Tildacerfont is a potent and selective, oral, non-steroidal investigational small molecule currently being evaluated 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 downstream 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, metabolic disease, increased cardiovascular risk, further contribute to the significant CAH disease burden. The goal of therapy in CAH is to achieve a balance of the effects of excess androgen production and toxicities from supraphysiologic glucocorticoids, which is often hard to achieve in practice.
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 2019, Spruce Biosciences completed two Phase 2 clinical studies, of up to 12 weeks in duration, demonstrating proof-of-concept for tildacerfont in the treatment of patients with classic CAH by reducing and normalizing ACTH and downstream androgens. Tildacerfont is the first non-steroidal investigational therapy to demonstrate normalization of ACTH and androstenedione, a key androgen used to manage glucocorticoid treatment in CAH patients. Previously, Orphan Drug Designation was granted by both the US Food and Drug Administration (in 2017) and the European Medicines Agency (in 2018).
The company has initiated a placebo-controlled, double-blind Phase 2b clinical trial in adult patients with classic CAH with poor disease control and anticipates topline results in the fourth quarter of 2021. The company also initiated a second placebo-controlled, double-blind Phase 2b clinical trial in adult patients with classic CAH with good disease control focused on glucocorticoid reduction and anticipates topline results in the first half of 2022. The company also plans to evaluate tildacerfont in pediatric classic CAH and polycystic ovary syndrome.
Tildacerfont also has the possibility of treating other rare endocrine conditions with unmet medical need.