Iptacopan in IgA Nephropathy

Iptacopan in IgA Nephropathy — Final 24-Month Data
Published March 28, 2026
N Engl J Med 2026;395:465-477
DOI: 10.1056/NEJMoa2600743
Abstract
Background
Overactivation of the alternative complement pathway contributes to IgA nephropathy and glomerular inflammation. In the 9-month interim analysis of this phase 3 trial, iptacopan, a complement factor B inhibitor, led to a significant reduction of 38.3% in the 24-hour urinary protein-to-creatinine ratio as compared with placebo and had an acceptable safety profile.
Methods
In this phase 3 trial, we enrolled adults who had IgA nephropathy, an estimated glomerular filtration rate (eGFR) of at least 30 ml per minute per 1.73 m2 of body-surface area, and a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite supportive care. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily. The primary end point for the final analysis was the annualized total eGFR slope as estimated over a 24-month period. Secondary end points included a composite kidney-failure end point (i.e., a sustained decline in eGFR of ≥30%, a sustained eGFR of <15 ml per minute per 1.73 m2, the initiation of maintenance dialysis, receipt of kidney transplant, or death from kidney failure), assessed in a time-to-event analysis. Safety was also assessed.
Results
Among 477 patients included in the final analysis, 238 had been randomly assigned to iptacopan and 239 to placebo. The annualized total eGFR slope was −3.10 ml per minute per 1.73 m2 per year with iptacopan, as compared with −6.12 ml per minute per 1.73 m2 per year with placebo (difference, 3.02 ml per minute per 1.73 m2 per year; 95% confidence interval [CI], 2.02 to 4.01; adjusted P<0.001). A composite kidney-failure end-point event occurred in 21.4% of the patients in the iptacopan group, as compared with 33.5% of those in the placebo group (hazard ratio, 0.57; 95% CI, 0.40 to 0.81; adjusted P=0.003). The incidence of adverse events was 87.0% in the iptacopan group and 89.1% in the placebo group. Serious adverse events occurred in 12.2% of the patients who received iptacopan and in 11.7% of those who received placebo, and serious infections in 6.7% and 2.1%, respectively. No deaths occurred.
Conclusions
Iptacopan therapy led to a significantly slower decline in kidney function than placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.)
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Notes
This article was published on March 29, 2026, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by Novartis.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the patients who participated in this trial and their families, the members of the data monitoring committee (see the Supplementary Appendix), and Yumiko Abeynayake, M.D., of Amiculum, for medical writing assistance, funded by Novartis Pharma in accordance with Good Publication Practice guidelines.
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Copyright © 2026 Massachusetts Medical Society. All rights reserved.
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History
Published online: March 28, 2026
Published in issue: July 30, 2026
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Cited by
- Evidence-Based Medicine versus Personalized Medicine when attempting to block complement in IgA nephropathy, Nephrology Dialysis Transplantation, (2026).https://doi.org/10.1093/ndt/gfag159
- Complement Inhibition in the Clinic: Are We Doing Enough to Protect Patients From Infection?, European Journal of Immunology, 56, 7, (2026).https://doi.org/10.1002/eji.70233
- Complement Genetics in IgA Nephropathy, Clinical Journal of the American Society of Nephrology, 21, 7, (1123-1125), (2026).https://doi.org/10.2215/CJN.0000001125
- Complement inhibitors and B cell–modifying agents for IgA nephropathy—a Kidney Disease: Improving Global Outcomes (KDIGO) commentary, Kidney International, (2026).https://doi.org/10.1016/j.kint.2026.03.003
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* The trial included 477 patients with IgA nephropathy, an eGFR of at least $30 \text{ ml/min/1.73 m}^2$, and a 24-hour urinary protein-to-creatinine ratio of 1 or higher despite supportive care.
* Patients were randomized $1:1$ to receive oral iptacopan ($200 \text{ mg}$ twice daily) or placebo.
* The primary endpoint was the annualized total eGFR slope over a 24-month period.
* The annualized total eGFR slope with iptacopan was $-3.10 \text{ ml/min/1.73 m}^2/\text{year}$, compared to $-6.12 \text{ ml/min/1.73 m}^2/\text{year}$ for placebo.
* The difference in eGFR slope was $3.02 \text{ ml/min/1.73 m}^2/\text{year}$ with a $95\%$ CI of $2.02$ to $4.01$, adjusted $P<0.001$.
* A composite kidney-failure end-point occurred in $21.4\%$ of the iptacopan group versus $33.5\%$ in the placebo group (Hazard Ratio, $0.57$; $95\% \text{ CI}, 0.40$ to $0.81$).
* Adverse event incidence was $87.0\%$ in the iptacopan group and $89.1\%$ in the placebo group.
* Serious adverse events occurred in $12.2\%$ of the iptacopan group and $11.7\%$ of the placebo group.
* No deaths were reported in either group.

A phase 3 trial involving adults with IgA nephropathy was conducted to assess the effect of oral iptacopan on kidney function. Patients were randomized to receive either iptacopan (200 mg twice daily) or a placebo over 24 months. The primary endpoint was the annualized total eGFR slope. With iptacopan treatment, the estimated annualized total eGFR slope over 24 months was $-3.10 \text{ ml/min/1.73 m}^2/\text{year}$, compared to $-6.12 \text{ ml/min/1.73 m}^2/\text{year}$ in the placebo group, representing a difference of $3.02 \text{ ml/min/1.73 m}^2/\text{year}$. The trial also assessed a composite kidney-failure end point, which occurred in $21.4\%$ of the iptacopan group versus $33.5\%$ in the placebo group (hazard ratio of $0.57$). Furthermore, the therapy demonstrated an improvement in urinary protein-to-creatinine ratio, with a significant $38.3\%$ reduction observed in the 24-hour measurement compared to placebo. The safety profile was acceptable, with adverse event rates being similar between the two groups, and no deaths recorded.

The study demonstrates that targeted inhibition of the alternative complement pathway via iptacopan results in a significantly slower decline in estimated glomerular filtration rate compared to placebo in patients with IgA nephropathy over two years. The magnitude of the observed difference in eGFR trajectory suggests that controlling complement activation may mitigate the progression of renal damage in this condition. However, the key finding regarding the composite kidney-failure endpoint is complex; while the hazard ratio for this event was favorable ($0.57$), the incidence rate remains substantial across both arms. This raises a critical tension: does slowing the decline equate to preventing catastrophic failure events within the study window? The pattern suggests that the mechanism of action successfully modulates the rate of decline, but the ultimate outcome of kidney failure is influenced by inherent disease variability and patient factors not fully captured in this metric alone. Further inquiry must focus on correlating the reduction in protein-creatinine ratio with sustained functional outcomes and refining predictive models for these composite endpoints beyond a binary failure state to understand the full spectrum of benefit derived from complement inhibition.

Iptacopan in IgA Nephropathy

Facts Only

Executive Summary

Full Take

Sentinel — Human

Iptacopan in IgA Nephropathy

Facts Only

Executive Summary

Full Take

Sentinel — Human