Evaluating sparsentan for the treatment of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) represents a histopathologic pattern of glomerular injury rather than a single disease entity. In FSGS, prognosis varies substantially according to the degree of proteinuria. Despite optimized supportive therapy and, in presumed primary FSGS, immunosuppression, many patients continue to manifest significant proteinuria and progressive loss of kidney function, highlighting an unmet need for new therapies. Sparsentan, a single-molecule dual endothelin receptor A and angiotensin II type 1 receptor antagonist, has emerged as a novel antiproteinuric therapy for FSGS.

This review discusses the role of endothelin-1 in FSGS, as well as the pharmacodynamic rationale, pharmacokinetic properties, clinical efficacy, and safety and tolerability of sparsentan.

Sparsentan provides antiproteinuric benefits beyond renin-angiotensin system blockade, supporting the endothelin pathway as an important therapeutic target in FSGS. However, the absence of a definitive kidney function benefit in the DUPLEX trial, together with the heterogeneous study population, limits firm conclusions. Sparsentan can be used in secondary and genetic FSGS, and in presumed primary FSGS with residual proteinuria after immunologic control. Future studies should better define the subgroups most likely to benefit and clarify the optimal dosing strategy.