DENVER — New data from a trio of phase 3 trials showed unprecedented benefits of three drugs — atacicept, telitacicept, and sibeprenlimab — in stabilizing kidney function and preventing disease progression of immunoglobulin A (IgA) nephropathy, with effect sizes well exceeding those of existing therapies.

The common mechanism the three drugs share is inhibition of a proliferation-inducing ligand (APRIL), with atacicept and telitacicept having dual inhibition by also targeting the Blymphocyte stimulator (or B-cell activating factor, BAFF).

"The important, consistent message is when we inhibit or modulate B cells, we are hitting at the heart of IgA nephropathy disease pathogenesis," said Dana V. Rizk, MD, of the Division of Nephrology, Department of Medicine, Heersink School of Medicine at the University of Alabama at Birmingham, in discussing the results on sibeprenlimab at a press briefing at Kidney Week 2026: American Society of Nephrology Annual Meeting.

"We're seeing consistently significant proteinuria reduction, stabilization of estimated glomerular filtration rate (eGFR), and a good safety profile," she said. "This is great news for the medical community." 

IgA nephropathy, the most common primary glomerular disease, typically diagnosed in young adulthood, is characterized by a high risk of disease progression to kidney failure.

Recommended therapies such as SGLT2 inhibitors and renin-angiotensin-aldosterone system (RAAS) inhibitors may slow disease progression, but they commonly fail to prevent patients from progressing to kidney failure.

Underscoring the high anticipation of much-needed tools to transform care for IgA nephropathy, the latest results were spotlighted at the meeting's presidential plenary session.

VISIONARY Trial: Sibeprenlimab 

The results regarding sibeprenlimab are from the phase 3, double-blind, placebo-controlled VISIONARY trial, which enrolled 510 adults with IgA nephropathy. 

Patients were randomized 1:1 to sibeprenlimab 400 mg or placebo subcutaneously every 4 weeks. About 98% of patients had a background regimen of RAAS inhibitors, and about 45% used SGLT2 inhibitors.

In a previously reported prespecified interim analysis, the trial's primary endpoint of 24-hour urinary protein-to-creatinine ratio (UPCR) at 9 months vs baseline was significantly reduced with sibeprenlimab, with a placebo-adjusted reduction at 9 months of 51.2% (P < .001). 

Those data resulted in an accelerated FDA approval of sibeprenlimab for adults with primary IgA nephropathy who are at risk for disease progression.

At the session, Rizk described 24-month secondary outcomes with sibeprenlimab on eGFR and a composite kidney endpoint of kidney function decline and kidney failure. The updated trial results were published this week in the New England Journal of Medicine (NEJM).

The findings showed the annualized eGFR slope over 24 months was 0.3 mL/min/1.73 m²per year with sibeprenlimab vs -4.2 for placebo, for a between-group difference of 4.5 mL/min/1.73 m² per year (P < .0001). 

Only one patient (0.4%) in the sibeprenlimab group progressed to at least one composite kidney outcome event over the 24 months vs 28 (11.2%) in the placebo group, corresponding to a 97.1% risk reduction with sibeprenlimab (adjusted difference -10.8 percentage points; hazard ratio [HR], 0.029; P < .001) — a striking finding prompting an outbreak of applause from the audience of nephrologists.

Adverse events were similar between the treatment and placebo groups. 

"By achieving the 2025 KDIGO eGFR preservation target [< 1 mL/min/1.73 m² per year], reducing the risk of progression to kidney function loss and kidney failure, sibeprenlimab has the potential for disease-modification and long-term kidney protection in IgA," Rizk concluded.

ORIGIN-3 Trial: Atacicept 

The ORIGIN-3trial included 428 patients with biopsy-confirmed IgA nephropathy and substantial disease burden who were randomized 1:1 (n = 214 per group) to treatment with atacicept 150 mg or placebo as once-weekly self-administered injections. 

At baseline, 61% of patients in the two groups reported use of SGLT2 inhibitors, and their mean eGFR was 64 mL/min/1.73 m².

In a previous interim analysis presented at Kidney Week 2025 and published in the NEJM, the drug was associated with a 45.7% reduction of proteinuria (UPCR) from baseline to 36 weeks compared with just 6.8% with placebo. 

In response to those findings, the FDA granted an accelerated approval of the drug.

The current final efficacy analysis of the trial was presented here in Denver by Jonathan Barratt, PhD, University of Leicester, England, and simultaneously published in NEJM. 

Among key findings were a significantly greater mean change in eGFR at week 52 with atacicept compared with placebo (-0.11 vs -5.69 mL/min/1.73 m²), with a mean difference of 5.58 mL/min/1.73 m² (P < .001). 

Through week 104, the mean annualized eGFR slope of atacicept and placebo, respectively, were -0.60 and -5.60 mL/min/1.73 m², for a difference of 5.00 mL/min/1.73 m²per year (P < .001).

