Nephrology · Medical Literature
Iptacopan in IgA Nephropathy — Final 24-Month Data
Abstract
New England Journal of Medicine, Volume 395, Issue 5, Page 465-477, July 30, 2026.
Clinical relevance
In adults with biopsy-proven IgA nephropathy and persistent proteinuria despite optimized supportive care, does oral iptacopan (200 mg twice daily), a complement factor B inhibitor, slow the decline in kidney function and reduce the risk of kidney failure events compared with placebo over 24 months? __SNAPSHOT__ {"studyDesign":"Randomized, double-blind, placebo-controlled phase 3 trial (APPLAUSE-IgAN; NCT04578834) with a prespecified 9-month interim analysis for proteinuria and a 24-month primary eGFR slope analysis","setting":"Multicenter, international; specific countries not reported in the abstract","sampleSize":"n=477 (iptacopan: ~239, placebo: ~238; final cohort); a prespecified interim analysis used the first 250 randomized patients (125 per arm)","population":"Adults (≥18 years) with biopsy-confirmed primary IgA nephropathy, baseline eGFR ≥30 mL/min/1.73 m², and 24-hour urinary protein-to-creatinine ratio (UPCR) ≥1 g/g despite stable, maximally tolerated ACE inhibitor or ARB therapy; approximately 19.3% were receiving SGLT2 inhibitors at baseline","intervention":"Oral iptacopan 200 mg twice daily (complement factor B inhibitor; selective alternative pathway inhibitor), in addition to background supportive care","comparator":"Oral placebo twice daily, in addition to background supportive care","primaryOutcome":"Annualized total eGFR slope (mL/min/1.73 m² per year) over 24 months; 24-hour UPCR reduction at 9 months was the primary endpoint of the prespecified interim analysis","followUp":"24 months (with prespecified interim analysis at 9 months)","fundingSource":"Industry (Novartis)"}
Key findings
Primary outcome (eGFR slope, 24 months): The annualized total eGFR slope was −3.10 mL/min/1.73 m² per year with iptacopan versus −6.12 mL/min/1.73 m² per year with placebo — an absolute between-group difference of +3.02 mL/min/1.73 m² per year (95% CI: 2.02 to 4.01; adjusted p<0.001). This represents approximately a 49.3% relative attenuation of eGFR loss (calculated). Interim proteinuria outcome (9 months): Iptacopan reduced the adjusted geometric mean 24-hour UPCR by 38.3% compared with placebo (95% CI: 26.0 to 48.6; p<0.001). At month 9, a greater proportion of iptacopan-treated patients achieved UPCR <1 g/g, with an absolute difference of 26.4 percentage points (95% CI: 18.7 to 34.0; odds ratio, 4.45; adjusted p<0.001). These proteinuria reductions persisted through 24 months. Composite kidney failure events (key secondary endpoint): Occurred in 21.4% of the iptacopan group versus 33.5% of the placebo group (HR 0.57; 95% CI: 0.40 to 0.81; adjusted p=0.003) — a 43% relative risk reduction. NNT to prevent one composite kidney failure event over 24 months: approximately 8.2 (calculated from 33.5% vs. 21.4% absolute risk difference of 12.1%). Rescue or alternative therapy was required by 4.6% of the iptacopan group versus 13.4% of the placebo group. Hematuria rates at month 24 were 36.1% with iptacopan versus 62.7% with placebo. Treatment effects on eGFR decline were consistent across prespecified subgroups including age, degree of proteinuria, baseline eGFR, hematuria status, and SGLT2 inhibitor use. Safety: Overall adverse event incidence was comparable (iptacopan 87.0% vs. placebo 89.1%), with most events mild to moderate. Serious adverse events occurred in 12.2% (iptacopan) versus 11.7% (placebo). Importantly, serious infections were observed in 6.7% of iptacopan-treated patients versus 2.1% of placebo-treated patients — a clinically significant imbalance consistent with the mechanism of complement inhibition. No deaths occurred in either arm. Discontinuation rates were lower in the iptacopan arm (18.9%) versus placebo (36.8%).
