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

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

POVETACICEPT, AN ENHANCED DUAL BAFF/APRIL ANTAGONIST, IN AUTOANTIBODY-ASSOCIATED GLOMERULONEPHRITIS (ISN-WCN 2024) - P1/2 | "Initial experience indicates that povetacicept is well tolerated during multiple-dose administration in glomerulonephritis, with very promising activity including reductions in disease-specific biomarkers in participants with IgAN and pMN. These results strongly support further study of povetacicept in IgAN as well as other glomerulonephritis and autoantibodyassociated diseases."

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

Povetacicept (ALPN-303), a Potent Dual BAFF/APRIL Antagonist, Suppresses Disease in a Mouse Model of Autoimmune Encephalitis (AAN 2024) - "Povetacicept demonstrates promising efficacy in a preclinical model of autoimmune encephalitis, reducing pathogenic autoantibodies and cerebral Ig deposition. Povetacicept may hold promise in the treatment of autoimmune encephalitis and other autoantibody-related neurological diseases."

Preclinical • CNS Disorders • Immunology • Myasthenia Gravis

Upregulation of both APRIL and BAFF in systemic lupus erythematosus suggests non-redundant roles; further revealed by potent dual inhibition with povetacicept (TACI vTD-Fc; ALPN-303) (LUPUS 2024) - P1/2 | "PBMCs from healthy donors were stimulated with CD40L, IL-21, BAFF, and APRIL prior to treatment with Fc control, povetacicept, belimumab (anti-BAFF), anti-APRIL mAb, telitacicept (WT TACI-Ig), or combined anti-BAFF/anti-APRIL, then harvested for flow cytometry and RNA-seq analyses. Povetacicept was also evaluated in an IFNα-accelerated NZB/W mouse model of SLE alongside a matched Fc control, telitacicept, a depleting anti-mouse CD20 mAb, and cyclophosphamide...These results strongly support the clinical evaluation of povetacicept in SLE and other B cell- and/or autoantibody-related diseases. A clinical study of povetacicept in SLE is in preparation; clinical trials are ongoing in autoimmune cytopenias (NCT05757570) and glomerulonephritides, including LN (NCT05732402)."

IO biomarker • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Systemic Lupus Erythematosus • CD40LG • IFNA1 • IL21

Alpine Immune Sciences Presents New Translational Data on Povetacicept at the European Lupus Meeting 2024 (Businesswire) - "A phase 2 study in SLE (DENALI) is in preparation for initiation in 2H 2024....Alpine Immune Sciences....announced today that the Company presented new translational data for povetacicept (ALPN-303) at the SLEuro 14th European Lupus Meeting in Bruges, Belgium, March 19-22, 2024. Presentation Highlights Include: BAFF- and APRIL-related genes are increased in myeloid and B cells in systemic lupus erythematosus (SLE) patients compared to healthy adults. Povetacicept significantly reduces multiple disease parameters in the NZB/W mouse model of lupus, more effectively than WT TACI-Ig or B cell depletion."

New P2 trial • Preclinical • Systemic Lupus Erythematosus

Alpine Immune Sciences Provides Corporate Update and Full Year 2023 Financial Results (Businesswire) - "Corporate Updates:...(i) The Company intends to initiate RAINIER, a pivotal phase 3 study of povetacicept in IgA nephropathy and DENALI, a phase 2 study of povetacicept in systemic lupus erythematosus in the second half of 2024, pending regulatory agreement; (ii) The Company plans to share initial data from RUBY-4 in autoimmune cytopenias in the first half of 2024 at a relevant scientific congress."

New P2 trial • New P3 trial • P1/2 data • Autoimmune Hemolytic Anemia • IgA Nephropathy • Systemic Lupus Erythematosus • Thrombocytopenic Purpura

Alpine Immune Sciences Provides Corporate Update and Full Year 2023 Financial Results (Businesswire) - "Corporate Updates: (i) The Company plans to present additional data on povetacicept in IgA nephropathy, including follow up data from the 80 mg Q4W and initial data from the IgAN 240 mg Q4W dose cohorts, during a Late Breaking Abstract session at the World Congress of Nephrology 2024; (ii) The Company plans to present new preclinical data on povetacicept, demonstrating its greater distribution to disease-related end organs compared with WT TACI-Ig, at the 14th European Lupus Meeting."

Late-breaking abstract • P1/2 data • Preclinical • IgA Nephropathy

RUBY-3: An Open-label Study of Povetacicept (ALPN-303) in Autoimmune Kidney Diseases (clinicaltrials.gov) - P1/2 | N=56 | Recruiting | Sponsor: Alpine Immune Sciences, Inc. | N=42 ➔ 56

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