atacicept (VT-001) / EMD Serono, Vera Therap - LARVOL DELTA

UNDERSTANDING DRIVERS OF LUPUS PATHOGENESIS THROUGH COMPARISON OF PRECLINICAL MODELS (EULAR 2025) - "B cell/plasma cell depletion by overexpressing TACI-Ig by HDD to bind and sequester BAFF and APRIL in the C9orf72-deficient lupus model reversed lupus-associated phenotypes... Here we describe two models of SLE-like disease that respond differently to manipulation of two of the pathways targeted by existing approved therapeutics. Taken together, these data suggest that NZB/W and C9orf72 -/- mice can recapitulate distinct disease mechanisms relevant in human lupus patients and can be used in preclinical efforts to validate therapeutic strategies to target a heterogeneous SLE patient population."

Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Renal Disease • Systemic Lupus Erythematosus

Upregulation of pro-survival receptors on antibody-secreting cells is linked to worse disease characteristics across SLE, Scleroderma and Sjögrens disease and offers potential new treatment angles (EULAR 2025) - "Given the divers disease manifestations in SLE, SSc and SjD, specific disease features in all three sARDs were investigated in the context of the blood ASC phenotypes. When engaged by the ligands CD80 or CD86, CD28 facilitates pro-survival signaling. Similarly, binding of the cytokines APRIL or BAFF to the ASC-specific receptors TACI and BCMA also induces pro-survival signals."

IO biomarker • Immunology • Inflammatory Arthritis • Lupus • Scleroderma • Sjogren's Syndrome • Systemic Lupus Erythematosus • Systemic Sclerosis • BCL2 • CD19 • CD20 • CD27 • CD28 • CD44 • CD80 • CD86 • CXCR3 • ITGA4 • MCL1 • NCAM1 • PRDM1 • SDC1

Atacicept in Subjects With Active Lupus Nephritis (COMPASS) (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: Vera Therapeutics, Inc. | N=360 ➔ 0 | Suspended ➔ Withdrawn

Enrollment change • Trial withdrawal • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology

ORIGIN Extend: A Long-Term Extension Study of Atacicept in IgA Nephropathy (ERA 2025) - "The ORIGIN Extend study will provide patients with extended access to atacicept prior to commercial availability in their country or region, capture longer-term data for research purposes, and generate data from reinitiation of atacicept treatment following an off-treatment period."

Glomerulonephritis • IgA Nephropathy • Renal Disease

ORIGIN 2b: Changes in Gd-IgA1 and eGFR After Discontinuation of Atacicept Treatment in IgA Nephropathy (ERA 2025) - "IgAN is a chronic and progressive disease of B-cell origin, in which cytokines BAFF and APRIL are sustaining factors in its pathophysiology. Treatment with atacicept, a precision B-cell modulator inhibiting both BAFF and APRIL, demonstrated significant and sustained reductions in Gd-IgA1, improvements in hematuria, and reductions in UPCR, along with stabilization of eGFR over 96 wk. Following discontinuation of atacicept, an increase in Gd-IgA1 and decline in eGFR were observed, consistent with the typical clinical progression of IgAN in high-risk patients despite standard-of-care treatments."

Glomerulonephritis • Hematological Disorders • IgA Nephropathy • Lupus Nephritis • Renal Disease

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

Atacicept in Multiple Glomerular Diseases (clinicaltrials.gov) - P2 | N=200 | Not yet recruiting | Sponsor: Vera Therapeutics, Inc.

New P2 trial • Focal Segmental Glomerulosclerosis • Glomerulonephritis • IgA Nephropathy • Immunology • Nephrology • Renal Disease

ORIGIN 3 Study Design: A Global, Randomized, Controlled, Phase 3 Study of Atacicept in IgA Nephropathy (ERA 2025) - "This pivotal Phase 3 study has a consistent design, patient population and atacicept dose and subcutaneous formulation with that of the completed ORIGIN Phase 2b study, which demonstrated the efficacy of atacicept in reducing Gd-IgA1, improving hematuria, reducing proteinuria, and stabilizing eGFR. This Phase 3 study will further evaluate atacicept's disease- modifying potential as a treatment for IgAN."

