Spruce Biosciences, Inc., a company progressing towards late-stage drug development, is committed to introducing groundbreaking treatments for neurological and endocrine disorders faced with significant unmet medical requirements. Recently, they unveiled the primary outcomes from their trial, CAHmelia-204, regarding tildacerfont’s role in treating adults with congenital adrenal hyperplasia (CAH) and the CAHptain-205 study, focused on both adult and pediatric CAH.
“Our heartfelt gratitude goes out to the patients, families, researchers, and the broader CAH community for their unwavering support during the CAHmelia-204 and CAHptain-205 clinical trials. These trials have yielded essential information on the safety and exposure response of tildacerfont, hinting that higher and more frequent dosages might be required for efficacy in CAH,” stated Javier Szwarcberg, CEO of Spruce.
“As we move forward, we aim to thoroughly explore strategic opportunities surrounding diseases that currently lack adequate treatment options for patients. Meanwhile, the ongoing CAHmelia-204 and CAHptain-205 trials will be concluded, and Spruce will reduce its financial commitment to tildacerfont for CAH treatment in a bid to preserve resources and enhance shareholder profit.”
The CAHmelia-204 clinical trial functioned as a phase 2b, randomized, double-blind, placebo-controlled study, examining the safety and efficacy of tildacerfont in reducing supraphysiologic glucocorticoid (GC) usage across 100 adult participants with classical CAH. These participants were on a mean GC dose of 35mg per day of hydrocortisone equivalents (HCe) (19mg/m2/day) and had a mean androstenedione (A4) level of 214 ng/dL at the start. The trial didn’t meet its primary efficacy target, which was the change in daily GC dose from initial levels at week 24, with a 200mg once-daily dose of tildacerfont showing a placebo-adjusted reduction of just 0.7mg HCe (95% CI: -4.3 to 2.9, p=0.7).
Almost 98% of participants showed high compliance with the study treatment. Tildacerfont was generally well tolerated with no serious adverse events (SAEs). “Though the study didn’t meet its main endpoint, the data garnered provides substantial insights that will influence future approaches to CAH treatment and research,” remarked Jung Hee Kim, Principal Investigator and Associate Professor of Internal Medicine at Seoul National University Hospital and College of Medicine. “My gratitude to nearly 400 CAH patients who contributed their data, and I eagerly anticipate sharing our findings at upcoming 2025 conferences.”
“The trial was executed with high compliance,” commented Paul Thornton, Principal Investigator and Medical Director of the Endocrine and Diabetes Programme at a Center of Excellence. “Findings suggest that a twice-daily dosing might yield better results.”
The CAHptain-205 trial, categorized as phase 2 open-label, incorporated a sequential nine-cohort design to study the safety, efficacy, and pharmacokinetics of tildacerfont in children and adults aged two to 17 years with CAH. Cohorts 1-3 focused on weight-adjusted doses of tildacerfont ranging from 50mg once daily to 200mg once daily in pediatric CAH patients and monitored changes in androgen levels across 12 weeks of therapy, as well as the potential to decrease daily GC dose upon A4 normalization. Meanwhile, cohorts 4-9 evaluated doses ranging from 200mg twice daily to 400mg twice daily in both children and adults, aiming to measure androgen level fluctuations over four weeks.
CAH is genetically inherited on an autosomal recessive pattern, triggered by a mutation in the gene responsible for encoding an enzyme necessary for crucial adrenal hormone production. CAH patients are unable to produce cortisol, leading to severe health issues. The absence of cortisol causes disruptions in the hypothalamic-pituitary-adrenal (HPA) axis feedback loop, increasing adrenocorticotropic hormone (ACTH) secretion, adrenal gland hyperplasia, and high adrenal androgen levels. Consequently, CAH patients can experience early puberty, fertility challenges, excess facial or body hair, acne, adrenal tumors, and diminished quality of life; women may also face virilized genitalia and menstrual irregularities. Current treatments involve administering supra-physiological GC dosages, which can induce additional side effects like diabetes, heart disease, growth retardation, bone thinning, fragile skin, digestive issues, and reduced lifespan.
Tildacerfont is a highly potent and selective non-steroidal oral antagonist targeting the CRF1 receptor, which interacts with corticotropin-releasing factor (CRF) produced by the hypothalamus. The CRF1 receptor, predominantly present in the pituitary gland, primarily controls the HPA axis. By inhibiting the CRF1 receptor, tildacerfont potentially addresses imbalances in cortisol regulation within CAH, subsequently lowering ACTH in the pituitary and decreasing subsequent androgen production in the adrenal gland. Thus, tildacerfont may curb excess adrenal androgens using a novel method, reducing related symptoms and possibly decreasing the required supraphysiologic GC doses in CAH patients to more normal levels. No drug-related SAEs have been associated with tildacerfont in concluded trials.