DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS

Summary

An analysis of the Phase 2 DUET study for focal segmental glomerulosclerosis (FSGS) of sparsentan compared to irbesartan¹

Background

Focal segmental glomerulosclerosis (FSGS) is a group of heterogeneous conditions with a glomerular histopathology.² It typically presents with proteinuria and nephrotic syndrome.³

Immunomodulating treatments for FSGS aim to reduce proteinuria, a predictor of renal survival.⁴ These treatments are often used in conjunction with renin-angiotensin system inhibitors (RASi).⁴ However, these immunomodulators have therapy-limiting side effects highlighting the need for additional effective, safe, and well-tolerated options.^5,6 Simultaneous blockade of the endothelin type A receptor (ET_AR) and the angiotensin II subtype 1 receptor (AT₁R) may be a promising treatment for FSGS.^1,7

Sparsentan for FSGS is a first-in-class selective dual endothelin and angiotensin receptor antagonist.⁸

Aim

The trial evaluated the efficacy and safety of sparsentan for FSGS compared with irbesartan.¹

Approach

DUET was a Phase 2, randomized, double-blind, active-control trial comparing sparsentan with irbesartan.¹

Inclusion criteria were¹:

Patients were assigned to one of three sparsentan doses (200, 400, or 800 mg/day) or irbesartan 300 mg/day for 8 weeks.¹ Patients were then eligible to receive sparsentan during an open-label period.¹

The primary endpoint was change in UPCR from baseline to Week 8.¹ The secondary endpoint was proportion of patients achieving the FSGS partial remission endpoint (FPRE), defined as UPCR ≤1.5 g/g and >40% UPCR reduction from baseline to Week 8.¹

Read more about the DUET study design.

Findings

The treatment groups had similar baseline characteristics.¹

Greater reductions in proteinuria were seen with sparsentan in FSGS versus irbesartan.¹

The pooled analysis (all doses of sparsentan combined) demonstrated a 44.8% (95% CI: -52.7% to -35.7%) proteinuria reduction with sparsentan versus a 18.5% reduction with irbesartan (95% CI: -34.6% to 1.7%; P=0.006).

Treatment differences at Week 8 were larger for the pooled higher-dose sparsentan groups (400 and 800 mg/day) with a 47.4% reduction in UPCR versus 19% with irbesartan (P=0.01).

More patients receiving sparsentan for FSGS achieved FPRE versus irbesartan.¹

FPRE was achieved by 28% of patients receiving sparsentan for FSGS, compared with 9% who received irbesartan (P=0.04).¹

The incidence of adverse events (AE) was similar between groups.¹

The following AEs were more frequent with sparsentan than irbesartan¹:

No deaths occurred.¹

Read more about the findings from the DUET post hoc analysis.

Key takeaway

In this sparsentan for FSGS clinical trial, sparsentan ≥400 mg/day reduced proteinuria more than using irbesartan 300 mg/day after 8 weeks.¹ Both groups had a similar incidence of AEs.¹

Footnotes

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

AE, adverse event; AT₁R, angiotensin subtype 1 receptor; CI, confidence interval; CR, complete remission; eGFR, estimated glomerular filtration rate; ET_AR, endothelin type A receptor; FPRE, focal segmental glomerulosclerosis partial remission endpoint; FSGS, focal segmental glomerulosclerosis; RASi, renin-angiotensin system inhibitor; TEAE, treatment-emergent adverse event; UPCR, urine protein-creatinine ratio; US, United States.

MA-SP-24-0120 | November 2024