Aug. 21, 2025 -- Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX) today announced that the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation (ODD) for atumelnant, a novel, once-daily oral adrenocorticotropic hormone (ACTH) receptor antagonist candidate for the proposed treatment of classic congenital adrenal hyperplasia (CAH). Atumelnant is the first and only small molecule ACTH receptor antagonist in clinical development.
“Receiving Orphan Drug Designation from the FDA underscores the significant unmet need faced by people living with CAH,” said Dana Pizzuti, M.D., 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.”
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 study also demonstrated meaningful improvements in multiple clinical signs and symptoms of the disease affecting patient health, including resumption of menses and reduction of adrenal size. 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.
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. Patients also need cortisol supplementation to replace the missing cortisol. However, the current treatment paradigm 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.
The FDA provides ODD 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 may 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.
Atumelnant, Crinetics’ second investigational compound, is the first in class and only once-daily, oral adrenocorticotropic hormone (ACTH) receptor antagonist that acts selectively at the melanocortin type 2 receptor (MC2R) on the adrenal gland. Diseases associated with excess ACTH can have significant impact on physical and mental health. Novel atumelnant has exhibited strong binding affinity for MC2R in preclinical models and has demonstrated suppression of adrenally derived glucocorticoids and androgens that are under the control of ACTH. Data from a 12-week Phase 2 study consistently demonstrated compelling treatment benefits of atumelnant, evidenced by the rapid, substantial and sustained statistically significant reductions in key CAH disease related biomarkers, including A4 and 17-hydroxyprogesterone, in a diverse population. Currently in development, atumelnant holds the potential to offer transformational care for individuals living with congenital adrenal hyperplasia and ACTH-dependent Cushing’s syndrome. This breakthrough could revolutionize the management of these conditions, providing hope for unprecedented improvements in quality of life.
Crinetics Pharmaceuticals is a clinical-stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for endocrine diseases and endocrine-related tumors. All of the company’s drug candidates are small molecule, new chemical entities resulting from in-house drug discovery efforts. Crinetics’ lead development candidate, PALSONIFY™ (paltusotine), is the first investigational once-daily, oral, selective somatostatin receptor type 2 (SST2) nonpeptide agonist that is in clinical development for acromegaly. Paltusotine is also in clinical development for carcinoid syndrome associated with neuroendocrine tumors. Atumelnant is currently in development for congenital adrenal hyperplasia and ACTH-dependent Cushing’s syndrome. Additional discovery programs address a variety of endocrine conditions, such as hyperparathyroidism, polycystic kidney disease, Graves’ disease (including thyroid eye disease), diabetes, obesity and GPCR-targeted oncology indications.
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