FDA Grants Atumelnant Orphan Drug Designation for Congenital Adrenal Hyperplasia

The US Food and Drug Administration (FDA) has granted Orphan Drug Designation to atumelnant, an investigative treatment for the treatment of congenital adrenal hyperplasia (CAH).

Announced on August 21, 2025, by parent company Crinetics Pharmaceuticals, Inc., this decision comes in response to positive topline results from the phase 2 TouCAHn trial, reported in January 2025. Atumelnant demonstrated rapid, substantial, and sustained reductions in key biomarkers across all doses, including up to an 80% mean reduction in androstenedione. TouCAHn also showed meaningful improvements in multiple signs and symptoms of CAH, including resumption of menses and reduction of adrenal size.1

“Receiving Orphan Drug Designation from the FDA underscores the significant unmet need faced by people living with CAH,” said Dana Pizzuti, MD, chief medical and development officer of Crinetics. “Through atumelnant’s innovative mechanism of action, we have developed an ambitious and uncompromising endpoint for our phase 3 trial, which can demonstrate the ability to restore normal levels of adrenal androgens and reduce glucocorticoid supplementation to physiologic levels. We will also document other changes in clinical disease markers and symptoms that improve quality of life for patients.”1

Atumelnant is a novel, once-daily oral adrenocorticotropic hormone (ACTH) receptor antagonist candidate, and the only small molecule ATCH receptor antagonist currently in development. It acts selectively at the melanocortin type 2 receptor on the adrenal gland, displaying a strong binding affinity and suppression of adrenally derived glucocorticoids and androgens under the control of ACTH.1

TouCAHn is an ongoing interventional, open-label phase 2 trial including 42 patients with CAH. For inclusion, patients were required to be between 18-75 years of age, exhibit classic 21-hydroxylases deficiency, be on a stable regimen of glucocorticoid replacement (e.g. hydrocortisone, prednisolone, methylprednisolone), display compliance with glucocorticoid and mineralocorticoid replacement regimens during screening (if applicable), and having a minimum dose of ≥15 mg hydrocortisone or equivalent.2

Patients were excluded if they had a diagnosis of any other form of CAH besides classic 21-hydroxylase deficiency, dexamethasone use within 30 days of screening for cohorts 1-3, history of bilateral adrenalectomy, hypopituitarism, or other conditions requiring chronic glucocorticoid therapy, or clinically significant unstable medical conditions beyond CAH, among other factors.2

Investigators included 4 cohorts with varying degrees of disease severity, all of whom received a sequential 12-week fixed-dose treatment of atumelnant. Primary outcome measures included change from baseline in the morning serum androstenedione and incidence of treatment-emergent adverse events during the study. A secondary outcome of change from baseline in morning serum 17-hydroxyprogesterone was also noted.2

No severe treatment-emergent adverse events were noted during the study, irrespective of disease severity or dose level. Additionally, no patients required dose reduction or were discontinued from the trial. Atumelnant was generally well-tolerated with a positive safety profile.3

Crinetics has noted plans to randomize the first participants in the CALM-CAH phase 3 trial and the BALANCE-CAH phase 2/3 study in pediatrics in the second half of 2025.1

References

1. Crinetics Receives FDA Orphan Drug Designation for Atumelnant in the Treatment of Congenital Adrenal Hyperplasia (CAH). Crinetics Pharmaceuticals, Inc. August 21, 2025. Accessed August 21, 2025. https://crinetics.com/crinetics-receives-fda-orphan-drug-designation-for-atumelnant-in-the-treatment-of-congenital-adrenal-hyperplasia-cah/

2. Evaluate the Safety, Efficacy, and Pharmacokinetics of CRN04894 in Participants with Congenital Adrenal Hyperplasia (TouCAHn). ClinicalTrials.gov identifier: NCT05907291. Updated July 2, 2025. Accessed August 21, 2025. https://clinicaltrials.gov/study/NCT05907291?

3. Crinetics Announces Positive Topline Results from Phase 2 Trial of Atumelnant in Congenital Adrenal Hyperplasia (CAH). Crinectics Pharmaceuticals, Inc. January 10, 2025. Accessed August 21, 2025. https://crinetics.com/crinetics-announces-positive-topline-results-from-phase-2-trial-of-atumelnant-in-congenital-adrenal-hyperplasia-cah/