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. • Sparsentan is a single molecule that antagonizes two different receptors, with a higher affinity for AT 1 R than ET A R. • A dual antagonist cannot be assumed to share the risks of molecules belonging solely to either class of ARBs or ERAs. • The integrated analysis approach assessing nonclinical data, shows no sign of human male infertility risk with sparsentan. • Sparsentan is not toxic to the testes or spermatogenesis, its male fertility toxicity profile is like an ARB not an ERA.