Novartis’ Phase III APPLAUSE‑IgAN trial published in the New England Journal of Medicine and presented at the 2026 World Congress of Nephrology found that Fabhalta (iptacopan) cut the rate of kidney function loss by roughly half over two years and substantially reduced progression to kidney‑failure events, offering a targeted option for adults with biopsy‑confirmed IgA nephropathy (IgAN) who continue to have proteinuria despite standard care.
What the trial measured and the headline results
APPLAUSE‑IgAN used the annualized eGFR slope over 24 months as its primary endpoint. Fabhalta slowed decline in estimated glomerular filtration rate (eGFR) by 49.3% versus placebo. The study also reported a 43% reduction in the risk of a composite kidney‑failure outcome (≥30% sustained eGFR decline, initiation of dialysis, kidney transplant, or death from kidney failure) over the two‑year period.
On proteinuria, 40.7% of patients receiving Fabhalta achieved sustained reduction to a urine protein‑to‑creatinine ratio (UPCR) under 1 g/g, compared with 23.7% on placebo—an effect that often correlates with slower long‑term progression although it is not itself proof of cure.
| Outcome | Fabhalta (24 months) | Placebo | Difference |
|---|---|---|---|
| Annualized eGFR decline | 49.3% slower vs placebo | Reference | Relative reduction in slope |
| Composite kidney‑failure events | 43% lower risk | Reference | Fewer progressions to dialysis/transplant |
| Sustained UPCR < 1 g/g | 40.7% | 23.7% | +17.0 percentage points |
How Fabhalta works and which patients the data apply to
Fabhalta inhibits Factor B in the alternative complement pathway, aiming to reduce complement‑mediated inflammation and tissue damage that drive IgAN progression. That mechanism is the reason regulators in the U.S. and China granted accelerated approval for proteinuria reduction in adults with IgAN at risk of rapid progression; Novartis has submitted the two‑year APPLAUSE‑IgAN results for traditional FDA approval and received priority review.
The main APPLAUSE‑IgAN cohort included adults with biopsy‑confirmed IgAN, persistent proteinuria despite optimized supportive care (stable renin‑angiotensin system inhibitors; many were also on SGLT2 inhibitors), baseline eGFR ≥30 mL/min/1.73 m² and UPCR ≥1 g/g. Novartis also enrolled a smaller cohort with eGFR 20–30 mL/min/1.73 m², but that group did not contribute to the primary efficacy analysis—so benefits remain best established for patients meeting the main‑cohort thresholds.
Safety, monitoring, and clinical decision thresholds
Across two years the adverse‑event profile was similar to placebo: most common events were mild‑to‑moderate infections (including COVID‑19 and upper respiratory infections), headache, diarrhea, and hyperlipidemia. Treatment discontinuation rates were low and comparable to placebo, supporting tolerability in patients with moderate impairment—but clinicians should monitor lipids and infection signs routinely while on therapy.
Practical thresholds and stop signals supported by the trial: consider Fabhalta for adults with UPCR ≥1 g/g who remain proteinuric despite optimal supportive care, and prefer patients with eGFR ≥30 mL/min/1.73 m² where primary efficacy was demonstrated. Reassess or pause treatment if eGFR falls rapidly despite therapy, if serious infection occurs, or if lipid elevations are severe and unmanageable; those are the concrete decision points the APPLAUSE data imply.
Open questions and the next checkpoints
The immediate verification steps to watch are longer follow‑up and broader experience in more advanced kidney disease. Novartis’ submission to the FDA relies on two‑year data; the key unanswered items are whether protection of eGFR is sustained beyond 24 months and whether patients with eGFR 20–30 mL/min/1.73 m² see comparable benefit and safety. Independent long‑term registries and post‑approval studies will be important to confirm durability and rare adverse events.
Short Q&A
Who is a likely candidate now? Adults with biopsy‑confirmed IgAN, persistent proteinuria despite stable supportive care, and baseline eGFR ≥30 mL/min/1.73 m²—especially those with higher UPCR where accelerated approvals focus (U.S./China approvals were for patients typically defined by UPCR ≥1.5 g/g).
Does Fabhalta reverse IgAN? No. APPLAUSE‑IgAN shows slowed progression and reduced risk of kidney‑failure events over two years; it does not cure or reverse established kidney damage.
When should clinicians stop or rethink therapy? Reassess if eGFR declines rapidly despite treatment, if serious or recurrent infections occur, or if lipid abnormalities require discontinuation. Those are the practical stop signals reflected in the trial’s safety data and patient selection criteria.