What are the effects and functions of sparsentan?

It is an oral dual endothelin-angiotensin receptor antagonist that combines endothelin type A (ETA) receptor blockade and angiotensin II type 1 (AT1) receptor antagonism in a single molecule.

Sparsentan, developed by Travere Therapeutics, has hemodynamic and anti-inflammatory properties for the treatment of immunoglobulin A (IgA) nephropathy and focal segmental glomerulosclerosis (FSGS).

In February 2023, sparsentan received accelerated approval in the United States for reducing proteinuria in adults with primary IgA nephropathy who are at risk for rapid disease progression.

Clinical Advantages of Sparsentan

PROTECT is an international, randomized, double-blind, active-controlled study conducted at 134 clinical practice sites in 18 countries. The study compared sparsentan with irbesartan in adults (age ≥18 years despite maximizing renin-angiotensin system inhibitor therapy for at least 12 weeks) with biopsy-proven IgA nephropathy and proteinuria of 10 g/day or greater.

Subjects were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to < 60 mL/min/1 73 m2 and ≥60 mL/min/1 73 m2) and urinary protein excretion at screening (≤1 75 g/day and > 1 75 g/day).

A total of 404 participants were randomly assigned and treated with sparsentan (n=202) or irbesartan (n=202). The geometric least squares mean percent change from baseline in the urine protein/creatinine ratio at week 36 was statistically significant in the sparsentan group (49.8%) compared with the irbesartan group (15.1%), resulting in a 41% relative reduction between groups.

TEAEs with sparsentan were similar to those with irbesartan, with no cases of severe edema, heart failure, hepatotoxicity, or edema-related discontinuations.

Once-daily treatment with sparsentan was associated with a significant reduction in proteinuria compared with irbesartan in adults with IgA nephropathy.

Sparsentan

1. Hepatotoxicity: Sparsentan can cause ALT or AST to increase by at least 3 times ULN. In order to reduce the risk of potential severe hepatotoxicity, liver function should be tested every 3 months during treatment.

2. Embryo-fetal toxicity: The use of spasentan in pregnant patients may cause harm to the fetus, so it is contraindicated during pregnancy. Patients of childbearing potential should use effective contraceptive measures before starting treatment, during treatment and within 1 month after stopping treatment.

3. Acute kidney injury: Patients should regularly monitor kidney function during medication.

4. Hyperkalemia: Monitor serum potassium regularly and carry out appropriate treatment. It may be necessary to reduce the dose or discontinue sparsentan.

References:

Heerspink HJL, Radhakrishnan J, Alpers CE, Barratt J, Bieler S, Diva U, Inrig J, Komers R, Mercer A, Noronha IL, Rheault MN, Rote W, Rovin B, Trachtman H, Trimarchi H, Wong MG, Perkovic V; PROTECT Investigators. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomized, double-blind, active-controlled clinical trial. Lancet. 2023 May 13;401(10388):1584-1594. doi: 10.1016/S0140-6736(23)00569-X. Epub 2023 Apr 1. PMID: 37015244.

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