Implications of Complete Proteinuria Remission at Any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial

Summary

The DUET post hoc analysis of proteinuria remission and long-term safety in patients with focal segmental glomerulosclerosis (FSGS)¹

Background

Focal segmental glomerulosclerosis (FSGS) occurs due to podocyte injury.² It presents with a variable degree of proteinuria and often with concomitant nephrotic syndrome.²

Patients with proteinuria and FSGS are usually treated with renin-angiotensin system inhibitors (RASi), while nephrotic syndrome is typically treated with a trial of corticosteroids.³ Immunosuppressive therapies (ISTs) are offered to those with persistent proteinuria.³

There are no approved treatments for FSGS,* and assessing efficacy of novel treatments for FSGS has been proven difficult.¹ There has been a movement towards using proteinuria as a surrogate endpoint to support drug approvals.⁴

In the Phase 2 DUET study, sparsentan, a single-molecule Dual Endothelin Angiotensin Receptor Antagonist (DEARA), demonstrated a greater reduction in proteinuria at Week 8.⁵ A subset of patients who continued to the open-label extension (OLE) portion of the study achieved a sustained reduction in proteinuria with sparsentan.^1,6

Aim

The post hoc analysis of the DUET study aimed to evaluate the following¹:

Approach

DUET was a randomized, double-blind, active-controlled, dose-escalation Phase 2 study.¹

Findings

The DUET study enrolled 109 patients and 108 were included in the post hoc analysis¹

Patients who received ≥1 sparsentan dose in the double-blind and/or OLE portion of the study were included (n=108).¹

At the OLE data cutoff, the median duration of sparsentan treatment was 3.9 years.¹

In terms of proteinuria remission, 43% (n=46) of patients experienced ≥1 complete remission of proteinuria (UPCR ≤0.3 g/g), while 33% (n=33) experienced ≥2, and 26% (n=28) experienced ≥3¹

In those who achieved complete remission of proteinuria (UPCR ≤0.3 g/g), 43% reached onset within 6 months and 61% within 12 months of starting sparsentan treatment.¹

Those with ≥1 complete remission of proteinuria (UPCR ≤0.3 g/g) had significantly lower baseline proteinuria.¹ In addition, a higher proportion of patients with ≥1 were receiving IST.¹

During the OLE, there was a substantial and sustained reduction in proteinuria that reached approximately 80% in patients who experienced complete remission of proteinuria (UPCR ≤0.3 g/g) and 20% in those who did not¹

Similar findings were seen after adjusting for age, sex, race, ethnicity, nephrotic syndrome, baseline UPCR, and baseline estimated glomerular filtration rate (eGFR).¹

Over the treatment period, achieving ≥1 complete remission of proteinuria (UPCR ≤0.3 g/g) was associated with a significantly slower annual rate of decline in eGFR versus none (P<0.001)¹

eGFR slope estimates over the entire treatment period (according to achievement of complete remission of proteinuria [UPCR ≤0.3 g/g], yes or no) were:

During the first 2 years of the follow-up period, a significant difference in chronic eGFR rates was also seen between patients who reached complete remission of proteinuria (UPCR ≤0.3 g/g) and those who did not (P=0.002).¹

The incidence of treatment-emergent adverse events (TEAEs) was comparable between patients who achieved complete remission of proteinuria (UPCR ≤0.3 g/g) and those who did not¹

The most common TEAEs with overall incidence ≥20% in either group were¹:

These TEAEs were more common in patients who reached complete remission of proteinuria (UPCR ≤0.3 g/g).¹ Heart failure was not reported during the OLE phase.¹

Key takeaway

The DUET post hoc analysis demonstrated sustained complete remission of proteinuria (UPCR ≤0.3 g/g) and long-term safety with sparsentan.¹ The study found that a complete remission of proteinuria (UPCR ≤0.3 g/g) at any time point indicated a favorable response to sparsentan and predicted a better eGFR response, even if this achievement was not sustained.¹

Footnotes

The DUET trial with open-label extension was funded by Travere Therapeutics, Inc. Please see the publication for the full list of disclosures.

*As of February 2026, sparsentan is not FDA-approved for the treatment of FSGS.

DEARA, Dual Endothelin Angiotensin Receptor Antagonist; eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; IST, immunosuppressive therapy; OLE, open-label extension; RASi, renin-angiotensin system inhibitor; TEAE, treatment-emergent adverse events; UPCR, urine protein-to-creatinine ratio.

MA-SP-24-0111 | February 2026