Carla Nester, MD: 12-Month Data Informs Potential of Iptacopan in C3 Glomerulopathy

As Novartis prepares for a regulatory submission, new 12-month data from the APPEAR-C3G trial offer nephrologists with the greatest insight yet into the effects of iptacopan in patients with C3 glomerulopathy (C3G).

Presented at the American Society of Nephrology’s Kidney Week 2024, the 12-month data from the phase 3 trial confirm the findings from the 6-month analysis presented earlier in 2024, which concluded use was associated with a statistically significant reduction in urine protein-to-creatinine ratio (UPCR).

“These results mark an important milestone for the management of C3G, as the first study to shed light on longer-term treatment targeting the underlying mechanism of this disease via the alternative complement pathway,” said study investigator and steering committee member Andrew Bomback, MD, MPH, associate professor of Medicine at Columbia University Irving Medical Center.

The APPEAR-C3G trial evaluated the safety and efficacy of iptacopan in adult patients with biopsy-confirmed C3G. The multicenter, double-blind, placebo-controlled trial, launched in 2021, included a 6-month blinded phase where patients were randomized 1:1 to iptacopan or placebo, followed by a 6-month open-label period in which all patients could receive iptacopan. Data from the 6-month double-blind portion of the trial were presented at the 61st European Renal Association Congress.

Among 74 randomized patients, 43 completed 12 months of treatment at the data cut-off. Results demonstrated a statistically significant reduction in 24-hour UPCR at 6 months with iptacopan, achieving a 35.1% reduction (95% CI, 13.8% to 51.1%; 1-sided P = .0014) that persisted at 12 months. Iptacopan also improved the proportion of patients reaching the composite renal endpoint—defined as a 50% or greater UPCR reduction and a 15% or less eGFR decrease—with 43.5% meeting this endpoint versus 25.0% of those who initially received placebo.

Additionally, iptacopan was associated with favorable changes in eGFR trajectory relative to historical patterns. Safety analysis of the 12-month data revealed no new safety signals, indicating a safety profile consistent with prior studies.

“As a clinician treating young people living with C3G, I see firsthand the challenges with therapies used to treat this condition today, underscoring the vital need for dedicated treatment for these patients,” said study investigator Carla Nester, MD, the Jean E. Robillard Chair in Pediatric Nephrology and the director of the Pediatric Glomerular Disease Clinic at the University of Iowa.

For more from that study, check out our interview with Nester from Kidney Week 2024:

Relevant disclosures for Nester include Apellis, Biocryst, Kira, Novartis, Silence Therapeutics, and Biocryst.

References:

1. Nester CM, Smith RJ, Kavanagh D, et al. Efficacy and Safety of Iptacopan in patients with C3 Glomeruloipathy: 12-Month Results from the Phase 3 APPEAR-C3G Study. Presented at American Society of Nephrology Kidney Week 2024. San Diego, CA. October 23-27, 2024.
2. Novartis oral Fabhalta® (iptacopan) sustained clinically meaningful results at one year in phase III C3 Glomerulopathy (C3G) trial . Novartis. October 27, 2024. Accessed October 27, 2024. https://www.novartis.com/news/media-releases/novartis-oral-fabhalta-iptacopan-sustained-clinically-meaningful-results-one-year-phase-iii-c3-glomerulopathy-c3g-trial.
3. 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 October 27, 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.