Tildacerfont (SPR001) is a potent and selective, oral, non-steroidal investigational small molecule currently being tested for the treatment of CAH and other endocrine disorders. Tildacerfont works by blocking CRF type-1 receptors on the pituitary gland to decrease ACTH release and, thus, reduce excessive adrenal androgen production.
The majority of CAH patients do not achieve optimal control of androgen levels despite being treated chronically with supraphysiologic doses of glucocorticoids, the current standard of care. High levels of ACTH and androgens lead to many clinical sequelae associated with CAH including precocious puberty, short-stature, hirsutism, genital virilization and menstrual irregularities in females, and testicular adrenal rest tumors (TARTs) in males. In addition, the side-effects from life-long, high-dose glucocorticoid use, including weight gain, bone loss, and metabolic disease, further contribute to the significant CAH disease burden.
Tildacerfont may allow for the maintenance of androgens at target levels in the context of physiologic doses of glucocorticoids, thereby reducing the risk of glucocorticoid toxicities. Additionally, based on tildacerfont’s novel mechanism of action, there is the potential to alleviate the clinical sequelae of CAH, and thus significantly reduce disease burden.
In early 2019, Spruce Biosciences completed a Phase 2 clinical study demonstrating proof-of-concept for tildacerfont in the treatment of patients with classic CAH. Previously, Orphan Drug Designation was granted by both the US Food and Drug Administration (in 2017) and the European Medicines Agency (in 2018). Spruce is currently preparing to initiate late-stage clinical trials to further demonstrate the safety and efficacy of tildacerfont to control adrenal hormones, improve clinical outcomes, and reduce patient dependence on supraphysiologic GCs.
Tildacerfont also has the possibility of treating other endocrine conditions with unmet medical need, such as Cushing’s Disease, which is caused by pituitary tumors that secrete high levels of ACTH. Patients with Cushing’s Disease suffer the sequelae of hypercortisolism (which include weight gain, obesity, muscle weakness and skin changes. Given tildacerfont’s ability to block CRF type-1 receptors on the pituitary gland, it has the potential to normalize ACTH levels in this condition.