Iptacopan Reduces Proteinuria, Demonstrates Benefit in C3 Glomerulopathy


In the APPEAR-C3G trial, iptacopan reduced proteinuria by 35.1% in patients with C3 glomerulopathy, with Novartis planning regulatory submissions for C3G before the end of 2024.

David Kavanagh, MBChB, PhD | Credit: NHS Foundation Trust

David Kavanagh, MBChB, PhD
Credit: NHS Foundation Trust

Use of the oral factor B inhibitor iptacopan (Fabhalta) was associated with a 35.1% reduction in proteinuria among patients with C3 glomerulopathy (C3G), according to results of the APPEAR-C3G trial.

Although the trial is set to continue with a 6-month, open-label period, results of the 6-month double-blind portion of the study provide hope to a community of nephrologists and patients that is currently without any approved therapies. According to Novartis, regulatory submissions for iptacopan in C3G are expected in the second half of 2024.1,2

“This is an exciting milestone for patients and the potential future management of C3G. The hallmark of C3G is overactivation of part of the immune system called the alternative complement pathway, which damages the kidneys and leads to severe loss of kidney function in many patients. Currently used treatments don’t address the underlying biology of C3G and often come with significant side effects that add to the burden of the illness,” said APPEAR-C3G Steering Committee Member David Kavanagh, MBChB, PhD, professor of Complement Therapeutics and Honorary Consultant Nephrologist at the Faculty of Medical Sciences at Newcastle University.2

A multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trial launched in 2021, APPEAR-C3G was designed to assess efficacy, safety, and tolerability of iptacopan relative to placebo therapy in patients with C3G. For inclusion in the trial, patients were required to have serum C3 less than 77 mg/dL, 24-hour urine protein to creatinine ratio (UPCR) of 1.0 g/g or greater, and eGFR of 30 mL/min/1.73m2 or greater.1,3

In total, 132 patients were screened and 74 patients were enrolled in the trial. These patients were randomized in a 1:1 ratio to receive either iptacopan 200 mg twice daily or placebo therapy, with 38 randomized to iptacopan and 36 to placebo therapy. Per trial protocol, patients were allowed to use mycophenolic acids, low-dose corticosteroids, SGLT2 inhibitors, and mineralocorticoid receptor antagonists when stable for 90 or more days prior to randomization.1

The primary outcome of interest for the trial was change in proteinuria, measured using 24-hour UPCR, from baseline to 6 months. The trial also included multiple secondary endpoints, including change in eGFR as well as a composite renal outcome of a 50% or greater reduction UPCR reduction plus a 15% or less reduction in eGFR reduction at 6 months relative to placebo.1

Upon analysis results indicated the trial had met its primary endpoint, with use of iptacopan associated with a statistically significant reduction 35% reduction in proteinuria at 6 months relative to placebo therapy (35.1%; 95% CI, 13.8 to 51.1; nominal 1-sided P = .0014). Analysis of secondary endpoints of interest revealed a 7-fold increase in likelihood of meeting the composite kidney outcome with iptacopan relative to placebo therapy (OR, 7.145; 95% CI: 1.429, 35.723; nominal 1-sided P = .0083).Further analysis suggested use of iptacopan was associated a numerical improvement of 2.2 mL/min/1.73 m2 (P = .1945) over 6 months compared to placebo therapy.1

Additionally, iptacopan use was associated with significant increases in serum C3 (185%), decreased alternative complement pathway activity (−37.3%), plasma sC5b-9 (−65.1%), and urinary sC5b9/creatine (−77.3%) at 6 months (nominal 1-sided P for all <.001). In his presentation at ERA 24, Kavanagh noted there were no new safety signals revealed in the trial.1

“Currently there are no therapies approved for C3G, but researchinto potential new treatments developed specifically for this disease gives us hope that we can improve outcomes for patients and blunt its emotional, physical and social effects,” said Marianne Silkjær Nielsen, founder of CompCure.2


  1. Kavanagh D, Bomback A, Vivarelli M, et al. Efficacy and safety of iptacopan in patients with C3 glomerulopathy: results from the Phase 3 APPEAR-C3G trial. Abstract presented at 61st European Renal Association Congress. Stockholm, Sweden. May 23-26, 2024.
  2. Novartis. Novartis presents latest phase III Fabhalta® (iptacopan) data in C3 glomerulopathy (C3G) showing clinically meaningful and statistically significant 35.1% proteinuria reduction vs. placebo. Novartis. May 25, 2024. Accessed May 26, 2024. https://www.novartis.com/news/media-releases/novartis-presents-latest-phase-iii-fabhalta-iptacopan-data-c3-glomerulopathy-c3g-showing-clinically-meaningful-and-statistically-significant-351-proteinuria-reduction-vs-placebo.
  3. ClinicalTrials.gov. Study of efficacy and safety of Iptacopan in patients with C3 glomerulopathy. - full text view. ClinicalTrials.gov. March 26, 2021. Accessed May 26, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04817618.
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