- Eptacopan significantly slowed the decline in kidney function over 24 months compared with placebo in adults with IgA nephropathy.
- The complement inhibitor was granted accelerated approval in 2024; Continued approval was dependent on demonstrating slow renal decline.
- Fewer participants in the iptacopan group reached the composite kidney-failure endpoint.
Eptecopan (Fabhalta) slowed the decline in kidney function in adults with immunoglobulin A (IgA) nephropathy, according to final data from the Phase III APPLIANCE-IgAN study.
The study met its primary endpoint, showing an annualized total eGFR slope of -3.10 mL/min/1.73 m.2 with eptacopan vs. -6.12 mL/min/1.73 m2 with placebo over a 24-month period (adjusted). P<0.001), according to Jonathan Barrett, PhD, of the University of Leicester in England, and his colleagues.
“The effects…appear to be consistent across all predefined subgroups, with a finding that eptacopan can reduce the rate of kidney-function decline in a wide range of patients with IgA nephropathy,” they wrote. New England Journal of Medicine.
The findings were presented together ISN World Congress of Nephrology In Japan.
A composite kidney-failure endpoint – including a sustained decline in eGFR of ≥30%, a sustained eGFR of <15 mL/min/1.73 m.2Initiation of maintenance dialysis, receipt of a kidney transplant, or death from kidney failure – also occurred less frequently in the eptacopan group (21.4% vs 33.5%; HR 0.57, 95% CI 0.40–0.81, adjusted P=0.003).
The results are based on 9-month interim findings, which supported accelerated approval of a first-in-class complement inhibitor in 2024. The drug also has indications for paroxysmal nocturnal hemoglobinuria and complement 3 glomerulopathy.
An interim analysis reported a 38.3% reduction in 24-hour urine protein-to-creatinine ratio (UPCR) compared to placebo, but continued FDA approval was contingent on demonstrating slower renal decline.
IgA nephropathy, also known as Berger’s disease, is caused by a buildup of IgA in the glomeruli that prevents normal filtering, leading to proteinuria and possible kidney failure in 50% of patients within 20 years. It is one of the most common autoimmune kidney diseases.
“Traditionally, treatment has focused on lifestyle modifications, blood pressure control, and antiproteinuric agents aimed at reducing glomerular hyperfiltration,” the researchers wrote. “However, a greater understanding of the pathophysiological features of IgA nephropathy has supported the development of treatments that target the underlying pathobiological mechanisms.”
The therapeutic landscape for IgA nephropathy has recently expanded rapidly, to include the monoclonal antibody sibeprenlimab (Vioxact), the endothelin A receptor antagonist atrasentan (Vanrafia), the endothelin and angiotensin II receptor antagonist sparsentan (Filsparri), and the targeted-release corticosteroid budesonide (Tarpeo).
Applause-Egan The trial, which ran from January 2021 to September 2025, involved 477 patients – 238 given eptacopan (200 mg) and 239 given a placebo twice a day. All had eGFR ≥30 mL/min/1.73 m2 and a 24-hour UPCR of ≥1 despite the maximum, stable dose of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.
The average age was approximately 40 years, 53.5% were male, 51.8% were Asian, and 46.3% were white. About 21% of the eptacopan group were on an SGLT2 inhibitor at baseline.
SGLT2 inhibitor users showed a more pronounced treatment effect than those who did not take them, but this was not tested for significance. “This finding potentially indicates that combination therapy may provide additional benefit,” Barrett’s team said.
“Given the long-term therapeutic goal of reducing the rate of kidney-function loss to less than 1 mL/min/1.73 m2 per year, future studies will be needed to assess the effects of eptacopan in combination with other disease-modifying treatments,” they suggested.
The reduction in proteinuria persisted for a full 24 months. Fatigue scores were not affected, but the researchers said this was likely because baseline scores were similar to those in the general healthy population.
Safety was consistent with the known profile of iptacopan. Adverse events were mostly mild or moderate and occurred in 87% of the eptacopan group and 89.1% of the placebo group. Serious adverse events were reported in 12.2% and 11.7%, respectively. Serious infections occurred more frequently with eptacopan (6.7% vs. 2.1%), including four cases of pneumonia in the eptacopan group.
Discontinuations due to adverse events were less than 5% in both groups, and there were no deaths.
The researchers said some important clinical questions are still pending, including how eptacopan should be integrated into treatment sequences and which patients will benefit most. Long-term safety data of more than 2 years is also required.
