Atacicept for IgA nephropathy succeeds in phase III trial

Treatment with the self-administered atacicept injectable yields a significant reduction in proteinuria in patients with IgA nephropathy, according to interim data from the phase III ORIGIN 3 trial.

At week 36, the 24-h urinary protein-to-creatinine ratio decreased by 45.7 percent with atacicept vs only 6.8 percent with placebo (mean between-group difference, 41.8 percentage points, 95 percent confidence interval [CI], 28.9–52.3; p<0.001). [N Engl J Med 2025;doi:10.1056/NEJMoa2510198]

“Proteinuria appeared to decrease as early as week 12, with apparent sustained improvement through week 36 in the atacicept group,” the authors noted.

Secondary endpoints

Analyses of secondary endpoints showed improvements in other markers of disease activity favouring atacicept.

Galactose-deficient IgA1 levels dropped by 68.3 percent in the atacicept arm and by 2.9 percent in the placebo arm, while urinary albumin-to-creatinine ratio decreased by 47.3 percent and 8.8 percent, respectively. Among patients with haematuria at baseline, the condition resolved in 81 percent of those who received atacicept and 20.7 percent of those who received placebo.

“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. [This] supports the idea that treatment with atacicept early in the disease course of IgA nephropathy may result in downstream clinical benefits,” the authors said.

Safety profile

As for safety, adverse events (AEs) were documented in 59.3 percent of patients in the atacicept arm and in 50 percent in the placebo group. Most AEs were mild or moderate in severity. The most common AEs were injection-site reaction (19.2 percent vs 1.9 percent), upper respiratory tract infection (12.1 percent vs 8.9 percent), nasopharyngitis (7.9 percent vs 6.1 percent), and injection-site erythema (5.6 percent vs 0.5 percent).

Serious AEs occurred in 0.5 percent of patients in the atacicept arm and 5.1 percent in the placebo arm. There were no deaths recorded.

“The safety profile of atacicept observed in this trial was consistent with the results of previous trials of atacicept in patients with IgA nephropathy,” the authors said.

ORIGIN 3 population

The interim analysis included 203 adult patients with biopsy-confirmed IgA nephropathy confirmed by biopsy. They also had an UPCR of at least 1.0 or proteinuria, an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m², treatment with a stable RAS inhibitor at the maximum labelled or tolerated dose for at least 12 weeks, and a blood pressure of 150/90 mm Hg or lower.

The patients were randomly assigned to receive atacicept at a dose of 150 mg once weekly (n=106; mean age 40.1 years, 54 percent male, 56 percent Asian) or matching placebo (n=97; mean age 40.9 years, 58 percent male, 54 percent Asian). Treatment was administered subcutaneously by patients at home.

At baseline, 99.5 percent of the patients overall were receiving a maximum labelled or maximum tolerated stable dose of an RAS inhibitor, and 53.2 percent were on a stable dose of an SGLT2 inhibitor.

“In the ORIGIN 3 trial, the participants were representative of the general population of patients with IgA nephropathy and persistent proteinuria despite appropriate standard care, including treatment with RAS inhibitors and, in many cases, SGLT2 inhibitors. Such patients are considered to be at high risk for progressive loss of kidney function and kidney failure, despite the available treatment options,” according to the authors.

The findings of ORIGIN 3 confirm those of the phase IIb trial, which had a similar patient population and used the same atacicept dose and regimen. [Kidney Int 2024;105:1306-1315]

“The consistency of these findings in both trials suggests that dual BAFF and APRIL inhibition with atacicept may modify the disease course, presumably by targeting the underlying pathophysiology of IgA nephropathy,” they said.

ORIGIN 3 was presented at the opening plenary session of the annual ASN meeting by first author Dr Richard Lafayette from Stanford University, Stanford, California, US.