Alternative Pathway Inhibition Makes Good in IgA Nephropathy

SAN DIEGO — There was a clinically meaningful reduction in proteinuria with iptacopan (Fabhalta), and a confirmed clinical benefit of alternative pathway inhibition, in a rare kidney disorder, according to an interim analysis of the APPLAUSE-IgAN study.

In the phase III study, among the first 250 patients with IgA nephropathy who underwent randomization, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio (UPCR) was 38.3% (95% CI 26.0-48.6, two-sided PAmerican Society of Nephrology Kidney Week meeting.

Also at this time point, the adjusted geometric mean UPCR based on the first morning urine sample was 35.8% (95% CI 22.6-46.7) lower in the iptacopan group than in the placebo group.

Having met the primary endpoint, this is “a finding that is likely to translate to important clinical benefits for kidney function,” the researchers pointed out in a simultaneous publication in the New England Journal of Medicine (NEJM).

And new insights from the current analysis found significant changes from baseline in complement pathway biomarkers. In the iptacopan arm, urinary sC5b-9 levels — a marker of complement activation and immune disease activity in the kidneys — decreased a median of 97.6%, “almost down to levels seen in healthy volunteers,” Rizk said. Meanwhile, the placebo group increased a median of 47% by month 9.

Plasma sC5b-9 also decreased with iptacopan (-17.2% vs -2.1% with placebo), but C4 serum remained relatively unchanged in both groups (-2% vs -3.8%, respectively).

Changes in complement pathway biomarkers were consistent with selective alternative pathway inhibition, marked by median changes from baseline in the following:

• Bb plasma: -21.1% with iptacopan vs 2.1% with placebo
• Wieslab serum: -89.4% vs 0%
• C3 serum: 16.4% vs -4.3%

“Combined evidence from both the phase II and phase III studies suggest an early systemic alternative pathway inhibition and reduction of intrarenal alternative pathway activation … which is sustained up to 9 months,” Rizk said.

Granted accelerated FDA approval in August 2024, iptacopan acts as a factor B inhibitor of the immune system’s alternative complement pathway. It was the first complement inhibitor indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid progression, generally defined as a UPCR of 1.5 g/g or above. These interim findings, initially reported at the 2024 National Kidney Foundation (NKF) Spring Clinical meeting, underpinned the approval.

Despite the preliminary success of the ongoing trial, Julie R. Ingelfinger, MD, NEJM deputy editor, pointed out that “it remains to be shown whether iptacopan slows or interrupts the functional decline of kidney function in patients with IgA nephropathy.”

“Thus, data on the estimated glomerular filtration rate (eGFR), anticipated at the 2025 trial completion, will be key for ‘traditional approval,'” she said in an accompanying editorial.

The main trial included 222 patients in the iptacopan group and 221 in the placebo group, but this interim data only included the first 250 patients — 125 patients in each group — and who remained in the trial until month 9 or discontinued the trial by month 9. Patients were randomly assigned to receive oral iptacopan (200 mg) or placebo twice daily for 24 months while continuing to receive supportive therapy.

Among the first 250 patients, average age was 39, 47.6% were women, and 51.2% were from Asia. Average eGFR was 62.7±26.0 mL/min/1.73 m² in the iptacopan group and 65.5±26.7 mL/min/1.73 m² in the placebo group. Median 24-hour UPCR was 1.81 in the iptacopan group and 1.87 in placebo.

Hematuria was also no longer present at month 9 in 38.7% of the iptacopan group and 16.3% of the placebo group.

In a subgroup analysis, the treatment effect on the primary outcome — adjusted geometric mean 24-hour UPCR — was consistent across groups stratified by sex, geographic region, baseline 24-hour UPCR, baseline eGFR, baseline SGLT2 inhibitor use, baseline hematuria level, MEST-C score, and previous use of glucocorticoids or other immunosuppressants.

Rates of severe adverse events (AEs, 3.2% vs 3.2%) and AEs leading to discontinuation (2.7% vs 2.7%) were comparable between the two groups. The most common AEs in the iptacopan group were COVID-19 infection (14%), upper respiratory tract infection (9%), nasopharyngitis (5%), headache (4.1%), and hypertension (1.8%). No deaths or meningococcal infections occurred in either group.

According to the iptacopan label, patients should be up to date on their vaccination for encapsulated bacteria at least 2 weeks prior and there is a boxed warning about increased risk of infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b that could be serious and life-threatening.