Abstract: FR-PO0646
Sparsentan in APOL1-Mediated Kidney Disease: A DUPLEX Post Hoc Signal and Trial Roadmap
Session Information
- Glomerular Diseases: Clinical, Outcomes, and Therapeutics Research - ANCA/FSGS
October 23, 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
Authors
- Urhoghide, Eseosa Omosivie, Authority Health, Detroit, Michigan, United States
- Leslie, Merfilius, Trinity Health Oakland Hospital, Pontiac, Michigan, United States
- Joseph, Chedis, Ross University School of Medicine, Miami, Florida, United States
- Hirani, Chetna N., Trinity Health Oakland Hospital, Pontiac, Michigan, United States
- Kargbo, Sorie P., Authority Health, Detroit, Michigan, United States
- Kakulavaram, Amitha, Trinity Health Oakland Hospital, Pontiac, Michigan, United States
Background
APOL1-mediated kidney disease (AMKD) disproportionately affects individuals of African ancestry, driving rapidly progressive CKD. High-risk APOL1 variants (G1, G2) are linked to focal segmental glomerulosclerosis (FSGS) and collapsing glomerulopathy through toxic gain-of-function podocyte injury, amplified downstream by endothelin and angiotensin pathways. While inaxaplin offers a targeted APOL1 approach, complementary downstream strategies remain limited. Sparsentan, a dual endothelin type A and angiotensin II type 1 receptor antagonist, may provide biologically plausible adjunctive renoprotection.
Methods
We synthesized AMKD pathophysiology and endothelin-angiotensin trial data to design a genotype-stratified trial for high-risk APOL1 populations.
Results
Endothelin-angiotensin signaling worsens proteinuria via vasoconstriction, inflammation, and fibrosis, with angiotensin II and endothelin-1 forming a self-sustaining cycle supporting dual pathway blockade. In the phase 3 DUPLEX trial, sparsentan showed sustained proteinuria reduction versus irbesartan, earning April 2026 FDA approval for FSGS. In a post-hoc subgroup of 14/371 (3.8%) participants with high-risk APOL1 genotypes, sparsentan achieved ~55% proteinuria reduction versus ~15% with irbesartan, and partial remission rates in high-risk patients on sparsentan (~45%) matched or exceeded those in low-risk participants (~41%). Though small, this biologically consistent signal supports confirmatory study. We propose a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of sparsentan 400 mg daily versus placebo in ~300 adults with biopsy-confirmed FSGS and high-risk APOL1 genotypes over 110 weeks, stratified by genotype, baseline proteinuria, and RAS blockade. The primary endpoint is proteinuria remission at Week 36; secondary endpoints include eGFR slope, kidney failure composite, and sustained remission at Week 110. Exploratory analyses examine responses by genotype, baseline kidney function, and African ancestry.
Conclusion
The DUPLEX post-hoc signal, though limited, supports formal evaluation of sparsentan through an APOL1-stratified trial to define its role in dual pathway blockade. Beyond therapeutics, this framework illustrates the importance of genotype-stratified design in addressing trial representation gaps.