DUPLEX: Sparsentan Could Offer Greater Benefit in Genetic FSGS

Author(s):

Key Takeaways

Sparsentan demonstrated a more pronounced antiproteinuric effect in gFSGS patients compared to irbesartan, sustained throughout the study period.
The DUPLEX trial, the largest in FSGS, showed sparsentan's superior efficacy in reducing proteinuria over 108 weeks.
Despite proteinuria reduction, no significant differences in eGFR slope were observed between sparsentan and irbesartan.
Sparsentan's effect was particularly notable in patients with NPHS2 mutations, suggesting potential for targeted therapy in gFSGS.

A posthoc analysis of the DUPLEX trial suggests patients with genetic FSGS may experience a more pronounced and sustained antiproteinuric response with sparsentan.

Jennifer Yi-Chun-Lai Yee, MD, PhD, MPH
Credit: Michigan Medicine

A posthoc analysis of the largest clinical trial to date in focal segmental glomerulosclerosis (FSGS) suggests patients with genetic FSGS (gFSGS) could derive benefit from sparsentan (Filspari) similar to patients with other forms of FSGS.

An analysis of the DUPLEX trial, which was presented at the American Society of Nephrology’s Kidney Week 2024 nearly 1 year to the day after the presentation of the original DUPLEX trial, results indicate patients with gFSGS experienced a more pronounced antiproteinuric response with sparsentan, with this effect sustained across the duration of the study period.¹

“Our study analyzed a subset group of patients with genetic FGS from the DUPLEX clinical trial, and, consistent with the overall FSGS population in DUPLEX, our patients displayed more pronounced early and durable antiproteinuria effect with sparsentan compared to irbesartan and also favorable outcomes in complete remission or kidney composite kidney failure,” explained principal investigator Jennifer Lai Yee, MD, PhD, MPH, of the Department of Pediatrics in the Division of Nephrology at the University of Michigan, in an interview with HCPLive.

A global, multicenter, randomized, double-blind, parallel-group, active-controlled study, DUPLEX was billed as the largest interventional study in FSGS to date and compared use of sparsentan against irbesartan among 371 patients. For inclusion, patients needed to be 8 to 75 years age, have biopsy-confirmed FSGS or a documented pathogenic variant in a podocyte protein associated with FSGS, a urinary protein-to-creatinine ratio (UPCR) of 1.5 or greater, and an eGFR of at least 30 mL/min/1.73m2 of body-surface area at screening. These patients were randomized in a 1:1 ratio to sparsentan or irbesartan for 108 weeks.^2,3

Results of the trial, which were presented as a late-breaking clinical trial at Kidney Week 2023, found use of sparsentan resulted in a greater reduction in proteinuria than use of irbesartan at 36 weeks, with this trend continuing through the duration of the 108-week trial. However, despite this difference in effect on proteinuria, there were no statistically significant between-group differences in eGFR slope at 108 weeks, which was the trial’s primary outcome of interest.²

Of the 371 patients who underwent randomization in the original trial, 355 were genotypes by the FSGS panel of prevention Genetics. For the purpose of analysis, investigators used Mendelian inheritance to classify patients with pathogenic or likely pathogenic variants in podocyte genes.¹

The primary outcome of interest for the ASN Kidney Week 2024 analysis was the change in proteinuria and the property of patients reaching end-stage kidney disease with sparsentan relative to irbesartan. Of note changes in proteinuria were assessed as the percentage reduction from baseline and as the proportion of patients achieving complete remission, which was defined as a UPCR <0.3 g/g at any time.¹

Investigators identified a total of 31 individuals identified as having gFSGS. Relative to the overall DUPLEX population, patients with gFSGS were younger and had a greater eGFR at baseline, with most having a nephrotic-range proteinuria.¹

Results of the analysis presented by Lai Yee at ASN Kidney Week 2024 suggested use of sparsentan was associated with a more rapid and more pronounced reduction in proteinuria relative to irbesartan, with this effect sustained throughout the duration of the treatment period. Further analysis revealed a similar pattern among patients with NPHS2 mutations.¹

Investigators pointed out complete remission was only achieved by 1 patient with gFSGS compared to 0 with irbesartan. Additionally, investigators highlighted 3 individuals reached end-stage kidney disease with irbesartan relative to 1 patient with sparsentan.¹

“As the largest clinical trial for patient with genetic FSGS to date, our results that suggest sparsenstan can provide a meaningful effect for this patient population that is historically resistant to treatment,” Yee added.

References:

Lai Yee J, Gong W, Inrig JK, et al. Outcomes of the DUPLEX Trial in Patients with Genetic Focal Segmental Glomerulosclerosis (gFSGS). Presented at American Society of Nephrology Kidney Week 2024. San Diego, CA. October 23-27, 2024.
Rheault MN, Alpers CE, Barratt J, et al. Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis. N Engl J Med. 2023;389(26):2436-2445. doi:10.1056/NEJMoa2308550
Trachtman H, Radhakrishnan J, Rheault MN, et al. Focal Segmental Glomerulosclerosis Patient Baseline Characteristics in the Sparsentan Phase 3 DUPLEX Study. Kidney Int Rep. 2024;9(4):1020-1030. Published 2024 Jan 28. doi:10.1016/j.ekir.2024.01.032