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 DUET study, sparsentan, a single-molecule dual endothelin angiotensin receptor antagonist, 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

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

Read more about the study design.

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 CR, 33% (n=33) experienced ≥2 CR, and 26% (n=28) experienced ≥3 CR¹

In those that achieved CR, 43% reached onset within 6 months and 61% within 12 months of starting sparsentan treatment.¹

Those with ≥1 CR 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 CR patients versus 20% in non-CR patients¹

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 CR was associated with a significantly slower annual rate of decline in eGFR versus non-CR patients (P<0.001)¹

eGFR slope estimates over the entire treatment period were¹:

During the first 2 years of the follow-up period, a significant difference in chronic eGFR rates was also seen between CR and non-CR patients (P=0.002).¹

The incidence of treatment-emergent adverse events (TEAEs) was comparable between CR and non-CR patients¹

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

These TEAEs were more common in the CR group.¹ Heart failure was not reported during the OLE phase.¹

Key takeaway

The DUET post hoc analysis demonstrated sustained proteinuria remission and long-term safety with sparsentan.¹ The study found that achieving CR at any time point indicated a favorable response to sparsentan and predicted a better eGFR response, even if CR achievement was not sustained.¹

Footnotes

As of September 2024, sparsentan is not FDA-approved for the treatment of FSGS.

CR, complete remission; eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; IST, immunosuppressive therapy; OLE, open-label extension; RAAS, renin-angiotensin-aldosterone system; TEAE, treatment-emergent adverse events; UPCR, urine protein-creatinine ratio.

MA-SP-24-0111 | October 2024