Jonathan Barratt, MD: Targeting the Alternative Complement Pathway in IgAN with Iptacopan

Results from a pre-specified interim analysis of the phase 3 APPLAUSE-IgAN study of iptacopan (Fabhalta) in patients with IgA nephropathy (IgAN) showed participants treated with the investigational Factor B inhibitor of the alternative complement pathway achieved a 38.3% (P <.0001) proteinuria reduction at 9 months when compared to placebo on top of supportive care.¹

The results were presented on April 15, 2024, during a late-breaking clinical trials session at the World Congress of Nephrology in Buenos Aires, Argentina, and make APPLAUSE-IgAN the first and only phase 3 study to demonstrate significant proteinuria reduction by targeting the complement system in patients with IgAN.¹

“The hit 4 is all around the inflammatory response for immune complex deposition, and we know most of that inflammation is driven by activation of the complement system. Targeting the alternative pathway is a really good way of controlling that inflammation,” Jonathan Barratt, MD, Mayer Professor of Renal Medicine at the University of Leicester, explained in an interview with HCPLive.

Referencing phase 2 data showing a dose-dependent reduction in proteinuria, Barratt described it as “really interesting data that supports the benefit of blocking complement in IgA nephropathy.” He also mentioned the significance of data about the use of iptacopan in other diseases, including its approval for paroxysmal nocturnal hemoglobinuria, that confirm it blocks the alternative pathway, giving confidence that's what it's also doing in IgAN.²

“The phase 3 data is really going to give us that important extra step and extra piece of information to know how well targeting the alternative pathway is actually controlling inflammation by how much proteinuria reduction we see,” he said.

A phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group study, APPLAUSE-IgAN will evaluate the efficacy and safety of twice-daily oral iptacopan 200 mg in 518 adult patients with primary IgAN. The pre-specified interim analysis included 250 patients for the efficacy analysis and 443 for the safety analysis. Of note, the APPLAUSE-IgAN study continues in a double-blind fashion, with the primary endpoint evaluating iptacopan’s ability to slow IgAN progression by measuring the annualized total estimated glomerular filtration rate (eGFR) slope over 24 months expected at study completion in 2025.¹

The main study population enrolled patients with an eGFR ≥30 mL/min/1.73 m2 and urine protein to creatinine ratio (UPCR) ≥1 g/g at baseline. In addition, a smaller cohort of patients with severe renal impairment (eGFR 20–30 mL/min/1.73 m2 at baseline) was also enrolled but will not contribute to the main efficacy analyses.¹

In the presentation at the World Congress of Nephrology, use of iptacopan was associated with a statistically significant dose-response effect, with a 23% (80% confidence interval, 8-34%) reduction in UPCR observed in the achieved with iptacopan 200 mg arm at 3 months. Further analysis revealed UPCR decreases continued through 6 months in both the iptacopan 100 and 200 mg arms from a mean of 1.3 g/g at baseline to 0.8 g/g at 6 months.

Analysis of safety endpoints from the trial suggested iptacopan was well-tolerated, with no reports of deaths, treatment-related serious adverse events, or bacterial infections reported in the trial.

“In IgAN, part of the immune system called the alternative complement pathway can become overly activated in the kidneys, which causes an inflammatory response, leading to progressive kidney damage and gradual loss of kidney function. The loss of kidney function, together with potential side effects of IgAN treatments available until recently, significantly impact patients’ lives,” said Professor Dana Rizk, Investigator and APPLAUSE-IgAN Steering Committee Member and professor in the UAB Division of Nephrology.³ “Fabhalta is the first potential treatment for IgAN that specifically targets the alternative complement pathway.”

References:

1. ^{Novartis. New Novartis Fabhalta® (iptacopan) data show clinically meaningful and statistically significant proteinuria reduction of 38.3% versus placebo for patients with IgA nephropathy (IgAN). Apr 15, 2024. Accessed April 15, 2024. https://www.novartis.com/news/media-releases/new-novartis-fabhalta-iptacopan-data-show-clinically-meaningful-and-statistically-significant-proteinuria-reduction-383-versus-placebo-patients-iga-nephropathy-igan}
2. ^{Brooks, A. FDA Approves Iptacopan (Fabhalta) for Paroxysmal Nocturnal Hemoglobinuria. HCPLive. December 6, 2023. Accessed April 15, 2024. https://www.hcplive.com/view/fda-approves-iptacopan-fabhalta-for-paroxysmal-nocturnal-hemoglobinuria}
3. Novartis. New novartis fabhalta® (iptacopan) data show clinically meaningful and statistically significant proteinuria reduction of 38.3% versus placebo for patients with IGA nephropathy (IgAN). Novartis. April 15, 2024. Accessed April 15, 2024. https://www.novartis.com/news/media-releases/new-novartis-fabhalta-iptacopan-data-show-clinically-meaningful-and-statistically-significant-proteinuria-reduction-383-versus-placebo-patients-iga-nephropathy-igan.