Dual Blocking Effect Is Better For FSGS
Focal Segmental Glomerulosclerosis (FSGS) is a common glomerular disease with different levels of proteinuria and Nephrotic Syndrome. Its incidence is increasing. About 50% primary FSGS and proteinuria patients of kidney scope needs to take RRT treatment 5-10 years after treatment. The prognosis of FSGS is poor. It is a common cause of end-stage renal disease (ESRD) in adults (5%) and children (12%).
Currently, the main therapeutic agents are corticosteroids and other immunosuppressants which aims at reducing proteinuria, an independent predictor of renal survival in patients with primary FSGS. These drugs are often used in combination with renin-angiotensin system inhibitors (RASIs) but side effects from immunosuppressive agents often limit their clinical application. Therefore, there is an urgent need for drugs that can effectively and safely relieve FSGS proteinuria with good tolerance. Studies have shown that endothelin (ET) and angiotensin II can damage podocytes through a variety of molecular mechanisms, while endothelin receptor antagonist (ERAs) and RASIs can improve parenchymal injury and reduce proteinuria.
Sparsentan is a drug that blocks both angiotensin II and endothelin 1 receptors. To determine its efficacy and safety in the treatment of FSGS, Howard Trachtman's team at New York university has conducted a double-blind, randomized controlled trial.
Review of research
A total of 185 FSGS patients, aged 8-75 years, 30 ml/min/1.73 m2 eGFR>, urine protein creatinine ratio 1.0g /g, were included in the phase 2 randomized controlled study. Sparsentan (200mg/d, 400mg/d, 800 mg/d) and irbesartan (300 mg/d) were randomly administered for 8 weeks. The primary endpoint was the change in urinary protein creatinine ratio compared to baseline after 8 weeks of treatment, and the secondary endpoint was the proportion of patients who obtained part of the patients (urinary protein creatinine ratio < 1.5 g/g, a decrease of >40% compared to baseline).
Compared with patients irbesartan group, patients in sparsentan group have a greater reduction in proteinuria. In the Sparsentan high-dose group (400 and 800 mg), patients’ urinary protein creatinine ratio after 8 weeks of treatment was significantly lower than that in the irbesartan group.
28% of sparsentan patients got partial relief while 9% of irbesartan group had relief. After 8 weeks of treatment, 3 patients in the sparsentan group had complete response, while no patients in the irbesartan group had complete response.
The baseline eGFR of sparsentan and irbesartan patients was similar and remained stable during the study period.
The total incidence of emergency adverse events (TEAE), drug-related TEAE or severe TEAE was similar in sparsentan and irbersartan groups, and there were no deaths in the study. Low blood pressure, dizziness, edema, and gastrointestinal TEAE (such as vomiting, diarrhea, and nausea) were more common in the sparsentan group, compared to the irbesartan group. However, irbesartan group patients often suffer from fatigue, nasal congestion, upper respiratory tract infection, muscle spasms and hyperkalemia.
The results of this study showed that the decrease of proteinuria in FSGS patients treated with AT1 and ETA receptor double blocker sparsentan (400mg/d) for 8 weeks was greater than that of the AT1 receptor single blocker irbexatan (300 mg/d), with good safety and tolerance.
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