Abstract: SA-PO0673
Composite Kidney Failure End Points in Contemporary Phase 3 Randomized Controlled Trials of Novel Therapies for IgAN: A Systematic Review and Meta-Analysis Stratified by Mechanism of Action
Session Information
- Glomerular Diseases: Clinical, Outcomes, and Therapeutics Research - Other
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Author
- Tripathi, Ohm S., University of Connecticut, Storrs, Connecticut, United States
Background
Multiple novel therapies have received regulatory approval for IgA nephropathy (IgAN) based largely on surrogate endpoints. Whether these agents collectively reduce hard kidney failure outcomes — and whether mechanistic class predicts the magnitude of benefit — remains unquantified across the contemporary phase 3 trial landscape.
Methods
We conducted a systematic review and meta-analysis of phase 3 RCTs in biopsy-proven IgAN that prespecified a composite kidney failure endpoint comprising sustained ≥40% eGFR decline, end-stage kidney disease (ESKD), or death due to kidney disease. Pooled hazard ratios (HRs) were estimated using a random-effects model (DerSimonian-Laird). Subgroup analyses were performed stratified by mechanistic class: intestinal/mucosal immunosuppression (targeted-release budesonide, methylprednisolone), complement factor B inhibition (iptacopan), and dual RAAS/endothelin antagonism (sparsentan).
Results
Four phase 3 RCTs comprising 1,714 participants met primary inclusion criteria: NefIgArd (budesonide TRF, HR 0.45, 95% CI 0.26–0.75), PROTECT (sparsentan, RR 0.70, 95% CI 0.40–1.20), APPLAUSE-IgAN (iptacopan, HR 0.57, 95% CI 0.40–0.81), and TESTING (methylprednisolone, HR 0.53, 95% CI 0.39–0.72). The pooled HR for the composite kidney failure endpoint was 0.52 (95% CI 0.40–0.67; I = 18%), corresponding to a 48% relative risk reduction. Mechanistic stratification showed consistent benefit across classes (Pinteraction = 0.42), with intestinal/mucosal immunosuppression showing a pooled HR of 0.50 (95% CI 0.37–0.68) and complement inhibition an HR of 0.57 (95% CI 0.40–0.81). The sensitivity analysis including the DAPA-CKD IgAN subgroup (HR 0.29, 95% CI 0.12–0.73; ≥50% threshold) yielded a pooled HR of 0.50 (95% CI 0.37–0.67). Serious adverse event rates were higher with methylprednisolone (10.9% vs. 2.8%) but comparable to placebo for targeted therapies.
Conclusion
Contemporary phase 3 IgAN therapies across distinct mechanistic classes consistently reduce composite kidney failure risk by approximately 48% relative to control. Low heterogeneity suggests that the composite KF endpoint captures a shared final common pathway amenable to therapeutic modification regardless of upstream target.