The dual endothelin A and angiotensin II type 1 receptor antagonist sparsentan (FILSPARI®) exhibits a safe nonclinical male fertility toxicity profile.

Marketed endothelin receptor antagonists (ERAs) have been associated with testicular tubular atrophy and decreases in male animal fertility in chronic toxicity studies in rats and dogs. Consistent with these findings, reduced sperm count has been observed in the clinical setting and is considered a potential class risk with chronic administration of ERAs. In contrast, no such effects on male animal fertility are noted with angiotensin II type 1 receptor blocker (ARB) treatment. Sparsentan (FILSPARI®) is a novel single molecule dual antagonist that antagonizes both the endothelin type A and angiotensin II type 1 receptors. We explored whether the reproductive toxicology profile of this dual endothelin angiotensin antagonist is more like that of marketed ERAs or ARBs. A full package of repeat dose general toxicity, juvenile toxicity, carcinogenicity, and reproductive and developmental toxicity studies was completed with sparsentan. A thorough review of the results from these studies has shown no evidence of effects of sparsentan on spermatogenesis or testicular histopathology. The overall conclusion of this assessment is that sparsentan is not toxic to the testes or the spermatogenic process and is more like ARBs than ERAs in its male fertility toxicity profile.