Crinetics Pharmaceuticals announced positive initial findings for atumelnant (CRN04894), a novel, once-daily oral adrenocorticotropic hormone (ACTH) receptor antagonist, in two ongoing open-label studies for congenital adrenal hyperplasia (CAH) and ACTH-dependent Cushing's syndrome (ADCS). The data, presented at the Endocrine Society’s annual meeting (ENDO2024), highlight the drug's potential to normalize hormone levels in these challenging endocrine disorders.
Atumelnant in Congenital Adrenal Hyperplasia (CAH)
In the Phase 2 TouCAHn study, initial results from participants with classic CAH treated with 80 mg of once-daily oral atumelnant demonstrated significant reductions in key adrenal steroids. 100% of participants (n=6) maintained androstenedione (A4) levels below the upper limit of normal (ULN) at all time points during the 12-week treatment period. Furthermore, A4 levels decreased by 91% at two weeks, 93% at six weeks, and 96% at 12 weeks from baseline. 17-hydroxyprogesterone (17-OHP) levels also saw substantial reductions, with a 97% decrease at two weeks, 95% at six weeks, and 94% at 12 weeks.
Dr. Umasuthan Srirangalingam, consultant physician in endocrinology and diabetes at University College London Hospitals NHS Foundation Trust and TouCAHn investigator, noted, "Atumelnant's unique ability to inhibit ACTH directly at its receptor sets it apart from how we've historically pursued controlling androgen production through supra-physiological doses of glucocorticoids."
The TouCAHn study is ongoing, evaluating atumelnant at doses of 40 mg, 80 mg, and 120 mg once daily. Topline results from the complete study are expected in the second half of 2024.
Atumelnant in ACTH-Dependent Cushing's Syndrome (ADCS)
In the Phase 1b/2a study conducted in collaboration with the National Institutes of Health, atumelnant (80 mg) normalized 24-hour urinary free cortisol levels in 100% of participants (n=5) during the 10-day treatment period. All five participants experienced serum cortisol levels below 5 mcg/dL within 10 days of administration. Additionally, two or more clinical symptoms improved in all patients.
Dr. Lynnette Nieman, senior investigator at the National Institutes of Health and principal investigator of the Phase 1b/2a atumelnant trial, stated, "This initial data showed atumelnant's ability to rapidly reduce — and normalize — cortisol levels in people with ADCS... I am hopeful for further promising results as we continue our research on this drug candidate."
Safety and Tolerability
Atumelnant was generally well-tolerated in both studies. Adverse events were mild to moderate, with the most frequently reported being headache, nausea, and decreased appetite, consistent with symptoms of adrenal insufficiency. These symptoms were reversed with oral hydrocortisone replacement treatment. No participants discontinued from either trial due to adverse events.
About Atumelnant (CRN04894)
Atumelnant is an investigational, first-in-class, oral ACTH antagonist that selectively targets the melanocortin type 2 receptor (MC2R) on the adrenal glands. By blocking ACTH, atumelnant aims to reduce the production of glucocorticoids and androgens, offering a potential new approach to treating endocrine disorders driven by excess ACTH.
