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

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

Longer Follow-up of Povetacicept Shows Potential for Treatment of IgA Nephropathy (RUBY-3 Study): Glomerulonephritis (KSN 2025) - No abstract available

Glomerulonephritis • IgA Nephropathy • Lupus Nephritis • Nephrology • 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. | 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

RUBY-3: An Open-label Study of Povetacicept in Autoantibody-Associated Glomerular Diseases (clinicaltrials.gov) - P1/2 | N=296 | Recruiting | Sponsor: Alpine Immune Sciences, Inc. | N=56 ➔ 296

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

Zai Lab and Vertex Announce Strategic Agreement to Develop and Commercialize Povetacicept in Mainland China, Hong Kong SAR, Macau SAR, Taiwan region and Singapore (Businesswire) - "Zai Lab Limited...and Vertex Pharmaceuticals Incorporated...today announced an exclusive collaboration and license agreement for the development and commercialization of Vertex’s povetacicept (pove) in mainland China, Hong Kong SAR, Macau SAR, Taiwan region and Singapore (the licensed territory). Pove is a recombinant fusion protein therapeutic and dual antagonist of BAFF (B cell activating factor) and APRIL (a proliferation inducing ligand) with best-in-class potential being studied for the treatment of Immunoglobulin A nephropathy (IgAN) and other B cell-mediated diseases. Under the terms of the agreement, Vertex will receive an upfront payment, as well as certain regulatory milestone payments and tiered royalties, on net sales of pove in the region of focus for Zai Lab. Zai Lab will utilize its extensive research and development expertise to help advance clinical trials and make regulatory submissions in the licensed territory."

Licensing / partnership • IgA Nephropathy • Immunology

Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy. (PubMed, Transfus Med Hemother) - "Therapy is quite different, as steroids and rituximab are effective in the former, but have a lower response rate and duration in the latter...Several new drugs are increasingly used or are in trials for relapsed/refractory AIHAs, including B-cell (parsaclisib, ibrutinib, rilzabrutinib), and plasma cell target therapies (bortezomib, daratumumab), bispecific agents (ianalumab, obexelimab, povetacicept), neonatal Fc receptor blockers (nipocalimab), and complement inhibitors (sutimlimab, riliprubart, pegcetacoplan, iptacopan)...Along with all these variables, there are rare forms like mixed (wAIHA plus CAD), atypical (IgA or warm IgM driven), and DAT negative, where the diagnosis and clinical management are particularly challenging. This article covers the classic clinical features, diagnosis, and therapy of wAIHA and CAD, and focuses, with the support of clinical vignettes, on difficult diagnosis and refractory/relapsing cases requiring novel therapies."

Journal • Review • Anemia • Autoimmune Hemolytic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Immunology • Infectious Disease • Oncology • Rare Diseases • Thrombosis • Transplantation

A first-in-human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF/APRIL antagonist, in healthy adults. (PubMed, Clin Transl Sci) - "Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on-target reductions in antibody-secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease-related biomarker galactose-deficient-immunoglobulin A1 (Gd-IgA1), and were superior to results reported for wild-type TACI-Fc. These data strongly support further development of povetacicept for the treatment of B-cell-mediated automimmune diseases."

Clinical • Journal • P1 data • PK/PD data • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Oncology • Renal Disease • Systemic Lupus Erythematosus • TNFA

Results from Longer Follow-Up with Povetacicept, an Enhanced Dual BAFF/APRIL Antagonist, in IgA Nephropathy (RUBY-3 Study) (KIDNEY WEEK 2024) - P1/2 | "Experience with povetacicept to date strongly supports its further development in glomerulonephritis and particularly in IgAN, for which a pivotal trial (RAINIER) is in preparation and planned for initiation later this year."

ANCA Vasculitis • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Renal Disease • Vasculitis

Updated Results with Povetacicept, an Enhanced Dual BAFF/APRIL Antagonist, in Primary Membranous Nephropathy (RUBY-3 Study) (KIDNEY WEEK 2024) - P1/2 | "In these initial findings, povetacicept demonstrates promising activity in pMN, strongly supporting its further development in autoantibody-associated glomerulonephritis."

ANCA Vasculitis • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Renal Disease • Vasculitis

Evaluation of Efficacy of Povetacicept in Adults With Immunoglobulin A Nephropathy (IgAN) (clinicaltrials.gov) - P3 | N=480 | Recruiting | Sponsor: Alpine Immune Sciences Inc, A Subsidiary of Vertex | Not yet recruiting ➔ Recruiting

Enrollment open • Glomerulonephritis • IgA Nephropathy • Renal Disease

Evaluation of Efficacy of Povetacicept in Adults With Immunoglobulin A Nephropathy (IgAN) (clinicaltrials.gov) - P3 | N=480 | Not yet recruiting | Sponsor: Alpine Immune Sciences Inc, A Subsidiary of Vertex

New P3 trial • Glomerulonephritis • IgA Nephropathy • Renal Disease

Povetacicept (ALPN-303), a Potent Dual BAFF/APRIL Inhibitor, Inhibits Key Inflammatory Pathways and Demonstrates Greater Efficacy in Murine Lupus (APLAR 2024) - No abstract available

Preclinical • Immunology • Inflammatory Arthritis • Lupus

Anti-B-Cell-Activating Factor (BAFF) Therapy: A Novel Addition to Autoimmune Disease Management and Potential for Immunomodulatory Therapy in Warm Autoimmune Hemolytic Anemia. (PubMed, Biomedicines) - "Although rituximab is not specifically approved for the treatment of warm autoimmune hemolytic anemia (WAIHA), the First International Consensus Group recommends considering its use as part of the initial therapy for patients with severe disease and as a second-line therapy for primary WAIHA...This article reviews the role of BAFF in autoimmune disorders and the currently available literature on the use of BAFF-directed therapies in various immunologic disorders, including WAIHA. Collectively, the clinical data thus far shows robust potential for targeting BAFF in WAIHA therapy."