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

ORIGIN: Atacicept in Subjects With IgA Nephropathy (clinicaltrials.gov) - P3 | N=376 | Active, not recruiting | Sponsor: Vera Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Glomerulonephritis • IgA Nephropathy • Renal Disease

ORIGIN EXTEND: A Rollover Study to Evaluate the Long-Term Safety and Efficacy of Atacicept (clinicaltrials.gov) - P2 | N=476 | Enrolling by invitation | Sponsor: Vera Therapeutics, Inc. | Recruiting ➔ Enrolling by invitation

Enrollment status • Glomerulonephritis • IgA Nephropathy • Renal Disease • CST3

Vera Therapeutics Completes Full Enrollment in Pivotal ORIGIN Phase 3 Trial for Atacicept in IgAN (GlobeNewswire) - "Vera Therapeutics, Inc...announced that it has completed full enrollment in the pivotal ORIGIN Phase 3 trial of atacicept in patients with IgA Nephropathy (IgAN)....The ORIGIN 3 trial (NCT04716231) is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the safety and efficacy of atacicept in patients with IgAN who have persistent proteinuria and remain at high risk of disease progression. Participants are randomized 1:1 to at-home self-administered once-weekly subcutaneous injections of atacicept 150 mg or placebo for a 104-week double-blind period, followed by a 52-week open-label extension."

Enrollment closed • IgA Nephropathy

Vera Therapeutics Provides Business Update and Reports Fourth Quarter and Full Year 2024 Financial Results (GlobeNewswire) - "Planned updates from the ongoing pivotal ORIGIN 3 trial: Anticipate full enrollment in 2Q 2025; On track to announce the primary endpoint result in 2Q 2025; Plan to submit a BLA to the U.S. FDA in 2H 2025 for atacicept in IgAN for accelerated approval assuming supportive data; and would expect a PDUFA date and commercial launch in 2026; QM dose finding study initiating in 2025 to evaluate extended dosing; Plan to initiate the PIONEER trial in 2025, which would evaluate atacicept in expanded IgAN populations and anti-PLA2R positive PMN and anti-nephrin positive FSGS and MCD."

Enrollment status • FDA approval • FDA filing • Launch US • New trial • P3 data: top line • IgA Nephropathy

Long-term Results from the ORIGIN Phase 2b Study of Atacicept for the Treatment of IgAN (ISN-WCN 2025) - "Baba M. PLoS One 2015. This abstract was also submitted for the ASN Kidney Week 2024 congress."

P2b data • Glomerulonephritis • IgA Nephropathy

ORIGIN Extend: A Long-Term Extension Study of Atacicept in IgAN (ISN-WCN 2025) - "Conclusions The ORIGIN Extend study will enable continued access to atacicept for participants of a parent study and provide extended long-term data on the disease-modifying potential of atacicept in IgAN. This abstract was also presented at the ASN Kidney Week 2024 congress."

Glomerulonephritis • IgA Nephropathy

TACI Ig Fusion Protein Inhibits TLR4/MyD88/NF-κB Pathway Alleviates Renal Injury in IgA Nephropathy Rats. (PubMed, Iran J Kidney Dis) - "TACI-Ig mitigates renal injury in IgAN rats by reducing inflammatory infiltration and IgA deposition and suppressing the pathway of TLR4/MyD88/NF-κB, offering data for developing effective treatments for IgAN."

Journal • Preclinical • Fibrosis • Glomerulonephritis • IgA Nephropathy • Immunology • Renal Disease • MYD88 • TLR4

ORIGIN EXTEND: A Rollover Study to Evaluate the Long-Term Safety and Efficacy of Atacicept (clinicaltrials.gov) - P2 | N=476 | Recruiting | Sponsor: Vera Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Glomerulonephritis • IgA Nephropathy • Renal Disease

Imbalanced Expression of TACI Isoforms Regulated By TNFRSF13B Variants Promotes the Progression of Epstein-Barr Virus-Associated Lymphoproliferative Diseases (ASH 2024) - "For patients who carry the gain-of-function germline mutations of TNFRSF13B, the inhibitory TACI-Ig or the TACI ligands BAFF and APRIL may efficiently prevent the serious progression of their EBV infection. Screening for possibly pathogenic variants, especially in the TNF-TNFR superfamily genes in EBV-LPD patients is necessary and valuable for understanding the pathogenesis of EBV-LPDs and optimizing the therapeutic regimen."

