EFFECT OF IPTACOPAN ON PROTEINURIA AND COMPLEMENT BIOMARKERS IN IGA NEPHROPATHY (IGAN): INTERIM ANALYSIS OF THE PHASE 3 APPLAUSE-IGAN STUDY

Introduction:

The alternative complement pathway (AP) plays a key role in IgAN pathogenesis and there is an unmet need for targeted disease-modifying treatments. In IgAN, the AP is often activated in urine but not in plasma, indicating renal complement activity. Iptacopan binds to Factor B and specifically inhibits the AP. In a Phase 2 study, iptacopan decreased plasma Bb and Wieslab activity, and urinary sC5b-9 decreased to almost healthy volunteer range. The APPLAUSE-IgAN trial is evaluating iptacopan vs placebo on top of optimized stable supportive therapy. In the pre-specified interim analysis (IA), iptacopan was superior to placebo in reducing proteinuria at Month 9 relative to baseline (24h urine protein-creatinine ratio reduction 38.3%; P<0.0001). Here, we present complement biomarker exploratory results from the IA.

Methods:

APPLAUSE-IgAN (NCT04578834), a Phase 3, randomized, double-blind, placebo-controlled trial, enrolled adults with biopsy-confirmed IgAN with proteinuria ≥1 g/g despite stable supportive therapy. Patients were randomized 1:1 to iptacopan 200 mg or placebo twice daily for 24 months while remaining on supportive therapy. IA was performed when 250 patients reached Month 9 or discontinued the study. Change from baseline in biomarkers of complement activity was assessed: C3 and C4 in all patients; Bb, sC5b-9, and Wieslab were only assessed in a subset of patients.

Results:

Iptacopan selectively inhibited the AP, with reductions in serum Wieslab activity, plasma Bb and sC5b-9, and increases in serum C3, while serum C4 was unchanged (Figure). Median decrease in urinary sC5b-9 was 97.6% (IQR 86.1-99.2) in the iptacopan arm; the Month 9 value was within the range observed in healthy individuals.

Conclusions:

Iptacopan inhibited systemic and intrarenal activation of the AP in patients with IgAN at Month 9, supported by reductions in serum Wieslab, plasma Bb and sC5b-9, and urinary sC5b-9.

This abstract was also submitted for the ASN Kidney Week, 23–27 October 2024, San Diego, CA, USA.

I have potential conflict of interest to disclose.
Dana V. Rizk reports grants (paid to institution) from Reata Pharmaceuticals, Otsuka Pharmaceuticals, Chinook Pharmaceuticals, LaRoche, Vera Therapeutics, and Vertex Pharmaceuticals, consulting fees from Vera Therapeutics, consulting fees for steering committee participation from Novartis, Otsuka Pharmaceuticals, Chinook Pharmaceuticals, and LaRoche, payments for educational events from Calliditas Therapeutics and Travere Therapeutics, payments for advisory boards or Alpine Immune Sciences, GSK, Biocryst, and Argenx, and support for attending meetings and/or travel from Otsuka Pharmaceuticals.

I did not use generative AI and AI-assisted technologies in the writing process.