Crinetics Pharmaceuticals announced that the U.S. Food and Drug Administration has granted orphan drug designation to atumelnant, the company's investigational oral adrenocorticotropic hormone (ACTH) receptor antagonist for treating classic congenital adrenal hyperplasia (CAH). The designation recognizes the significant unmet medical need for patients with this rare genetic disorder affecting the adrenal glands.
Promising Phase 2 Results Drive Development Forward
In January 2025, Crinetics reported robust positive topline results from the Phase 2 TouCAHn trial of atumelnant in adults with classic CAH. The study demonstrated substantial, rapid and sustained reductions of key biomarkers across doses, including up to an 80% mean reduction in androstenedione. The trial also showed meaningful improvements in multiple clinical signs and symptoms of the disease, including resumption of menses and reduction of adrenal size.
"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," said Dana Pizzuti, M.D., Chief Medical and Development Officer of Crinetics.
Novel Mechanism Addresses Treatment Limitations
Atumelnant represents the first and only small molecule ACTH receptor antagonist in clinical development. The drug acts selectively at the melanocortin type 2 receptor (MC2R) on the adrenal gland, offering a novel approach to managing CAH.
CAH is caused by genetic mutations that result in impaired cortisol synthesis. This lack of cortisol leads to a breakdown of feedback mechanisms and results in persistently high levels of ACTH that in turn results in the over secretion of steroids, particularly androgens like androstenedione, and steroid precursors. High levels of androgens can manifest as reduced fertility in men and women, excessive facial hair and acne in women, and painful testicular adrenal rest tumors in men.
Current treatment involves chronic glucocorticoid steroid supplementation, often at supraphysiologic levels, which can lead to significant additional medical problems associated with glucocorticoid excess including weight gain, diabetes, cardiovascular issues, and osteoporosis.
Phase 3 Program Set to Launch
Crinetics expects the first participants randomized in the CALM-CAH Phase 3 study in adults and the BALANCE-CAH Phase 2/3 study in pediatrics in the second half of 2025. The Phase 3 program aims to demonstrate atumelnant's ability to restore normal levels of adrenal androgens and reduce glucocorticoid supplementation to physiologic levels while documenting improvements in clinical disease markers and symptoms that enhance quality of life for patients.
Regulatory Benefits and Market Exclusivity
The FDA provides orphan drug designation status to drugs intended for the safe and effective treatment, diagnosis, or prevention of rare diseases that affect fewer than 200,000 people in the U.S. Benefits of the designation include exemption from certain FDA fees, financial incentives for qualified clinical development, and seven years of market exclusivity in the U.S. if the treatment is approved.
"Receiving Orphan Drug Designation from the FDA underscores the significant unmet need faced by people living with CAH," Pizzuti noted, highlighting the potential for atumelnant to offer transformational care for individuals living with congenital adrenal hyperplasia and ACTH-dependent Cushing's syndrome.