Epstein-Barr Virus Infections • Infectious Disease • Oncology • TNFA • TNFRSF13B • TUSC3 • UNC13D

Comparative Efficacy and Safety of New Therapies for IgA Nephropathy: A Systematic Review and Network Meta-Analysis (KIDNEY WEEK 2024) - "This systematic review and network meta-analysis indicate Mycophenolate and Telitacicept are most effective in reducing UPCR and improving eGFR, suggesting these as preferable treatments for IgAN patients."

Retrospective data • Review • Glomerulonephritis • IgA Nephropathy • Renal Disease

ORIGIN EXTEND: A Rollover Study to Evaluate the Long-Term Safety and Efficacy of Atacicept (clinicaltrials.gov) - P2 | N=476 | Not yet recruiting | Sponsor: Vera Therapeutics, Inc.

New P2 trial • Glomerulonephritis • IgA Nephropathy • Renal Disease

Long-Term Results from the ORIGIN Phase 2b Study of Atacicept for the Treatment of IgA Nephropathy (IgAN) (KIDNEY WEEK 2024) - "Gd-IgA1, hematuria, and UPCR reductions with eGFR stabilization through 96 weeks demonstrate that atacicept offers a potentially safe, long-term, disease-modifying treatment for IgAN. Specifically, the conversion of an eGFR profile in patients with IgAN from one of steady decline to one representative of the general population without kidney disease1 supports the potential of atacicept to decrease the high lifetime risk of kidney failure in patients with IgAN."

Late-breaking abstract • P2b data • Glomerulonephritis • IgA Nephropathy • Renal Disease

ORIGIN Extend: A Rollover Extension Study to Continue to Evaluate the Long-Term Safety and Efficacy of Atacicept (KIDNEY WEEK 2024) - "The ORIGIN Extend study will enable continued access for participants of a parent study and provide extended long-term data for atacicept in IgAN.1Kwon CS. J Health Econ Outcomes Res 20212Pitcher D. Clin J Am Soc Nephrol 20233Lafayette R. Nephrol Dial Transplant 2024; abstr 812"

Clinical • Glomerulonephritis • IgA Nephropathy • Nephrology • Renal Disease

ORIGIN 3: Pivotal Ph3 Study Evaluating Effect of Atacicept vs. Placebo on Proteinuria and Kidney Function Preservation in IgAN (KIDNEY WEEK 2024) - "The key secondary endpoint is eGFR change from baseline at 104wk.This pivotal Ph3 study will further evaluate atacicept's disease-modifying potential as a treatment for IgAN.1Kwon CS. J Health Econ Outcomes Res 20212Pitcher D. Clin J Am Soc Nephrol 20233Lafayette R. Nephrol Dial Transplant 2024; abstr 812"

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

Complement and B Cell Modifying Pipeline to Address Unmet Needs in IgA Nephropathy (IgAN) (KIDNEY WEEK 2024) - "In upcoming years, new products will likely be available that will further help physicians address IgAN at the pathogenic level. Data from 454 audited patient charts were collected in partnership with 142 US nephrologists in January 2024 and in partnership with an additional 105 US nephrologists in February 2024 via online surveys. With the approvals of delayed-release oral budesonide and sparsentan in IgAN, most nephrologists (80%) indicate that they feel better equipped to treat their IgAN patients. Nephrologists continue to see an unmet need in the IgAN space, leaving room for new market entrants to effectively treat the root cause of the disease and further enable physicians to individualize treatments."

Glomerulonephritis • IgA Nephropathy • Inflammation • Renal Disease • CFB

Long-Term Results from an Open-Label Extension Study of Atacicept for the Treatment of IgA Nephropathy. (PubMed, J Am Soc Nephrol) - No abstract available

Journal • Glomerulonephritis • IgA Nephropathy • Renal Disease

Current status of BAFF targeting immunotherapy in B-cell neoplasm. (PubMed, Int J Clin Oncol) - "Therefore, BAFF-targeted therapies, such as belimumab, atacicept, and tabalumab, are being explored in clinical trials for conditions like chronic lymphocytic leukemia (CLL) and multiple myeloma. Belimumab, an anti-BAFF monoclonal antibody, is being investigated in combination with rituximab/venetoclax for CLL...The review emphasizes the importance of understanding the roles of BAFF and its receptors in the microenvironment of hematologic malignancies. Targeting BAFF and its receptors presents potential therapeutic avenues, and ongoing clinical trials provide valuable insights."

IO biomarker • Journal • Review • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Multiple Myeloma • Oncology