ERA 25: Data Underscore Iptacopan’s Effect on Proteinuria and Complement Activation in IgAN

New data from a phase 2 trial and its ongoing open-label extension (OLE) highlight the reversibility and reinducibility of the effects of iptacopan (Fabhalta) on proteinuria and complement activation in patients with IgA nephropathy (IgAN).

Presented at the 62nd European Renal Association (ERA 2025) Congress, the findings build on prior evidence supporting iptacopan, an oral factor B inhibitor from Novartis targeting the alternative complement pathway (AP), which received accelerated approval US Food and Drug Administration (FDA) in August 2024.

The phase 2, randomized, double-blind, placebo-controlled study enrolled 67 adults with biopsy-confirmed IgAN and elevated urine protein-creatinine ratio (UPCR), which was defined as greater than or equal to 0.8 grams per gram or 0.75 grams per day. Patients received placebo or iptacopan at various doses for up to 180 days, followed by a 90-day off-treatment period.

Overall, 40 participants entered the OLE, reinitiating treatment with iptacopan 200 mg twice daily and investigators assessed biomarkers of AP activity in patients from the 200 mg group during the core trial. Among patients who received effective AP-inhibiting doses, which was defined as more than 10 mg twice daily, UPCR decreased by 30.0% at day 90 and 35.4% at day 180.

After treatment discontinuation, proteinuria increased, returning to baseline within 30 days in the 90-day treatment group and trending upward in the 180-day group. Upon reinitiation in the OLE, proteinuria levels again decreased in both cohorts. In the 200 mg group, reductions in UPCR were 27.0% at day 90 and 23.2% at day 180, with levels rising off treatment and decreasing again after restarting therapy.

Complement biomarker trends were consistent with these findings. At day 90, urinary sC5b-9 levels decreased by a median of 97.2%, serum Wieslab activity by 81.4%, and plasma Bb levels by 24.5%. All markers rebounded after treatment cessation, which investigators suggest indicates reactivation of the AP.

For more insights into the clinical implications of these findings and how iptacopan may influence treatment strategies in IgAN, check out our interview with lead investigator Jonathan Barratt, MD, PhD, the Mayer Professor of Renal Medicine at the University of Leicester, from ERA 2025.

Relevant disclosures of interest for Barratt included Argenx, Calliditas Therapeutics, Chinook Therapeutics, Galapagos NV, GSK, Novartis, Travere Therapeutics, and others.

References:

1. Barratt J, Rizk D, Zhang H, et al. Effect of iptacopan discontinuation on proteinuria and complement biomarkers in patients with immunoglobulin A nephropathy (IgAN): a post hoc analysis from a Phase II trial. Presented at: 62nd European Renal Association Congress. June 04 – 07, 2025. Vienna, Austria.
2. Novartis. Novartis receives FDA accelerated approval for Fabhalta® (iptacopan), the first and only complement inhibitor for the reduction of proteinuria in primary IgA nephropathy (IgAN). Novartis. Published August 8, 2024. Accessed June 6, 2025. https://www.novartis.com/news/media-releases/novartis-receives-fda-accelerated-approval-fabhalta-iptacopan-first-and-only-complement-inhibitor-reduction-proteinuria-primary-iga-nephropathy-igan