Iptacopan Treatment Significantly Reduces Proteinuria in IgAN


Patients with IgAN receiving iptacopan achieved a 38.3% reduction in proteinuria at month 9.

Iptacopan Treatment Significantly Reduces Proteinuria in IgAN

Dana Rizk, MD

Credit: NKF

Patients with immunoglobulin A nephropathy (IgAN) treated with iptacopan (Fabhalta) demonstrated a superior reduction in proteinuria—with the most significant reductions observed at month 9—compared with placebo, according to a late-breaking presentation at the National Kidney Foundation (NKF) 2024 Spring Clinical Meeting.1

“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,” said lead investigator Dana Rizk, MD, APPLAUSE-IgAN Steering Committee Member and professor in the University of Alabama at Birmingham Division of Nephrology. “The loss of kidney function, together with potential side effects of IgAN treatments available until recently, significantly impact patients’ lives. Fabhalta is the first potential treatment for IgAN that specifically targets the alternative complement pathway.”

Ipatacopan was originally approved by the US Food and Drug Administration (FDA) for the treatment of paroxysmal nocturnal hemoglobinuria in 2023. IgAN—an incurable condition that can lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD)—currently has no approved treatments. Proteinuria reduction has recently been recognized as a surrogate marker linked to the progression of kidney failure and has been used in clinical trials in IgAN to help accelerate approvals for this condition.

The phase 3, randomized, double-blind, placebo-controlled APPLAUSE-IgAN study evaluated treatment with iptacopan in addition to optimized supportive care among this patient population. Eligible patients had biopsy-confirmed IgAN and proteinuria ≥ 1 g/g, as determined from a urine protein-creatinine ratio (UPCR) from 24-hour urine collection (UPCR-24h), despite being treated with maximally tolerated renin-angiotensin system (RAS) inhibition for ≥ 3 months. Patients were randomized 1:1 to receive iptacopan 200 mg or placebo twice daily.

The primary outcome for the interim analysis was proteinuria reduction at month 9 as assessed by UPCR. The primary endpoint for the final analysis will be the annualized total estimated glomerular filtration rate (eGFR) slope over a span of 24 months.

Secondary endpoints in the final analysis will include the proportion of patients who are able to achieve UPCR < 1 g/g without being treated with corticosteroids/immunosuppressants or newly approved drugs, without initiating new background treatment for IgAN, or beginning kidney replacement therapy (KRT). Other endpoints were the time from randomization to the first occurrence of composite kidney failure endpoint event and changes in fatigue from baseline to 9 months as evaluated using the Functional Assessment of Chronic Illness Therapy-Fatigue Questionnaire (FACIT-F).

The efficacy analyses enrolled 125 patients each to receive iptacopan and placebo, while safety analyses included 222 patients in the iptacopan cohort and 221 patients in the placebo cohort. Baseline characteristics were comparable among both groups.

Findings revealed patients in the iptacopan cohort achieved a 38.3% proteinuria reduction (according to the UPCR-24h) at month 9 (95% confidence interval [CI] 26.0%‒48.6%; P <.0001) compared with placebo. The UPCR began to decrease as early as week 2, culminating in the most significant decreases observed at month 9 (35.8%; 95% CI 22.6%‒46.7%).

Twice as many patients treated with iptacopan were able to achieve UPCR-24h < 1 g/g at month 9 compared with placebo (42.5% [95% CI 34.5%‒50.5%] vs 21.9% [95% CI 14.8%‒29.0%], respectively).

Additionally, iptacopan was well tolerated and demonstrated a favorable safety profile that was consistent with previous research.2,3 Only 2.7% in each cohort discontinued treatment due to adverse events and the infection rate in the iptacopan group did not exceed the placebo group.

“There is a need for effective, targeted therapies for IgAN patients and the detailed Applause-IgAN study gives valuable, promising insights to healthcare providers and patients living with IgAN,” NKF President, Sylvia Rosas, MD, MSCE, said in a statement. “The alternative complement pathway has been implicated in the pathogenesis of IgAN, so it gives patients hope that a novel therapeutic intervention may lead to slowing progression of chronic kidney disease and avoiding kidney failure.”


  1. Rizk D, Kollins D, Papachristofi O, Hach T, et al. Efficacy and safety of iptacopan in patients with IgA nephropathy (IgAN): Interim analysis (IA) of the Phase 3 APPLAUSE-IgAN study. Poster presented at: National Kidney Foundation 2024 Spring Clinical Meeting (SCM). Long Beach, CA. May 14 – 18, 2024.
  2. Perkovic V, Kollins D, Renfurm R, et al. Efficacy and Safety of Iptacopan in Patients with IgA Nephropathy: Interim Results from the Phase 3 APPLAUSE-IgAN Study. Presented at the World Congress of Nephrology (WCN); April 15, 2024; Buenos Aires, Argentina.
  3. Zhang H, Rizk DV, Perkovic V, et al. Results of a Randomized Double-Blind Placebo-Controlled Phase 2 Study Propose Iptacopan as an Alternative Complement Pathway Inhibitor for IgA Nephropathy. Kidney Int. 2024;105(1):189-199. doi:10.1016/j.kint.2023.09.027
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