The dual endothelin (ET) and angiotensin (AT) receptor antagonist sparsentan lowers proteinuria in patients with immunoglobulin A (IgA) nephropathy, according to preliminary phase 3 trial data reported in The Lancet.
The authors report a planned interim analysis from the ongoing PROTECT trial, which enrolled patients at 134 sites in 18 countries. Eligible patients had biopsy-confirmed IgA nephropathy with proteinuria of 1.0 g/day or greater, despite at least 12 weeks of maximized renin-AT inhibitor therapy. Patients were randomly assigned to treatment with sparsentan, 400 mg once daily, or as an active control, irbesartan. The groups were stratified by a baseline estimated glomerular filtration rate (eGFR) and urinary protein excretion. Changes in the urine protein-creatinine ratio were measured in 24-hour urine samples.
Analysis included 280 of 404 treated patients who had attended the 36-week visit. The mean age was 46 years; the mean eGFR, 57.0 mL/min/1.73 m2; and the median urine protein excretion, 1.8 g/day. On efficacy analysis, geometric mean least-squares change in the urine protein-creatinine ratio was −49.8% in patients assigned to sparsentan versus −15.1% with irbesartan, for a relative reduction of 41%. Complete remission of proteinuria occurred in 21% of patients with sparsentan versus 8% with irbesartan: odds ratio (OR), 3.1. Partial remission rates were 70% and 40%, respectively, with the OR, 4.5. Rates of treatment-emergent adverse events were high but similar between groups. There were no cases of severe edema, heart failure, liver toxicity, or edema-related treatment discontinuation.
Sparsentan selectively targets the ET receptor A (ETA) and AT II subtype 1 receptor (AT1), which contribute to the pathophysiology of IgA nephropathy. In a previous trial in patients with focal segmental glomerulosclerosis, sparsentan reduced proteinuria compared with irbesartan.
The PROTECT data show a similar effect in patients with IgA nephropathy at high risk of disease progression due to continued proteinuria. Safety outcomes appear similar to those of irbesartan. Planned 2-year assessments will evaluate the long-term nephroprotective effects of sparsentan.
Heerspink HJL, et al. Sparsentan in patients with IgA nephropathy: A prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet 2023; 401:1584–1594. doi: 10.1016/S0140-6736(23)00569-X