Summary

The PROTECT interim analysis demonstrated reduction in proteinuria and a comparable safety profile with sparsentan in IgA nephropathy versus irbesartan¹

Background

IgA nephropathy is an important cause of kidney failure and is the most prevalent primary chronic glomerular disease worldwide.²

Proteinuria is a risk factor for loss of kidney function in patients with IgA nephropathy.² Treatment of proteinuria >0.5 g/day with renin-angiotensin system inhibitors (RASi) is recommended in treatment guidelines.³

Studies suggest that in addition to activation of the renin-angiotensin system (RAS), endothelin-1 (ET-1) signaling is a potential therapeutic target for renal diseases.⁴ Combined use of RASis and endothelin type A receptor (ET_AR) antagonists have shown additional beneficial effects in experimental models of kidney disease and in those with diabetic and non-diabetic nephropathies.^5-8

Sparsentan is a non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist that can be used to reduce proteinuria in adults with IgA nephropathy.⁹

Aim

The Phase 3 PROTECT study evaluated the long-term efficacy and safety of sparsentan in IgA nephropathy versus irbesartan.¹

Approach

PROTECT is a large, international, randomized, double-blind, active-controlled Phase 3 trial of sparsentan versus irbesartan in adults with IgA nephropathy.¹ Eligibility criteria included¹:

Participants were randomized to sparsentan 400 mg once daily (QD) (n=202) or irbesartan 300 mg QD (n=202).

The primary efficacy endpoint was change from baseline to Week 36 in urine protein-creatinine ratio (UPCR).¹ Safety endpoints included treatment-emergent adverse events (TEAE) and liver enzyme elevations.¹ The data herein are from a prespecified interim analysis and derived from the on-treatment full analysis set, which included all participants who received at least one dose of randomized treatment.¹

Read more about the two-year efficacy and safety findings from the PROTECT trial or listen now.

Findings

Baseline demographic and characteristics were well balanced between treatment groups¹

The primary endpoint, reduction in UPCR from baseline, was greater with sparsentan versus irbesartan¹

At Week 36, the mean change in UPCR was significantly greater in the sparsentan group than in the irbesartan group (-49.8% versus -15.1%, respectively).¹ The between group relative reduction was 41% (geometric least squares mean ratio [sparsentan/irbesartan] = 0.59, 95% CI: 0.51-0.69; P<0.0001).¹

This reduction was evident at Week 4 of the study and was maintained throughout follow-up.¹

The beneficial effect of sparsentan versus irbesartan on UPCR was consistent across subgroups¹

Subgroup analysis showed a consistent benefit from sparsentan versus irbesartan among demographic subgroups, and notably, in subgroups stratified by baseline eGFR and urine protein excretion.¹

Safety was similar between sparsentan and irbesartan¹

TEAEs were mostly similar across treatment groups.¹ TEAEs that occurred in a greater proportion (≥4% difference) of patients receiving sparsentan versus irbesartan were, respectively¹:

There were no cases of heart failure, hepatotoxicity, or severe edema or edema-related discontinuations.¹

Key takeaway

The interim analysis of the PROTECT study demonstrated a meaningful antiproteinuric effect of sparsentan in IgA nephropathy versus irbesartan and a comparable safety profile.¹

Footnotes

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; ET-1, endothelin-1; ET_AR, endothelin type A receptor; QD, once daily; RAS, renin-angiotensin system; RASi, renin-angiotensin system inhibitor; TEAE, treatment-emergent adverse event; UPCR, urine protein-creatinine ratio.

MA-SP-24-0102 | October 2024