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Effect of iptacopan on proteinuria and complement biomarkers in IgAN: Interim analysis of the phase 3 APPLAUSE-IgAN study

Presenter: Dana V. Rizk, MD, University of Alabama at Birmingham, Birmingham, Alabama, United States. 

Iptacopan inhibits systemic and intrarenal activation of the alternative complement pathway in patients with immunoglobulin A nephropathy.  


Iptacopan inhibited both systemic and intrarenal activation of the alternative complement pathway at 9 months in patients with immunoglobulin A nephropathy (IgAN), according to results from the phase 3 APPLAUSE-IgAN (NCT04578834) study presented by Dana V. Rizk, MD, University of Alabama at Birmingham, in a Kidney Week 2024 oral presentation. 

In patients with IgAN, a leading cause of glomerulonephritis and renal failure, the alternative complement pathway is often activated in urine but not in plasma, which indicates renal complement activity, Dr. Rizk said. Iptacopan (Fabhalta), a first-in-class oral factor B complement inhibitor, was granted accelerated approval in August 2024 by the US Food and Drug Administration for adults at risk of rapid progression of primary IgAN. Given that the alternative complement pathway plays a key role in IgAN pathogenesis, there is an unmet need for disease-modifying agents that target thepathway, Dr. Rizk added.  

She noted that in a phase 2 study, iptacopan reduced factor B breakdown (plasma Bb levels), Wieslab activity, and urinary sC5b-9 to nearly healthy volunteer ranges. The phase 3 APPLAUSE-IgAN study included 250 adult patients with biopsy-confirmed IgAN, as indicated by proteinuria levels of at least 1 g/g (grams of protein per grams of creatinine) despite stable supportive therapy. All subjects were randomized in a double-blind format to either iptacopan 200 mg or placebo twice daily for 24 months while continuing supportive therapy with maximally tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. At the pre-specified interim analysis (when 250 patients reached month 9 or discontinued the study), investigators assessed changes from baseline in biomarkers of complement activity (C3 and C4 in all patients, and plasma Bb, sC5b-9, and Wieslab levels in a subset of 105 patients). 

The analysis showed that iptacopan selectively inhibited the alternative complement pathway, with median plasma Bb activity (minus 21.1 for iptacopan vs plus 2.1 for placebo), median Wieslab serum (minus 89.4 for iptacopan vs zero for placebo), median sC5b-9 plasma (minus 17.2 iptacopan vs minus 2.1 placebo), and median sC5b-9 urine (minus 97.6 vs plus 47.0 for placebo) all reduced from baseline. Serum C3 (16.4 iptacopan vs minus 4.3 for placebo) and serum C4 (minus 2.0  iptacopan vs minus 3.8 placebo) levels were statistically unchanged, Dr. Rizk reported.  

“Iptacopan inhibited systemic and intrarenal activation of the alternative complement pathway in patients with IgAN at month 9, as supported by reductions in serum Wieslab activity, plasma Bb and sC5b-9, and urinary sC5b-9,” Dr. Rizk concluded. 

Funding 

  • Commercial Support – Novartis Pharma AG 

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