HOUSTON — Atacicept, an investigational dual B-cell activating factor and a proliferation-inducing ligand (BAFF/APRIL) inhibitor, showed substantial reductions of proteinuria and benefits in other prespecified endpoints in patients with immunoglobulin A (IgA) nephropathy, according to the results of a new study.

“We found that for the majority of patients, atacicept controls proteinuria, and the safety profile is the same as placebo, without evidence of immunosuppression,” said first author Richard A. Lafayette, MD, of the Division of Nephrology at The University of British Columbia in Vancouver, British Columbia, Canada, who presented the findings here at Kidney Week 2025: American Society of Nephrology Annual Meeting.

These findings — published concurrently in The New England Journal of Medicine — “will support applications for accelerating approval and the idea that this drug can be given very long term, in a safe, well-tolerated, and effective way,” he added.

IgA nephropathy, the most commonly diagnosed primary glomerulopathy, is predominantly diagnosed in young adults, with as many as half of the patients progressing to kidney failure or death within 10-15 years from diagnosis, Lafayette told meeting attendees.

Existing therapies show some benefit in controlling the disease; however, treatments that can adequately slow the decline in estimated glomerular filtration rate (eGFR) and hence provide a disease-modifying effect in reducing the risk for kidney failure are lacking.

ORIGIN 3 Trial: 36-Week Results

Atacicept’s mechanism of inhibiting BAFF/APRIL is important in addressing IgA pathology, and in earlier phase 2 trials, the drug has shown significant, clinically meaningful improvements in various key measures of the disease with as much as a 96-week follow-up.

To further investigate the drug’s effects in the phase 3 setting, Lafayette and colleagues launched the ongoing multicenter ORIGIN 3 trial. In the current prespecified interim analysis, they reported on 36-week results of 203 patients with IgA nephropathy who were randomly assigned to treatment either with 150 mg atacicept, administered at home via a once-weekly subcutaneous injection (n = 106), or a placebo (n = 97).

The patients had a mean age of around 40 years; males made up 54% and 60% in the atacicept and placebo groups, respectively, and they were predominantly non-Hispanic or non-Latino.

At baseline, nearly all study participants were receiving a maximum labeled or maximum tolerated stable dose of a renin-angiotensin system inhibitor, and 53.2% of the patients (108 patients; 59 in the atacicept group and 49 in the placebo group) were receiving a stable dose of an SGLT2 inhibitor.

For the primary endpoint of percentage of change in the urinary protein-to-creatinine ratio from baseline to week 36, patients receiving atacicept had a reduction of 45.7% compared with 6.8% in the placebo group (P < .001), reflecting a significant reduction in proteinuria.

The decreases emerged as early as week 12, with the improvements sustained through week 36 and observed across prespecified subgroups.

Further analysis of secondary endpoints showed reductions from baseline in the galactose-deficient IgA1 level of 68.3% in the atacicept group and 2.9% in the placebo group at 36 weeks, with those declines observed as early as week 4.

“Reduced levels of galactose-deficient IgA, associated autoantibodies, and circulating immune complexes among participants treated with atacicept suggest that this therapy may help mitigate the glomerular injury that gives rise to hematuria,” the authors noted in the study.

Indeed, the results further showed that among 122 patients with hematuria, the condition resolved in 81% of those in the atacicept group vs only 20.7% in the placebo group.

“The decrease in the level of galactose-deficient IgA1 occurred very early in the trial, at 4 weeks, preceding the proteinuria reduction at 12 weeks, which supports the idea that treatment with atacicept early in the disease course of IgA nephropathy may result in downstream clinical benefits,” the authors explained.

The timing of improvement in both hematuria and proteinuria further suggests that atacicept may have anti-inflammatory activity similar to that of systemic glucocorticoids and complement inhibitors,” they noted.

Adverse events occurred in 59.3% of patients in the atacicept group and 50% in the placebo group, with most events being mild to moderate in both groups.

Chance to Avoid Dialysis?

Lafayette noted that atacicept’s effects on eGFR are still being analyzed in the ongoing blinded portion of the trial and will be reported when 2-year results are available.

He underscored that in the phase 2 trials, the highly favorable results with atacicept were observed despite patients losing approximately 10% of their kidney function per year, starting at 60%.

“These were patients facing imminent dialysis, with transplantation and its life-threatening complications,” he said.

“So if it can be shown that this [therapy] does get the eGFR progression to 1 mL/min/y or less [considered the normal rate of progression due to aging], then you’re talking about a lifetime without dialysis or the need for transplant for some of these patients,” he said.

Caveats include that “these are averages, and, of course, there is heterogeneity of response,” he noted.

“But that’s a tremendous impact, and for it to be well-tolerated and not have adverse events or a reduced quality of life, then this is a major ray of sunshine for patients.”

Getting to the Root Cause

Commenting on the study, Nirupama Ramkumar, MD, MPH, associate professor of internal medicine at the University of Utah Health in Salt Lake City, said the findings suggest an important new approach to IgA nephropathy that moves closer to disease-modifying potential compared with the current standards of care.

“I think the big difference is that atacicept is targeting the pathology at its source — the B cell, an immune cell responsible for generating the antigens as well as the antibodies that then deposit in the kidney to cause the disease,” Ramkumar told Medscape Medical News.

“So this is kind of trying to treat it at the root cause,” she explained.

“SGLT2 inhibitors and other commonly used drugs don’t actually affect the immune cell population; they don’t affect how much antibodies or antigens are produced, or levels such as galactose-deficient IgA1, so this would be one more [tool] in our armamentarium.”

However, “we don’t have long-term data to see what happens with the B-cell population,” Ramkumar cautioned.

And there may be other ways that the antigens and antibodies could be produced that we don’t yet know about, she said.

In addition to the promising efficacy and safety, the drug also offers the appealing benefit of its once-weekly administration.

Weekly injections, self-administered at home “would also make atacicept a lot easier than having to take a pill,” she said.

The study was supported by Vera Therapeutics. Lafayette reported consulting and other relationships with Alexion, BeiGene, Calliditas, Amgen, Chinook, Novartis, Roche, Travere, Omeros, Otsuka, and Vera Therapeutics. Ramkumar reported having no disclosures.