Iptacopan slows the decline in kidney function while reducing proteinuria, hematuria, and the risk of kidney failure through 2 years of treatment in patients with IgA nephropathy (IgAN), according to final results of the phase 3 APPLAUSE-IgAN trial presented at the National Kidney Foundation’s Spring Clinical Meetings.
Though 2 years, the annual decline in estimated glomerular filtration rate (eGFR) was roughly halved in patients treated with the oral, selective complement factor B inhibitor compared with those who received placebo (3.10 vs 6.12 mL/min/1.73 m2; P<0.001).
The drug was well tolerated, with no new safety concerns emerging since the release of the 9-month interim results, which supported FDA accelerated approval of the agent. There were no deaths.
“These results demonstrate the clinical benefit of sustained alternative complement pathway inhibition with iptacopan in patients who have IgAN and glomerular inflammation,” according to slides presented by Brad Rovin, MD, a nephrologist at The Ohio State University Wexner Medical Center in Columbus.
Iptacopan addresses the overactivation of the alternative complement pathway involved in IgAN. Though most patients have a chronic progressive disease course characterized by persistent proteinuria, a subset also have glomerular inflammation.
The APPLAUSE-IgAN trial evaluated the medication in adults with biopsy-proven IgAN, an eGFR ≥30 mL/min/1.73 m2, and a 24-hour urinary protein-to-creatinine ratio (UPCR) ≥1 g/g. Investigators enrolled 477 patients (mean age 39 years; 52% men), with a median 24-hour UPCR of 1.7 g/g and a mean eGFR of about 64 mL/min/1.73 m2.
After a run-in period, patients were randomized to iptacopan 200 mg twice daily or placebo, both on top of optimized supportive care.
Results of the prespecified interim analysis at 9 months were reported previously, showing a 38.3% greater reduction in 24-hour UPCR with iptacopan versus placebo.
Dr. Rovin presented the final 24-month results of the trial, for which the primary endpoint was the annualized total eGFR slope. The decline in eGFR was 3.02 mL/min/1.73 m2 less per year with iptacopan versus placebo (P<0.001).
The effect was consistent across various demographic and clinical subgroups, including patients with either inflammatory or non-inflammatory lesions.
This raises questions about the mechanism of benefit of iptacopan, Dr. Rovin said. “Is it solely anti-inflammatory in the IgA area, or is it actually doing other things that might be relevant to chronic damage and fibrosis?”
There was a higher proportion of patients who had a 24-hour UPCR less than 1 g/g in the iptacopan group at 9 months (43.9% vs 17.5%; P<0.001), a difference that remained at 2 years.
Through 2 years, iptacopan-treated patients also had a lower risk of a composite kidney failure endpoint consisting of a sustained decline in eGFR ≥30%, a sustained eGFR <15 mL/min/1.73 m2, initiation of maintenance dialysis, kidney transplant, or death from kidney failure (21.4% vs 33.5%; HR 0.57; 95% CI 0.40-0.81).
Patients treated with iptacopan also were less likely to have hematuria at 24 months (36.1% vs 62.7%).
No new safety concerns emerged after 9 months, with a rate of serious adverse events of 12.2% with iptacopan and 11.7% with placebo at 2 years. Blood pressure, lipid parameters, and liver function did not differ between groups.
Serious infections were more frequent with iptacopan (6.7% vs 2.1%), consistent with a boxed warning on the drug’s label.
Illustration by April Brust
