Atacicept significantly reduced proteinuria in patients with IgA nephropathy, phase 3 data show
Presenter: Richard A. Lafayette, MD, Stanford University Medical Center, Stanford, CA
ORIGIN 3: A phase 3 trial of atacicept in IgAN. Abstract TH-OR083. Presented November 6, 2025.
In patients with immunoglobulin A (IgA) nephropathy, treatment with the investigational B-cell targeted recombinant fusion protein atacicept significantly reduced proteinuria in a 36-week interim analysis of a randomized, placebo-controlled, phase 3 trial presented at American Society of Nephrology Kidney Week 2025.
Treatment with atacicept also significantly reduced hematuria and galactose-deficient IgA1 compared with placebo, with a favorable safety profile, according to primary investigator Richard A. Lafayette, MD, of Stanford University Medical Center.
Together, these results demonstrate the potential of atacicept as a targeted, disease-modifying therapy to address the underlying pathophysiology of IgA nephropathy, Dr. Lafayette, said in a late-breaking oral presentation at the meeting’s opening plenary session.
“These results build on earlier studies with similar findings, and suggest that atacicept may preserve kidney function in patients with IgA nephropathy to a similar degree as in other individuals,” Dr. Lafayette said.
IgA nephropathy is the most common primary glomerulopathy worldwide, Dr. Lafayette and co-authors wrote in a report on the study, known as ORIGIN 3, which was published simultaneously in the New England Journal of Medicine.
The disease, a B-cell–mediated glomerulonephritis, is characterized by accumulation of IgA-containing immune complexes, leading to kidney failure or death in 50% or more of patients within 10 to 20 years of diagnosis.
Atacicept inhibits two key immunoregulatory cytokines, known as B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), considered very important to the pathophysiology of the disease.
The prespecified interim analysis of ORIGIN 3 included 203 patients with IgA nephropathy randomized to atacicept 150 mg self-administered subcutaneously once weekly, or placebo.
The primary endpoint was the change from baseline to week 36 in the 24-hour urinary protein-to-creatinine ratio.
At week 36, the percentage reduction in the urinary protein-to-creatinine ratio was 45.7% with atacicept and 6.8% for placebo, a between-group difference of 41.8 percentage points (P < .001), Dr. Lafayette reported.
At the same time point, galactose-deficient IgA1 levels decreased by 68.3% with atacicept and 2.9% with placebo, with reductions evident as early as week 4. Hematuria resolved in 81.0% of the atacicept group and 20.7% of the placebo group.
Adverse events were mostly mild, occurring in 59.3% of atacicept-treated patients and in 50.0% of placebo-treated patients, according to the safety analysis.
According to Dr. Lafayette, ORIGIN 3 is the first phase 3 clinical trial of a B-cell modulator to show concurrent improvements in proteinuria, galactose-deficient IgA1, and hematuria in patients with IgA nephropathy.
Full 2-year results from the ongoing study are awaited and will provide longer-term safety and efficacy data for atacicept in IgA nephropathy, said Dr. Lafayette.
Disclosures
Richard A. Lafayette, MD, and co-authors reported commercial support from Vera Therapeutics, Inc.
References
Brenner RM, Campbell KN, Doan T, et al. ORIGIN 3: a phase 3 trial of atacicept in IgAN [abstract]. Presented at: American Society of Nephrology Kidney Week 2025; November 6–9, 2025; Houston, TX.
Lafayette R, Barbour SJ, Brenner RM, et al. A phase 3 trial of atacicept in patients with IgA nephropathy. N Engl J Med. Published online November 6, 2025. doi:10.1056/NEJMoa2510198