Sparsentan

Sparsentan is a molecule that acts as a dual antagonist of the endothelin type A receptor (ETAR) and the angiotensin II (Ang II) type 1 receptor (AT1R). It possesses two clinically validated mechanisms of action and selectively blocks the action of two potent vasoconstrictor and mitogenic agents, Ang II and endothelin 1 (ET-1), at their respective receptors. ET-1 and Ang II contribute to the pathogenesis of immunoglobulin A nephropathy (IgAN), a condition characterized by the increased production of galactose-deficient IgA1 (Gd-IgA1) antibodies. Gd-IgA1 antibodies lead to mesangial cell activation and proliferation, which stimulates and is stimulated by ET-1 and Ang II production. The pathological cycle of IgAN results in a compromised glomerular filtration barrier and subsequent proteinuria and haematuria. By acting as both an angiotensin receptor blocker (ARB) and an endothelin receptor antagonist (ERA), sparsentan reduces proteinuria in patients with IgAN. Sparsentan has a high affinity for both ETAR (Ki= 12.8 nM) and AT1R (Ki=0.36 nM), and greater than 500-fold selectivity for these receptors over the endothelin type B and angiotensin II subtype 2 receptors.