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

An Open-label Study of Povetacicept in Participants With Autoimmune Cytopenias (RUBY-4) (clinicaltrials.gov) - P1/2 | N=30 | Completed | Sponsor: Alpine Immune Sciences Inc, A Subsidiary of Vertex | Active, not recruiting ➔ Completed

Trial completion • Anemia • Autoimmune Hemolytic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Immune Thrombocytopenic Purpura • Immunology • Thrombocytopenia • Thrombocytopenic Purpura

Atacicept in IgA nephropathy. (PubMed, Expert Rev Clin Immunol) - "This is a very promising finding, and long-term results with atacicept, and a similarly promising BAFF and APRIL inhibitors, telitacicept and povetacicept in nephropathy are eagerly awaited. Of particular interest is whether long-term suppression of immunoglobulins with these inhibitors has adverse effects. Further trials will be needed to determine the respective roles of these inhibitors with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs) and/or sodium-glucose cotransporter 2 (SGLT 2) inhibitors in IgA nephropathy."

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

A Phase 3 Open-Label Study of Long-term Treatment With Povetacicept in Adults With Immunoglobulin A Nephropathy (clinicaltrials.gov) - P3 | N=605 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

New P3 trial • Glomerulonephritis • IgA Nephropathy • Renal Disease

GAMGERTAMIG (OM336), A NOVEL B CELL MATURATION ANTIGEN (BCMA) X CD3 T CELL ENGAGER ANTIBODY, AMELIORATES DISEASE IN PATIENTS WITH WARM OR COLD AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA) (EHA 2026) - P1 | "Baseline Demographics Patient # Diagnosis Age, years Sex Sex Prior medications for AIHA Medications for AIHA at enrolment Baseline Hb (g/dL) Gamgertamig regimen 1 CAD (PMHx of RA & CLL) 76 F Zanubrutinib (CLL), Rituximab, Darbepoietin, Adalimumab (RA), Methotrexate (RA) Zanubrutinib (CLL) 8.6 High dose 2 wAIHA 44 F Prednisolone, Rituximab, Mycophenolate, Povetacicept Prednisolone, Folic Acid 6.8 Mid dose 3 wAIHA 71 M Prednisolone, Rituximab, Mycophenolate Prednisolone, Mycophenolate 9.9 High dose Results Administration of gamgertamig has been completed in two patients. Preliminary efficacy data suggest improvements in anemia and biomarkers of hemolysis following a short course of gamgertamig; short-term safety and PK were favorable. These data warrant additional clinical investigation, with longer-term follow-up to assess the durability of response."

Clinical • IO biomarker • Anemia • Autoimmune Hemolytic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Immunology • Infectious Disease • Inflammation • HP

Vertex Announces US FDA Acceptance of Biologics License Application for Accelerated Approval of Povetacicept in IgA nephropathy (Vertex Press Release) - "The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of November 30, 2026....The RAINIER trial met its primary objective..."

FDA filing • PDUFA • IgA Nephropathy

VX25-AIS-301: A Phase 2 Study to Evaluate Povetacicept in Adults With Generalized Myasthenia Gravis (clinicaltrialsregister.eu) - P1/2 | N=5 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Inc.

New P1/2 trial • CNS Disorders • Myasthenia Gravis

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 | N=181 ➔ 605

Enrollment change • Glomerulonephritis • IgA Nephropathy • Renal Disease

ETNA: A Phase 2 Study to Evaluate Povetacicept in Adults With Generalized Myasthenia Gravis (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Myasthenia Gravis

ETNA: A Phase 2 Study to Evaluate Povetacicept in Adults With Generalized Myasthenia Gravis (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

New P2 trial • CNS Disorders • Myasthenia Gravis

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