Immunomodulating • Journal • Review • Anemia • Autoimmune Hemolytic Anemia • Hematological Disorders • Immunology

Efficacy of povetacicept (ALPN-303; TACI vTD-Fc), an enhanced, potent dual inhibitor of BAFF and APRIL, in murine allergic asthma (ERS 2024) - No abstract available

Preclinical • Asthma • Immunology • Respiratory Diseases

POVETACICEPT (ALPN-303; TACI vTD-Fc), AN ENHANCED, POTENT DUAL INHIBITOR OF BAFF AND APRIL, DEMONSTRATES GREATER TISSUE DISTRIBUTION VERSUS WILD-TYPE TACI-Fc IN ADULT MICE AND IMPROVED EFFICACY VERSUS WILD-TYPE TACI-Fc OR ANTI-CD20 IN THE IFNα-ACCELERATED NZB/W MOUSE MODEL OF SLE (EULAR 2024) - P1/2 | " Publicly available RNA Sequencing (RNA-Seq) datasets from healthy donors (HD) and SLE patients were utilized to assess APRIL and BAFF gene expression.[2-4] HD PBMC were stimulated in vitro with 1 nM CD40L and 50 ng/mL IL-21 and cultured for 24 hours with 10 nM APRIL and 25 nM BAFF in the presence of either 50 nM of Fc control, povetacicept, anti-BAFF mAb (belimumab), or anti-APRIL mAb...In the IFNα-accelerated NZB/W lupus mouse model[5], 11-week-old female NZB/W mice were administered twice weekly intraperitoneal injections of povetacicept (10 mg/kg), a molar-matched dose of an Fc control or telitacicept, or weekly cyclophosphamide or a depleting anti-mouse CD20 mAb... Dual inhibition of both BAFF and APRIL may be required to achieve optimal suppression of pathogenic pathways associated with SLE and related diseases. With improved affinity and enhanced tissue distribution over WT TACI-Fc, povetacicept may enable optimal BAFF/APRIL inhibition in SLE, as well as in..."

Preclinical • Anemia • Glomerulonephritis • Hematological Disorders • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Systemic Lupus Erythematosus • CD40LG • IFNA1 • IFNAR2 • IFNGR1 • IL10 • IL21 • IL6

Updated Results from the RUBY-3 Study of Povetacicept, an Enhanced Dual BAFF/APRIL Antagonist, in Autoantibody-Associated Glomerulonephritis (ERA-EDTA 2024) - "Povetacicept remains well tolerated with multiple dosing and continues to demonstrate very promising activity in IgAN, strongly supporting further study in IgAN as well as other glomerulonephritis and autoantibody-associated diseases."

Glomerulonephritis • IgA Nephropathy • Infectious Disease • Inflammatory Arthritis • Lupus Nephritis • Nephrology

INITIAL RESULTS OF A PHASE 1B/2 OPEN-LABEL STUDY OF POVETACICEPT IN PARTICIPANTS WITH AUTOIMMUNE CYTOPENIAS (RUBY-4) (EHA 2024) - No abstract available

Clinical • P1/2 data • Hematological Disorders • Immunology

Povetacicept, an Enhanced Dual BAFF/APRIL Antagonist, in Autoantibody-Associated Glomerulonephritis (GN) (NKF-SCM 2024) - P1/2 | "In summary, povetacicept is well tolerated during multiple dosing, with promising activity including reductions in IgAN- and pMN-specific biomarkers, supporting further study in IgAN and other GN."

Glomerulonephritis • IgA Nephropathy • Infectious Disease • Lupus Nephritis • Nephrology

Hitting the Four Hits: The Potential of Dual BAFF/APRIL Inhibition in IgA Nephropathy (ISN-WCN 2024) - "This Spotlight Session will review new agents in development for the treatment of IgA nephropathy, including the dual BAFF/APRIL antagonist, povetacicept. The presentation will focus on (1) how the various mechanisms of action being explored target different aspects of the multi-hit model of IgA nephropathy pathogenesis, (2) the relative pros and cons of targeting early versus late hits , and (3) how inhibition of both BAFF and APRIL may provide disease-modifying potential (including initial findings from the povetacicept RUBY-3 trial)."

Glomerulonephritis • IgA Nephropathy • Renal Disease

UPDATED RESULTS FROM THE RUBY-3 STUDY OF POVETACICEPT, AN ENHANCED DUAL BAFF/APRIL ANTAGONIST, IN AUTOANTIBODY-ASSOCIATED GLOMERULONEPHRITIS (ISN-WCN 2024) - P1/2 | "Povetacicept is well tolerated with multiple dosing and continues to demonstrate very promising activity in IgAN, strongly supporting further study in IgAN as well as other glomerulonephritis and autoantibody-associated diseases."

Late-breaking abstract • Glomerulonephritis • IgA Nephropathy • Infectious Disease • Inflammatory Arthritis • Lupus Nephritis • Nephrology