Patients in DUPLEX Achieved Partial or Complete Remission of Proteinuria Earlier and More Often With Sparsentan vs Irbesartan: Implications for Slowing Progression to Kidney Failure in Focal Segmental Glomerulosclerosis (FSGS)
2025
Estimating the Benefits of Proteinuria Reduction on Kidney Failure Risk in the DUPLEX Study Using an Aligned FSGS Cohort From the UK RaDaR Registry
About the research
Summary
Background
- In the PARASOL initiative, proteinuria-response endpoints were strongly associated with kidney failure risk in a large focal segmental glomerulosclerosis (FSGS) cohort.1,2
- Findings from PARASOL were validated in a UK National Registry of Rare Kidney Diseases (RaDaR) replication cohort.1,3
- DUPLEX was a 108-week Phase 3 randomized trial evaluating the efficacy and safety of sparsentan vs. irbesartan in patients with FSGS.1,4
- In DUPLEX, sparsentan significantly reduced proteinuria across multiple urine protein-to-creatinine ratio (UPCR) thresholds, and more patients achieved partial or complete remission of proteinuria with sparsentan than irbesartan.1,4
- Read more about the findings from the Phase 3 DUPLEX study
- Given the differences between PARASOL and DUPLEX populations, it is unclear how translatable PARASOL proteinuria findings are to the DUPLEX population in predicting kidney failure risk.1
Aim
To quantify the potential benefits of proteinuria reduction observed in the DUPLEX trial on long-term risk of kidney failure by analyzing a cohort from RaDaR aligned to the DUPLEX population.1
Approach
A RaDaR cohort (n=386) was formed based on characteristics of the DUPLEX population1:
- Biopsy-proven or genetic diagnosis of FSGS in the RaDaR Idiopathic Nephrotic Syndrome (INS) cohort
- First UPCR value ≥1.5 g/g that was ≥6 months from diagnosis
- 8-75 years of age at index
- Estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2
The association between proteinuria reduction with long-term risk of kidney failure was quantified for the DUPLEX-aligned RaDaR cohort. Using these findings, the long-term risk of kidney failure for the DUPLEX population was predicted based on proteinuria findings from DUPLEX.1
Clinical measures included1:
- Kidney failure defined as eGFR <15 mL/min/1.73 m2 or kidney replacement therapy
- Kidney failure survival defined as absence of kidney failure
- Proteinuria responder status defined as UPCR of <0.3 g/g and <0.7 g/g
- Change in UPCR from baseline (log-transformed)
Key findings
Baseline/Index characteristics
Demographics and clinical characteristics were similar in the DUPLEX and DUPLEX-aligned RaDaR cohorts.1,4
Kidney failure event rates over 24 months
Kidney failure rates were comparable between the DUPLEX-aligned RaDaR cohort and DUPLEX irbesartan arm (10.9% vs. 11.2%).1,4,5
A lower rate of kidney failure was observed in the DUPLEX sparsentan arm (6.5%) compared with all other patient cohorts.1
Association of 24-month proteinuria responder status and kidney failure
In the DUPLEX-aligned RaDaR cohort, achieving a 24-month UPCR of <0.3 g/g or <0.7 g/g was strongly associated with a lower risk of kidney failure over the 84-month follow-up.1-3
Those with 24-month UPCR of <0.3 g/g or <0.7 g/g had higher rates of survival1:
- Response threshold <0.3 g/g1:
- Non-responder survival estimate: 0.70 (95% CI 0.62-0.76)
- Responder survival estimate: 0.93 (95% CI 0.81-0.98)
- Hazard ratio (HR): 0.16 (95% CI 0.05-0.51)
- Response threshold <0.7 g/g1:
- Non-responder survival estimate: 0.66 (95% CI 0.58-0.73)
- Responder survival estimate: 0.94 (95% CI 0.84-0.98)
- HR: 0.14 (95% CI 0.05-0.38)
Findings from the DUPLEX-aligned RaDaR cohort were consistent compared to PARASOL findings.1-3
Time varying analysis (UPCR as a time-dependent variable)
Associations between achieving a UPCR <0.3 g/g or <0.7 g/g at any time and kidney failure events were also strong, although not as strong numerically as the 24-month landmark association.1
Change in UPCR from baseline at 24 months
The association between kidney failure events and change from baseline UPCR at 24 months showed a HR of 0.41 (95% CI 0.29-0.58) for each log unit reduction in UPCR.1
This corresponds to a 59% reduction in risk of kidney failure for each log-unit decrease in UPCR.1
When applied to the DUPLEX cohort, the observed 26% relative UPCR reduction at 24 months predicts a 24% reduction in kidney failure risk over 84 months.1,2
Conclusions
Consistent with findings from PARASOL, the DUPLEX-aligned RaDaR cohort demonstrated robust reductions in risk of kidney failure for patients who achieved UPCR <0.3 g/g or <0.7 g/g at 24 months.1
A clinically meaningful benefit was seen in those who achieved proteinuria <0.3 g/g and <0.7 g/g, which occurred more frequently in patients in the sparsentan arm vs. the irbesartan arm.1
A significant and clinically meaningful benefit in 5-year kidney survival is predicted based on the relative reduction in UPCR observed with sparsentan vs. irbesartan in DUPLEX.1 These results are corroborated by lower kidney failure event rates seen in the 108-week trial period.1
Related Content
Footnotes
CI, confidence interval; eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; HR, hazard ratio; INS, Idiopathic Nephrotic Syndrome; RaDaR, National Registry of Rare Kidney Diseases; UPCR, urine protein-to-creatinine ratio.
- Mercer A et al. Presented at: ASN Kidney Week; November 5-9, 2025; Houston, TX.
- Smith A et al. Presented at: ASN Kidney Week; October 23-27, 2024; San Diego, CA.
- Smith A et al. Nephrol Dial Transplant. 2025;40(Suppl 3):gfaf116.032.
- Rheault MN et al. N Engl J Med. 2023;389:2436-2445.
- Gipson DS et al. JAMA Netw Open. 2022;5(8):e2228701.
MA-SP-25-0211 | November 2025