Sparsentan significantly lowered proteinuria compared to Irbesartan in IgA nephropathy: Protect Trial

The ongoing Protect trial revealed that once-daily treatment with sparsentan was safe and efficacious as it has significantly lowered proteinuria in patients with IgA nephropathy compared with irbesartan in adults. The phase 3 trial results were published in the journal The Lancet.

IgA nephropathy (IgAN) is a glomerular disease characterized by the presence of IgA deposits prevalent over other classes of immunoglobulins. It is associated with microscopic hematuria or asymptomatic proteinuria. Recently, Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin, and angiotensin receptor antagonist, was examined in an ongoing phase 3 trial called the Protect trial in adults with IgA nephropathy. The trial is an international, randomized, double-blind, active-controlled study, carried out in 134 clinical practice sites in 18 countries where sparsentan was compared with irbesartan.

Adults aged ≥18 years with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher participated in the trial despite maximized renin-angiotensin system inhibitor treatment for at least 12 weeks. Based on estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m2 and ≥60 mL/min per 1·73 m2) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day), participants were randomized in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily. The primary efficacy endpoint was changes from baseline to week 36 in urine protein–creatinine ratio. This was assessed based on a 24-h urine sample, using mixed model repeated measures. For safety assessment, treatment-emergent adverse events (TEAEs) were calculated. Nearly all endpoints were examined in all participants who received at least one dose of randomized treatment.

Key findings:

• Nearly 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment during the treatment period.
• There was a statistically significant change in the geometric least squares mean percent of urine protein–creatinine ratio from baseline to week 36.
• The sparsentan group (–49·8%) showed greater change than the irbesartan group (–15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51–0·69; p<0·0001).
• TEAEs were similar in both groups.
• There were no cases of severe edema, heart failure, hepatotoxicity, or edema-related discontinuations.
• No differences were noted in the body weight changes between the two groups.

Thus, once-daily treatment with sparsentan was found to be safe and significantly lowered proteinuria in patients with IgA nephropathy.

Further reading: Heerspink HJL, Radhakrishnan J, Alpers CE, et al. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial [published online ahead of print, 2023 Mar 31]. Lancet. 2023;S0140-6736(23)00569-X. doi: 10.1016/S0140-6736(23)00569-X