Patients with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) may benefit from the drug tildacerfont, according to the results from two Phase 2 clinical studies recently published in The Journal of Clinical Endocrinology & Metabolism.
Researchers led by Chris N. Barnes, PhD, of Spruce Biosciences (who funded the trial), point out that the current approach to treating CAH is to downregulate the production of excess androgens by administering supraphysiologic levels of glucocorticoids (GC). However, this approach may lead to significant side effects such as stunted growth, obesity, and increased risk of developing type 2 diabetes, cardiovascular disease, osteoporosis, skin toxicities, gastrointestinal disorders, and reduced lifespan, the authors write.
“Tildacerfont (SPR001; LY2371712) is a potent, selective, nonsteroidal, oral, second generation CRF type-1 (CRF1) receptor antagonist that binds to CRF1 receptors in the pituitary gland with high affinity and reduces ACTH secretion,” the authors continue. “When administered to patients with CAH, the reduction in ACTH secretion is expected to reduce overproduction of adrenal cortisol precursors and androgens. By controlling excess adrenal androgens through an independent mechanism, tildacerfont may decrease the clinical symptoms associated with high androgen exposure and allow GC reduction to a dosing regimen nearing physiological levels, thereby reducing the adverse effects of supraphysiologic GCs.”
The researchers conducted two Phase 2 studies to assess the safety and efficacy of tildacerfront in adults with 21OHD. SPR001-201 was an open-label, multi-dose, Phase 2a dose-escalation study which evaluated the ability of tildacerfont to lower adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) at doses ranging from 200mg daily to 1,000mg daily in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
SPR001-202 was an open-label, 12-week Phase 2a clinical trial, which assessed the ability of a daily dose of 400mg of tildacerfont to lower ACTH, 17-OHP, and A4 over a 12-week dosing period. SPR001-201 and SPR001-202 comprised the entire Phase 2a clinical development program for tildacerfont in adult classic CAH. In the studies, efficacy was evaluated by changes from baseline in ACTH, 17-OHP, and A4 according to baseline A4 ≤2x upper limit of normal (ULN), denoted as baseline good disease control, or A4 >2x ULN, denoted as baseline poor disease control. Safety was evaluated using adverse events and laboratory assessments.
The results of the studies showed that tildacerfont reduced key hormone biomarkers towards normal levels in the baseline poor disease control group, including normalization of ACTH and A4 in 60% and 40% of patients, respectively. In patients with baseline good disease control, these hormones were maintained near or below normal levels. Tildacerfont was generally safe and well-tolerated. The findings from these studies support the ongoing global late-stage studies of tildacerfont in adults with classic CAH – CAHmelia-203 (assessing the ability of tildacerfont to reduce excessive adrenal androgens in patients with poor disease control) and CAHmelia-204 (assessing the ability of tildacerfont to reduce glucocorticoid usage in patients with good disease control while maintaining control of androgens).
“The data published in the Journal of Clinical Endocrinology and Metabolism demonstrate the potential of tildacerfont to reduce androgen excess without increasing the total daily glucocorticoid dose in patients with classic CAH,” says Kyriakie Sarafoglou, MD, associate professor in the Department of Pediatrics – Divisions of Endocrinology and Genetics & Metabolism at the University of Minnesota Medical School and first author of the JCEM paper.