Practice implications
⚠ Only the abstract is available; full methodology, statistical analysis plan details, handling of missing data, and complete subgroup analyses cannot be independently verified. This caveat should be weighed when applying findings to clinical decision-making. What the study established: Iptacopan, added to optimized background therapy (RAS blockade ± SGLT2 inhibitor), produced a statistically significant and clinically meaningful slowing of eGFR decline and a significant reduction in composite kidney failure events over 24 months in patients with biopsy-proven IgAN at high risk of progression. The roughly 3 mL/min/1.73 m² per year absolute attenuation of eGFR loss and a ~43% relative reduction in kidney failure events represent findings of substantive clinical magnitude, not merely statistical significance. What the study did not establish: Long-term hard outcomes beyond 24 months (e.g., ESKD requiring dialysis or transplant, cardiovascular events, mortality) were not individually reported as primary endpoints. The study does not establish optimal sequencing, combination, or duration of iptacopan therapy relative to other emerging IgAN agents (e.g., sparsentan, budesonide, endothelin antagonists, B-cell therapies). The composite kidney failure endpoint included a ≥30% eGFR decline, which is a surrogate component; absolute progression to dialysis was not separately reported in the abstract. Patient representativeness: The trial required UPCR ≥1 g/g and eGFR ≥30 mL/min/1.73 m², so patients with milder proteinuria or more advanced CKD are not well-represented. Approximately 19.3% used SGLT2 inhibitors, and subgroup consistency was demonstrated, which supports applicability to this growing contemporary patient population. The serious infection imbalance (6.7% vs. 2.1%) warrants prospective surveillance in clinical use, particularly given complement's role in host defense against encapsulated organisms; meningococcal and pneumococcal vaccination protocols should be applied per complement inhibitor guidelines. Practice implications: These 24-month data, in conjunction with prior FDA accelerated approval based on proteinuria reduction, provide confirmatory evidence of kidney function benefit. For high-risk IgAN patients meeting trial eligibility criteria, iptacopan represents a clinically viable addition to optimized supportive care. Clinicians should weigh the infection risk, especially for immunocompromised patients or those with recurrent infections. __LIMITATIONS__ Only the abstract is available; full methodology, statistical analysis plan, subgroup analyses, and handling of dropouts/missing data cannot be independently assessed.,Industry-funded by Novartis, with associated risk of outcome reporting and analysis bias.,The composite kidney failure endpoint includes ≥30% eGFR decline as a component, which is a surrogate marker; absolute rates of dialysis initiation or transplantation were not extractable from the abstract.,Relatively short 24-month follow-up for a progressive disease with a decades-long natural history; whether the eGFR benefit is sustained, accelerated, or attenuated beyond 24 months is unknown.,Discontinuation rates were high in both arms (iptacopan 18.9%; placebo 36.8%), with a large differential that could introduce informative censoring bias favoring the iptacopan arm.,Exclusion of patients with eGFR <30 mL/min/1.73 m² limits generalizability to patients with advanced CKD.,Only ~19.3% of participants used SGLT2 inhibitors at baseline; real-world patients are increasingly on dual or triple supportive therapy, and the comparative benefit of iptacopan on top of more intensive background therapy is not fully established.,The serious infection imbalance (6.7% vs. 2.1%) represents an important safety signal that requires longer-term, real-world pharmacovigilance.,Geographic and ethnic diversity of the trial population is not fully described in the abstract, limiting generalizability across all patient populations. __BOTTOM_LINE_CATEGORY__ practice_changing __BOTTOM_LINE__ In the 24-month APPLAUSE-IgAN phase 3 trial, iptacopan (200 mg twice daily) significantly slowed eGFR decline by approximately 3 mL/min/1.73 m² per year and reduced the risk of composite kidney failure events by 43% (HR 0.57) compared with placebo in high-risk IgAN patients on optimized supportive care. These findings confirm clinically meaningful kidney protection and support use in eligible patients, but clinicians must monitor for serious infections — observed at a notably higher rate with iptacopan (6.7% vs. 2.1%) — and apply appropriate vaccination and surveillance protocols consistent with complement inhibitor prescribing guidelines.