Atacicept Achieves Breakthrough Phase 3 Results in Immunoglobulin A Nephropathy with Favorable Safety and Disease-Modifying Potential

Vera Therapeutics recently announced highly positive results from its Phase 3 ORIGIN trial evaluating atacicept in patients with immunoglobulin A nephropathy (IgAN), a leading cause of kidney disease. These results were unveiled as a late-breaking oral presentation at ASN Kidney Week 2025 and simultaneously published in the prestigious New England Journal of Medicine (NEJM), marking a major milestone in IgAN treatment development.

Atacicept is a recombinant fusion protein developed initially by ZymoGenetics and later advanced by Merck Serono and Vera Therapeutics. It works by simultaneously inhibiting two key cytokines, B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL), which is crucial for B-cell maturation, activation, and survival. By blocking these targets via the TACI receptor, atacicept reduces the proliferation of mature B cells and plasma cells that produce harmful autoantibodies implicated in autoimmune diseases such as IgA nephropathy (IgAN). This dual inhibition mechanism differentiates atacicept from agents that block only BAFF, like belimumab, potentially offering broader immunomodulation.

Clinical Evidence

The ORIGIN Phase 3 trial (NCT04716231) investigated the efficacy and safety of atacicept, a biologic that modulates B-cell function through dual inhibition of BAFF and APRIL, targeting the underlying pathophysiology of IgAN. The primary endpoint was the change in proteinuria, assessed by the 24-hour urine protein-to-creatinine ratio (UPCR) at week 36. Participants treated with atacicept achieved a remarkable 46% reduction in proteinuria from baseline and a 42% reduction compared to placebo (p<0.0001), demonstrating both statistical significance and clinical relevance. This proteinuria reduction was consistent across key subgroups defined by age, sex, race, baseline kidney function, and concurrent SGLT2 inhibitor use.

Secondary Endpoints and Biomarker Effects

Atacicept also improved important secondary outcomes, including a 68% reduction in galactose-deficient IgA1 (Gd-IgA1), a pathogenic antibody linked to disease progression, and resolution of hematuria in 81% of patients who had blood in their urine at baseline. These biological and clinical improvements highlight atacicept’s disease-modifying potential.

 Safety Profile

Safety data from the ORIGIN trial program were favorable, with adverse event rates comparable to placebo. The incidence of serious adverse events was lower in the atacicept group (0.5%) than in placebo (5%), and no deaths or significant immunosuppression signals were observed. This supports a well-tolerated safety profile for atacicept in this patient population.

Regulatory Submission

Vera Therapeutics is preparing to submit a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) under the Accelerated Approval Program, aiming for a potential approval and U.S. commercial launch of atacicept in 2026. The continued ORIGIN 3 extension study will provide critical two-year outcome data expected in 2027.

Key Opinions

Dr. Richard Lafayette, lead investigator, stated that the ORIGIN 3 trial is the first Phase 3 study of a B-cell modulator in IgAN to show improvements in proteinuria, pathogenic antibodies, and hematuria, indicating that atacicept may modify the disease course by targeting its root causes. He anticipates full two-year results. Marshall Fordyce, CEO of Vera Therapeutics, expressed gratitude to everyone involved, highlighted plans to submit for FDA approval, and projected a potential U.S. launch of atacicept in 2026 as the first dual BAFF/APRIL inhibitor to advance IgAN treatment. Bonnie Schneider from the IgA Nephropathy Foundation emphasized the long wait for effective therapies and welcomed atacicept’s potential to improve patient outcomes and quality of life.

About Immunoglobulin A nephropathy

Immunoglobulin A nephropathy (IgAN), also known as Berger’s disease, is a kidney disorder characterized by the buildup of IgA antibodies in the glomeruli, the small filtering units of the kidneys. This accumulation causes inflammation and damage that can lead to blood and protein leakage into the urine, impaired kidney function, and potentially kidney failure over time. Symptoms can include blood in the urine, foamy urine due to protein, swelling in the hands and feet, and high blood pressure. IgAN is considered an autoimmune disease and is one of the most common causes of chronic kidney disease worldwide.