ➔ Completed

Trial completion

A Study to Evaluate the Relative Bioavailability of Povetacicept Formulations and Bioequivalence of Povetacicept Presentations (clinicaltrials.gov) - P1 | N=136 | Active, not recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Recruiting ➔ Active, not recruiting

Enrollment closed

A Study to Evaluate the Relative Bioavailability of Povetacicept Formulations and Bioequivalence of Povetacicept Presentations (clinicaltrials.gov) - P1 | N=136 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Not yet recruiting ➔ Recruiting

Enrollment open

RUBY-4: An Open-label Study of Povetacicept in Participants With Autoimmune Cytopenias (clinicaltrials.gov) - P1/2 | N=30 | Active, not recruiting | Sponsor: Alpine Immune Sciences, Inc. | Recruiting ➔ Active, not recruiting | N=126 ➔ 30 | Trial completion date: Nov 2027 ➔ Jul 2026 | Trial primary completion date: Nov 2027 ➔ Jul 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Anemia • Autoimmune Hemolytic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Immune Thrombocytopenic Purpura • Immunology • Thrombocytopenia • Thrombocytopenic Purpura

Longer Follow-Up of Povetacicept Shows Potential for Treatment of IgA Nephropathy (RUBY-3 Study): Glomerulonephritis (KSN 2025) - "These updated data reinforce the potential of povetacicept as therapy for IgAN; a Phase 3 randomized, controlled study of povetacicept in IgAN is well underway. RUBY-3 Study, 24-hour UPCR Mean Percent Change from Baseline to Week 48.jpg"

Glomerulonephritis • IgA Nephropathy • Inflammation • Lupus Nephritis • Nephrology • Renal Disease

Povetacicept (ALPN-303; TACI vTD-Fc), an enhanced, potent dual inhibitor of BAFF and APRIL, ameliorates experimental autoimmune myasthenia gravis in C57BL/6N mice. (PubMed, Front Immunol) - "In this study, the activity of povetacicept was evaluated in the mouse experimental autoimmune MG (EAMG) model, compared to (i) telitacicept, (ii) a depleting anti-CD20 antibody, (iii) neonatal Fc receptor blocker efgartigimod, (iv) a matched Fc control protein, and (v) PBS as vehicle. The potent, dual BAFF/APRIL inhibitor povetacicept significantly improves clinical disease activity in EAMG, associated with reductions in pathogenic anti-AChR autoantibodies and superior to comparator therapeutic interventions based on WT TACI-Fc, CD20 depletion, or FcRn inhibition. Povetacicept may therefore confer beneficial clinical outcomes in the treatment of MG and other autoantibody-related neurological diseases."

Journal • Preclinical • CNS Disorders • Immunology • Myasthenia Gravis

RUBY-3: An Open-label Study of Povetacicept in Autoantibody-Associated Glomerular Diseases (clinicaltrials.gov) - P1/2 | N=72 | Active, not recruiting | Sponsor: Alpine Immune Sciences, Inc. | Recruiting ➔ Active, not recruiting | N=296 ➔ 72

Enrollment change • Enrollment closed • ANCA Vasculitis • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Vasculitis

Vertex and Ono Pharmaceutical Announce Strategic Agreement to Develop and Commercialize Povetacicept in Japan and South Korea (Vertex Press Release) - "Vertex Pharmaceuticals...and Ono Pharmaceutical...announced an exclusive collaboration and license agreement for the development and commercialization of Vertex’s povetacicept in Japan and South Korea. Povetacicept is a recombinant fusion protein therapeutic and dual antagonist of the BAFF (B cell activating factor) and APRIL (a proliferation inducing ligand) cytokines with best-in-class potential being studied for the treatment of immunoglobulin A nephropathy (IgAN), primary membranous nephropathy (pMN) and other B cell-mediated diseases...Under the terms of the agreement, Vertex will receive an upfront payment, as well as certain regulatory and commercial milestone payments and tiered royalties. Ono will utilize its extensive development expertise to help advance Vertex’s clinical trials for povetacicept and will be responsible for obtaining marketing authorizations in Japan and South Korea."

Licensing / partnership • IgA Nephropathy • Immunology

Differential Impacts of APRIL and APRIL/BAFF Inhibition on Immune Populations: Implications for IgAN Treatment and Protective Immunity (ERA 2025) - " Mice were dosed twice per week with anti-APRIL antibody (4540), or APRIL/BAFF inhibitors (TACI- Fc fusion proteins POV and ATA, based on the sequences of povetacicept and atacicept, respectively), or isotype control antibody (MOTA). This study demonstrates that administration of both APRIL and APRIL/BAFF inhibitors reduce serum IgA, a desirable effect for kidney diseases like IgA nephropathy, in which elevated levels of aberrantly glycosylated IgA have a pathogenic role. However, dual APRIL/BAFF inhibition leads to significant ablation of most B cell subsets, ASCs, and Tfh cells, whereas APRIL-only inhibition does not substantially alter splenic cell populations. Broad immune cell ablation has implications for immune homeostasis and responses to vaccines and pathogens."

Clinical • Glomerulonephritis • IgA Nephropathy • Infectious Disease • CD21 • PTPRC

A Study to Evaluate the Relative Bioavailability of Povetacicept Formulations and Bioequivalence of Povetacicept Presentations (clinicaltrials.gov) - P1 | N=136 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

New P1 trial

Povetacicept (ALPN-303; TACI vTD-Fc), an Enhanced, Potent Dual Inhibitor of BAFF and APRIL, Ameliorates Experimental Autoimmune Myasthenia Gravis in C57BL/6N Mice (Frontiers) - "Therapeutic administration of povetacicept ameliorated clinical manifestations in EAMG mice and was associated with significantly lower levels of immunoglobulin subclasses and anti-AChR antibody titers in serum, along with increased muscle AChR content -superior to the evaluated comparators. Povetacicept treatment also reduced the number of total B220 + and Ki67 + proliferating cells in draining lymph node follicles and resulted in modifications of splenic T and B cell subset frequencies, compared to controls.The potent, dual BAFF/APRIL inhibitor povetacicept significantly improves clinical disease activity in EAMG, associated with reductions in pathogenic anti-AChR autoantibodies and superior to comparator therapeutic interventions based on WT TACI-Fc, CD20 depletion, or FcRn inhibition.Povetacicept may therefore confer beneficial clinical outcomes in the treatment of MG and other autoantibody-related neurological diseases."

Preclinical • Myasthenia Gravis

IgA Nephropathy (IgAN), Primary Membranous Nephropathy (pMN) and Other B Cell-Mediated Diseases (Vertex Press Release) - "The global Phase 3 RAINIER trial of povetacicept in patients with IgAN has completed enrollment of the interim analysis cohort. The interim analysis will be conducted once this cohort reaches 36 weeks of treatment, with the potential to file for Accelerated Approval in the U.S. in the first half of 2026...Vertex will initiate a single, adaptive Phase 2/3 trial of povetacicept vs. standard-of-care this year. In the Phase 2 portion, both 80 mg and 240 mg of povetacicept will be assessed and the selected dose will advance to Phase 3, where the primary endpoint of complete clinical remission at 72 weeks of treatment will be evaluated; Vertex plans to present updated data from the IgAN and pMN cohorts of the RUBY-3 study at upcoming medical congresses; Vertex expects to share data and next steps from other RUBY-3 renal diseases and the hematologic conditions in the RUBY-4 study later this year."

FDA filing • New P2/3 trial • P1/2 data • Trial status • ANCA Vasculitis • IgA Nephropathy • Immune Thrombocytopenic Purpura • Lupus Nephritis • Thrombocytopenia