12-Month APPEAR-C3G Data Highlight Potential of Iptacopan in C3 Glomerulopathy

Carla Nester, MD
Credit: University of Iowa

New 12-month data from the phase 3 APPEAR-C3G trial are shedding new light on the potential of iptacopan in the management of C3 glomerulopathy (C3G).

The data, which detailed the 12-month data from the trial and offered evidence of sustained proteinuria reduction, was presented at the American Society of Nephrology’s Kidney Week 2024. At the time of the presentation, Novartis had already completed regulatory submissions for their oral Factor B inhibitor in C3G are completed in the EU, China, and Japan, and expected in the US by year-end.

“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, MSA professor of Pediatrics-Nephrology at the University of Iowa.² “I am encouraged to see these data, which reinforce the clinically meaningful impact on kidney health measures we saw at 6 months. As the only oral complement inhibitor intended to treat C3G, [iptacopan] could provide new hope for people living with this condition.”

Launched in 2021, APPEAR-C3G was a multicenter, randomized, double-blind, placebo-controlled trial examining the safety and efficacy of iptacopan relative to placebo therapy among adult patients with biopsy-conformed C3G. The trial was designed with a 6-month randomized, double-blinded treatment period where patients were randomized 1:1 to iptacopan or placebo and a subsequent 6-month open-label period where all patients were offered the option to receive iptacopan.^1,2

The initial 6-month data from the trial was presented at the 61st European Renal Association Congress. This data demonstrated iptacopan was associated with favorable benefits on the trial's primary endpoint of urine protein-to-creatinine ratio (UPCR) as well as other markers of kidney health.³

Of the 74 patients who underwent randomization in the overall trial, 43 had 12 complete months at the data cut-off, which occurred when all patients had completed 6 months of treatment.¹

Upon analysis, results suggested the trial had met its primary endpoint of a statically significant reduction in 24-hour UPCR,with levels at 6 months indicating a 35.1% (95% CI, 13.8 5 to 51.1%; P 1-sided P = .0014) reduction, which was sustained out to 12 months.¹

Investigators also pointed out use of iptacopan was also associated with a sustained improvement in the proportion of patients meeting the composite renal endpoint, which consisted of a 50% or greater reduction in UPCR and a 15% or less reduction in eGFR, with rates of 43.5% for iptacopan vs placebo and 25.0% among those who switched from placebo to iptacopan at 6 months. Additional analysis suggested use of iptacopan was also associated with improvements in the trajectory of eGFR relative to historic eGFR trajectory among the cohort.¹

Safety data from the 12-month results of the trial suggested the safety profile of iptacopan was similar to that observed in previous trials and investigators identified no new safety signals during the open-label period.¹

“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.² “I am optimistic that these iptacopan APPEAR-C3G findings bring us a step closer to revolutionizing the treatment paradigm in this ultra-rare disease with no approved therapies.”

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.