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

DESIGN OF A PHASE 2B/3 ADAPTIVE, RANDOMIZED, ACTIVE-CONTROLLED TRIAL (OLYMPUS) EVALUATING POVETACICEPT IN PRIMARY MEMBRANOUS NEPHROPATHY (ISN-WCN 2026) - "Safety will be evaluated.Conclusion Povetacicept demonstrated transformational efficacy in reducing proteinuria and stabilizing renal function in pMN and was generally safe and well tolerated in Ph1/2. The OLYMPUS trial will further evaluate the efficacy and safety of povetacicept for pMN.I have potential conflict of interest to disclose.JS, RD, YC, ML and OE are employees of Vertex Pharmaceuticals and hold company stock.I did not use generative AI and AI-assisted technologies in the writing process."

Clinical • P2/3 data • P2b data • Glomerulonephritis • 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

Trial initiation date • Glomerulonephritis • Renal Disease

VX24-AIS-D10: A Study to Evaluate Efficacy, Safety, and Tolerability of Povetacicept in Participants With Primary Membranous Nephropathy (pMN) (OLYMPUS) (clinicaltrialsregister.eu) - P2/3 | N=30 | Recruiting | Sponsor: Vertex Pharmaceuticals Inc.

New P2/3 trial • Glomerulonephritis • Renal Disease

Vertex Announces Positive Week 36 Interim Analysis Results for Primary and All Secondary Endpoints in the RAINIER Phase 3 Trial of Povetacicept in Adults With IgA Nephropathy (Businesswire) - "The trial met its primary objective. In the interim analysis population, patients treated with povetacicept achieved a 52.0% reduction from baseline in urine protein to creatinine ratio (UPCR) at Week 36, with a statistically significant and clinically meaningful 49.8% UPCR reduction compared to placebo (P<0.0001)....The trial also met its secondary objective. For the first secondary endpoint, patients treated with povetacicept demonstrated a 77.4% reduction from baseline in serum galactose deficient IgA1 (Gd-IgA1) compared to an increase of +9.1% in the placebo group, yielding a reduction of 79.3% compared to placebo (P<0.0001)....Vertex has already submitted several modules and will complete the full BLA submission by the end of March for potential accelerated approval."

FDA filing • P3 data • IgA Nephropathy

Emerging Therapies in IgA Nephropathy: From A Proliferation-Inducing Ligand (APRIL) and B-cell Activating Factor (BAFF) Inhibitors to Precision Medicine. (PubMed, Cureus) - "This review synthesizes current evidence on evolving treatments, with a focus on A Proliferation-Inducing Ligand (APRIL) and B-cell Activating Factor (BAFF) (e.g., sibeprenlimab, atacicept, povetacicept, telitacicept), complement pathway modulators (e.g., iptacopan, cemdisiran, ravulizumab), and novel agents such as felzartamab and sparsentan. It also explores precision medicine strategies, including biomarker-guided therapy, individualized risk stratification, and combination regimens. Supported by high-quality recent clinical trial data and the latest kidney disease outcome guidelines, these innovations represent a paradigm shift toward personalized, disease-modifying treatment in IgAN, offering a new horizon for improved renal outcomes and long-term disease control."

Journal • Review • Chronic Kidney Disease • Glomerulonephritis • IgA Nephropathy • Nephrology • Renal Disease

Povetacicept for IgA Nephropathy and Primary Membranous Nephropathy. (PubMed, Kidney Int Rep) - "Similar results were observed in pMN. By inhibiting both BAFF and APRIL, povetacicept targets the underlying cause of disease and has potential to provide a significant therapeutic advancement for autoimmune glomerular diseases."

Journal • Glomerulonephritis • IgA Nephropathy • Immunology • Lupus Nephritis • Nephrology • Renal Disease

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 | Trial completion date: Sep 2028 ➔ Jan 2028 | Trial primary completion date: Sep 2028 ➔ Jan 2028

Trial completion date • Trial primary completion date • Glomerulonephritis • IgA Nephropathy • Renal Disease

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