Novartis' iptacopan slows kidney function decline by 49% in Phase III IgA nephropathy trial

Novartis (SWX: NOVN) reported final two-year results from the Phase III APPLAUSE-IgAN study showing that iptacopan (Fabhalta) slowed kidney function decline by 49.3% compared with placebo in adults with IgA nephropathy, data that now form the basis of a priority review submission to the FDA for traditional approval. The Fabhalta IgAN results, published simultaneously in the New England Journal of Medicine and presented as late-breaking data at the 2026 World Congress of Nephrology, position the oral complement factor B inhibitor as a contender in a treatment landscape that has shifted from supportive care to multiple mechanistically distinct targeted therapies in under five years.

APPLAUSE-IgAN is a global, randomized, double-blind, placebo-controlled Phase III trial that enrolled adults with biopsy-confirmed IgA nephropathy and persistent proteinuria despite optimized supportive care, randomizing them 1:1 to Fabhalta or placebo for up to 24 months.

Two years of eGFR slope and kidney failure data

The primary endpoint was the annualized total eGFR slope over 24 months. Patients receiving Fabhalta lost eGFR at a rate of −3.10 mL/min/1.73 m²/year, compared with −6.12 mL/min/1.73 m²/year in the placebo arm — a treatment difference of 3.02 mL/min/1.73 m²/year, translating to the 49.3% slowing of eGFR slope kidney function decline that serves as the headline figure. On the composite kidney failure endpoint — defined as sustained ≥30% eGFR decline, sustained eGFR below 15 mL/min/1.73 m², initiation of maintenance dialysis, kidney transplant, or death from kidney failure — Fabhalta reduced the likelihood of progression by 43% (hazard ratio 0.57; 21.4% vs. 33.5%). Additionally, 40.7% of patients on Fabhalta achieved a sustained 24-hour urinary protein-to-creatinine ratio below 1 g/g over two years, compared with 23.7% on placebo.

The safety profile over two years was consistent with earlier interim analyses. Rates of adverse events and treatment discontinuation were low and comparable between arms. The most common events were mild-to-moderate infections (including COVID-19 and upper respiratory tract infections), headache, diarrhea, and hyperlipidemia.

From accelerated to traditional approval

Fabhalta received accelerated approval in the United States in August 2024 and in China for proteinuria reduction in adults with primary IgA nephropathy, based on a prespecified interim analysis of the APPLAUSE-IgAN study. The two-year confirmatory data have now been submitted to the FDA, which granted priority review — a designation the agency reserves for therapies that may offer meaningful advances over available treatments. The Fabhalta New England Journal of Medicine publication provides the peer-reviewed evidence base that will underpin the regulatory review.

A crowded but mechanistically diverse field

The IgA nephropathy treatment landscape has undergone a transformation since 2021, when no targeted therapies carried a specific indication for the disease. Four FDA-approved options now exist: budesonide delayed-release capsules (Tarpeyo, Calliditas/Asahi Kasei), a targeted-release corticosteroid with full approval since December 2023; sparsentan (Filspari, Travere Therapeutics), a dual endothelin A/angiotensin II type 1 receptor antagonist that received full approval in 2025; Fabhalta itself, currently holding accelerated approval; and sibeprenlimab (Voyxact, Otsuka), an anti-APRIL monoclonal antibody that received accelerated approval in November 2025.

Novartis Fabhalta iptacopan occupies a distinct mechanistic niche as the only oral complement-targeted therapy approved in IgA nephropathy. By inhibiting factor B, it blocks the alternative complement pathway — a validated mediator of glomerular injury in IgAN — without the corticosteroid burden of Tarpeyo or the hepatotoxicity monitoring (REMS) required by Filspari. Unlike Voyxact, which requires intravenous infusion, Fabhalta is administered orally, though its twice-daily dosing is less convenient than the once-daily regimens of Tarpeyo and Filspari.

Cross-trial comparisons are limited by differences in patient populations, study designs, endpoints, and follow-up durations. The eGFR slope preservation observed with Fabhalta over two years is numerically in the range reported for other targeted agents, but direct comparison would require head-to-head data that do not yet exist.

Novartis builds a multi-asset IgAN portfolio

Beyond Fabhalta, Novartis is advancing atrasentan (Vanrafia), a selective endothelin A receptor antagonist that received NDA approval in April 2025, and zigakibart, an investigational compound targeting a distinct pathway. This multi-asset strategy reflects a broader industry recognition that IgA nephropathy — a progressive autoimmune kidney disease affecting approximately 25 per million people annually worldwide — may ultimately require combination or sequential therapy to address its multiple pathogenic drivers.

The APPLAUSE-IgAN study results provide the confirmatory efficacy and safety data needed to convert Fabhalta's accelerated approval to traditional approval. The FDA's priority review decision is the next milestone, with a regulatory action date expected later in 2026.

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