Mechanism of protective actions of sparsentan in the kidney: lessons from studies in models of chronic kidney disease

Abstract

Simultaneous inhibition of angiotensin II AT1 and endothelin ETA receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This therapeutic approach has been advanced by the introduction of sparsentan, the first dual AT1 and ETA receptor antagonist. Sparsentan is a single molecule with high affinity for both receptors. It is US Food and Drug Administration approved for immunoglobulin A nephropathy (IgAN) and is currently being developed as a treatment for rare kidney diseases, such as focal segmental glomerulosclerosis. Clinical studies have demonstrated the efficacy and safety of sparsentan in these conditions. In parallel with clinical development, studies have been conducted to elucidate the mechanisms of action of sparsentan and its position in the context of published evidence characterizing the nephroprotective effects of dual ETA and AT1 receptor inhibition. This review summarizes this evidence, documenting beneficial anti-inflammatory, antifibrotic, and hemodynamic actions of sparsentan in the kidney and protective actions in glomerular endothelial cells, mesangial cells, the tubulointerstitium, and podocytes, thus providing the rationale for the use of sparsentan as therapy for focal segmental glomerulosclerosis and IgAN and suggesting potential benefits in other renal diseases, such as Alport syndrome.

Keywords: Angiotensin II; Endothelin Type A receptor; Endothelin-1; FSGS; IgA nephropathy; Sparsentan.

Figure 1. Chemical structure of sparsentan

Chemical structure of the dual endothelin angiotensin receptor antagonist (DEARA), sparsentan, showing the key structural elements of the molecule responsible for antagonism of each receptor, ET_AR and AT₁R (adapted from [2]). Adapted from Murugesan N, et al. (2005) J. Med. Chem. 48(1):171–179. Copyright © 2005, American Chemical Society.

Figure 2. Mechanisms of action of sparsentan in the kidney

Schematic presentation of main actions of sparsentan in the kidney associated with long-term nephroprotective effects as observed in preclinical studies. These actions include anti-inflammatory and antifibrotic effects both in glomeruli and the tubulointerstitial compartment, podocyte protection, and preservation of the glomerular glycocalyx, in parallel with beneficial effects on glomerular hemodynamics. Created with Biorender.com by Wilmelenne Clapper. ECM, extracellular matrix; mRNA, messenger RNA.

Figure 3. Sparsentan ET_AR and ET_BR occupancies (right axis) and plasma concentration* (left axis) over 24 h for a single, daily, 400-mg oral dose at steady-state in the PROTECT study (adapted from [165])

Steady-state PK parameters calculated using population PK values for sparsentan 400 mg in the PROTECT study were used to estimate diurnal changes in receptor occupancy. Sparsentan AT₁R occupancy (>95%) consistently exceeds ET_AR occupancy (>60% and <90%) over a full 24-h period. ET_BR occupancy never exceeds 2%. *PK data are based on population PK model prediction for a patient with IgAN. AT₁R, angiotensin II receptor type 1; ET_AR, endothelin receptor type A; ET_BR, endothelin receptor type B; PK, pharmacokinetics.