The endpoint of composite kidney disease progression over the 104 weeks occurred in 11 patients (5.1%) in the atacicept group vs 38 patients (17.8%) in the placebo group, representing a 76% risk reduction (HR, 0.24; P < .001).

For context, Barratt noted that landmark trials of chronic kidney disease therapy have reported risk reductions in composite kidney outcomes in the range of 16%-55%.

Further significant reductions in UPCR, galactose-deficient IgA1, and hematuria were all seen with atacicept through 104 weeks (all P < .0001).

No patients in the atacicept group progressed to requirement of dialysis, transplantation, or death, compared with seven patients in the placebo group. 

"ORIGIN 3 met all prespecified endpoints, including placebo-adjusted eGFR and composite kidney disease progression benefits," said Barratt.

The drug was well tolerated, with a favorable safety profile. Adverse events were similar between the groups, occurring in 74.8% of atacicept patients and 78.0% in the placebo group. Rates of infection were also similar, at 51.4% and 52.3%, respectively.

Consideration of Placebo Risks 

Barratt noted that in consideration of the clear challenges and risks of subjecting patients to prolonged placebo-control group enrollment, efforts were underway to convert patients in the placebo group who reached 52 weeks to switch to counteractive treatment with atacicept.

"We as a steering committee felt very uncomfortable demanding that patients stay in a placebo group for 2 years," he said.

TELIGAN Trial: Telitacicept 

Results were also presented from the phase 3 TELIGAN trial by Jicheng Lv, MD, of the Renal Division at Peking University First Hospital, Beijing.

For that trial, 318 patients with IgA nephropathy in China were randomized 1:1 (159 patients per group) to treatment either with telitacicept 240 mg or placebo subcutaneously once weekly through week 39, followed by a maintenance regimen of 240 mg every 2 weeks through week 104.

At baseline, about 35% in each group reported use of SGLT2 inhibitors, and their mean eGFR was 76.53 mL/min/1.73 m² with telitacicept and 74.43 mL/min/1.73 m² with placebo.

For the primary outcome of the eGFR slope over 104 weeks, the rates were -0.6 vs -5.7 mL/min/1.73 m² per year in the telitacicept and placebo groups, respectively, for a between-group difference of 5.1 mL/min/1.73 m² per year (P < .001). 

Significantly fewer patients treated with telitacicept experienced a decline in eGFR of 30% or more, compared with placebo (2.5% vs 16.4%, respectively; HR, 0.11) and the rate of those with a decline in eGFR of 40% or more was also lower with telitacicept (2.5% vs 9.4%; HR, 0.19). 

There were no reports of composite kidney failure events with telitacicept vs 3.1% with placebo. 

As with the other two drugs, the long-term safety profile with telitacicept was favorable, with adverse events occurring in 95.0% with telitacicept vs 89.3% with placebo. Rates of serious adverse events were 8.2% vs 18.2%, respectively.

Serious infections occurred in 1.9% vs 4.4% of patients, and overall infection rates were 67.3% in each group. No deaths occurred.

"Telitacicept stabilized eGFR decline over 104 weeks [and] sustained proteinuria remission," Lv said, noting that "a full dose induction and low-dose maintenance therapy is reasonable." 

Findings Could Be 'Game-Changing' 

Commenting on the research, Nirupama Ramkumar, MD, MPH, an associate professor of internal medicine at the University of Utah Health in Salt Lake City, echoed that considering the much lower reductions of 25%-30% in IgA nephropathy seen with standard therapies (as observed in the placebo groups), the current findings are "very, very exciting." 

In terms of caveats, Ramkumar, who was co-moderator of the Kidney Week press briefing, noted that a key question is how patients with more advanced disease will fare. 

In general, "these were fairly healthy patients, with eGFR of around 65, so the big question is whether the effects will still be seen and persistent if the eGFR is below 40 or 30," she told Medscape Medical News. 

"If the effects are consistent, that would really be game-changing," she said. 

Keisha Gibson, MD, MPH, Kidney Week Education Committee co-chair and a professor of pediatrics and chief of pediatric nephrology at the UNC Kidney Center, in Chapel Hill, added that another caveat — as with any B cell-modulating therapies — is a need to be aware of a higher risk of infection. 

"Prior to treatment with these therapies, vaccination status should be confirmed and any live vaccines not previously provided [should be given] before B-cell depletion and avoided during depletion," Gibson told Medscape Medical News.

However, she agreed that the findings are encouraging.

"Clinicians can look at the results of these trials and feel assured that we have another class of therapy to offer patients," she said. 

These medications "have a real opportunity to reduce what used to be a 50% risk of progression to end-stage kidney disease in a disease that impacts so many around the globe," she added.

The ORIGIN trial was funded by Vera Therapeutics. The TELIGAN trial was funded by RemeGen Co., Ltd. The VISIONARY trial was funded by Otsuka Pharmaceutical Development and Commercialization. The study authors' disclosures are detailed in the published studies. Ramkumar and Gibson had no disclosures to report.