Spruce Biosciences announced positive results from a Phase 2a, multicenter, 12-week trial of tildacerfont, an investigational, oral, once-a-day corticotropin-releasing factor type-1 receptor antagonist, in development for the treatment of congenital adrenal hyperplasia (CAH).
The Phase 2a study enrolled patients with classic CAH accompanied by elevated androgens at baseline who were treated with tildacerfont once-daily over 12 weeks, resulting in clinically relevant reductions in key parameters. These included mean reductions from baseline of 74% for ACTH, 82% for 17-OHP and 55% for A4. ACTH is the direct target of tildacerfont, while A4 is the critical downstream biomarker used in clinical management of patients with CAH. Maximum mean reductions observed at any timepoint in the study were 84% for ACTH, 82% for 17-OHP and 79% for A4. In addition, 60% of patients with elevated, abnormal ACTH and 40% of patients with elevated A4 saw reductions to normalization by week 12. The primary endpoint of safety and tolerability was achieved, with no new safety signals observed in the study and the majority of adverse events classified as mild, not related to study drug and single event occurrences. No serious adverse events were observed.
"There is a significant and urgent need for new CAH treatments as there are currently no FDA-approved therapies," said Richard Auchus, M.D., Ph.D., an investigator in the study and professor of internal medicine and pharmacology, division of metabolism, endocrinology & diabetes at University of Michigan, Ann Arbor. "The results of this study are encouraging as they demonstrate, for the first time, that a novel non-steroidal treatment can produce clinically meaningful reductions across key biomarkers over a period of 12 weeks. These data indicate tildacerfont could be a promising new treatment option for patients with CAH."
Classic CAH is a rare genetic disorder affecting the ability of the adrenal glands to function properly. CAH results from a mutation in the gene that encodes the enzyme 21-hydroxylase, which is necessary for the synthesis of key adrenal hormones. As a result, people with CAH have an impaired ability to produce the hormone, cortisol, which can result in life-threatening adrenal crises. Cortisol is also known as "the stress hormone," and is critical for the body's response to stress, illness and injury.
In CAH, the adrenal glands often produce excessive levels of male sex hormones or androgens. While both sexes need androgens for proper growth and development, an excess can cause problems that may include precocious puberty, short stature, hirsutism, increased risk of testicular adrenal rest tumors (TART) in men, and virilization and menstrual dysfunction in women.
Although CAH testing is part of the newborn screening program, there are currently no FDA-approved therapies for CAH. Glucocorticoids (such as hydrocortisone, prednisone and dexamethasone) are commonly used to treat CAH but are associated with a wide-range of side effects, including weight gain, reduced bone mineral density, metabolic abnormalities and increased cardiovascular risk.
This Phase 2a study was a U.S. multicenter, open-label, 12-week active treatment trial designed to evaluate the safety, tolerability and efficacy of once-daily 400 mg tildacerfont in adult subjects with classic CAH. Efficacy was characterized by tildacerfont's ability to reduce key disease biomarkers over time in subjects with elevated baseline ACTH and adrenal hormones (17-OHP and A4). In addition, several clinical outcomes were also evaluated.
Spruce's investigational lead product candidate, tildacerfont (formerly SPR001) is a potent, highly selective, oral, small-molecule antagonist of the corticotropin-releasing factor type-1 (CRF1) receptor. Preclinical studies have shown that through targeted delivery, tildacerfont binds to CRF1 receptors to block CRF-stimulated receptor function, thereby decreasing the production of excess androgens (androstenedione [A4]), progestins (17-hydroxyprogesterone [17-OHP]) and adrenocorticotropic hormone (ACTH), the primary driver of adrenal gland enlargement. This may allow physicians to reduce the chronic, high-dose steroids used to treat patients with congenital adrenal hyperplasia (CAH), potentially allowing physicians and patients complete control of CAH.
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