Richard Auchus, MD, PhD

Crinecerfont Reduces Glucocorticoid Doses in CAH, With Richard Auchus, MD, PhD

Crinecerfont (Crenessity) has demonstrated substantial and sustained reductions in glucocorticoid doses among adults with 

classic congenital adrenal hyperplasia (CAH)

, according to 2-year data from the CAHtalyst Adult study.

American Association of Clinical Endocrinology (AACE) Annual Meeting 2026

 in Las Vegas, Nevada, by Richard Auchus, MD, PhD, professor of pharmacology and internal medicine at the University of Michigan.

“Glucocorticoids are not a good thing to be taking chronically – yes, you need them to survive, but you don’t really need them overnight,” Auchus told 

 in an exclusive interview. “What crinecerfont did was allow us to reduce the dose and put it in a more physiological regime, front-loading it in the morning, allowing them to have a circadian rhythm, and maintaining disease control at a level that the endocrinologist in the trial felt was appropriate for that patient.”

Crinecerfont, a selective oral corticotropin-releasing factor type 1 receptor (CRF1) antagonist, functions by reducing and controlling excess adrenocorticotropic hormone and adrenal androgens. It was first approved by the US Food and Drug Administration (FDA) in December of 2024 for the treatment of CAH in conjunction with glucocorticoids among adults and children ≥4 years.

CAHtalyst Adult was a randomized, double-blind, placebo-controlled phase 3 study evaluating crinecerfont in adults with classic CAH. It consisted of a 24-week randomized period during which patients were assigned to either crinecerfont or placebo, followed by 1 year of active treatment with crinecerfont. Patients were then given the option to participate in an open-label extension period, which is projected to last for roughly 3 years.

Patients were eligible for the study if they had a medically confirmed CAH diagnosis due to 21-hydroxylase deficiency and were on a stable steroid regimen. Patients with a diagnosis of any other known form of classic CAH, a history of bilateral adrenalectomy, hypopituitarism, or other conditions requiring chronic glucocorticoid therapy, or a clinically significant unstable medical condition or chronic disease aside from CAH, among other criteria, were excluded from the trial.

The present data highlights 2-year data from the open-label extension – by month 24, 69% of the participants (103/149) had achieved a physiologic glucocorticoid dose of ≤11 mg/m2/day of hydrocortisone equivalents. Additionally, many participants had eliminated nonphysiologic glucocorticoid types altogether. Among the patients initially taking dexamethasone (n = 20), 75% shifted to a dexamethasone-free regimen, while 62% (37/60) taking >2 doses of hydrocortisone per day were able to eliminate a dose.

Auchus also highlighted the significant retention throughout the open-label extension: >80% of patients were still taking crinecerfont at 2 years with no new safety signals detected.

“CAH is a chronic disease, and there’s a lot of disease burden for these patients,” Auchus said. “We want them to be able to just take their medicine and get on with their lives and not worry about things. I think that high retention rate tells you that people are on board with this system.”

Editors’ Note: Auchus reports disclosures with Adrenas Therapeutics, Corcept, Crinetics, Neurocrine Biosciences, Recordati, Astellas, and others.

Bancos I, Hamidi O, Kiefer F, et al. Adults With Classic Congenital Adrenal Hyperplasia Taking Crinecerfont Demonstrated Sustained Decreases in Glucocorticoid Doses: 2-Year Results from the CAHtalyst Adult Study. Presented at the American Association of Clinical Endocrinology Annual Meeting 2026, Las Vegas, NV. April 22-24, 2026.

Neurocrine Biosciences, Inc. Neurocrine Biosciences Presents New Two-Year CRENESSITY (crinecerfont) Data Showing Sustained Glucocorticoid Dose Reductions While Maintaining Androgen Control in Adults with Classic Congenital Adrenal Hyperplasia. 

. April 22, 2026. Accessed April 24, 2026. 

https://www.prnewswire.com/news-releases/neurocrine-biosciences-presents-new-two-year-crenessity-crinecerfont-data-showing-sustained-glucocorticoid-dose-reductions-while-maintaining-androgen-control-in-adults-with-classic-congenital-adrenal-hyperplasia-302749451.html

Iapoce C. FDA Approves Crinecerfont for Congenital Adrenal Hyperplasia. 

. December 13, 2024. Accessed April 24, 2026. 

https://www.hcplive.com/view/fda-approves-crinecerfont-for-congenital-adrenal-hyperplasia

Neurocrine Biosciences. Global Safety and Efficacy Registration Study of Crinecerfont for Congenital Adrenal Hyperplasia (CAHtalyst). ClinicalTrials.gov Identifier: NCT04490915. Updated February 5, 2025. Accessed April 24, 2026. 

https://clinicaltrials.gov/study/NCT04490915

Videos

Auchus discusses the 2-year results from CAHtalyst Adult, highlighting the substantial retention rates over the open-label extension period.

In their closing remarks, Auchus and DeFronzo emphasize routine screening of high-risk patients, the persistent cardiovascular burden of hypercortisolism despite risk-factor treatment, and the necessity of targeting cortisol excess itself.

Final Takeaways: Screening, Cardiovascular Risk, and Treating Cortisol as the Root Cause

In the concluding segment, Ralph DeFronzo, MD, returns to a central message: hypercortisolism in difficult-to-control type 2 diabetes is substantially more common than many clinicians appreciate. He compares the evolution of thinking around primary aldosteronism—once deemed rare, now recognized as prevalent in resistant hypertension—to the growing recognition of cortisol excess in refractory diabetes. Just as guidelines now recommend screening for primary aldosteronism in resistant hypertension, Dr DeFronzo argues that clinicians should adopt a similar posture toward hypercortisolism in complex diabetic patients, particularly those on advanced therapies such as glucagon-like peptide-1 receptor agonists and tirzepatide who nonetheless remain poorly controlled.

Richard Auchus, MD, underscores that the overnight 1-mg dexamethasone suppression test is inexpensive, technically simple, and well suited to broad use. A single tablet at bedtime and one morning cortisol measurement can identify a meaningful subset of patients—on the order of 1 in 4 in enriched populations—who warrant further evaluation. Rather than viewing this as an additional burden, he frames it as an opportunity: when potent agents such as semaglutide, tirzepatide, and sodium-glucose cotransporter 2 inhibitors fail to normalize glycemia or blood pressure, uncovering hypercortisolism offers a clear, pathophysiologic explanation and a new therapeutic avenue.

Both faculty members close by highlighting that hypercortisolism is not solely a glycemic or blood pressure issue; it is a major driver of atherosclerotic cardiovascular disease, atrial fibrillation, stroke, and myocardial infarction. Dr DeFronzo notes that even when traditional risk factors such as hypertension and dyslipidemia are well treated, cardiovascular risk remains elevated because cortisol exerts direct detrimental effects on the arterial wall, skeletal muscle, skin, and bone quality. Surgical removal of cortisol-producing adenomas or medical blockade of cortisol action is therefore essential to normalize risk. The discussion ends with a call for heightened awareness, systematic screening, and proactive cortisol-directed therapy to improve long-term outcomes in patients with complex metabolic disease.

Auchus and DeFronzo survey the broader pharmacologic armamentarium for Cushing syndrome and hypercortisolism, including metyrapone, osilodrostat, ketoconazole, levoketoconazole, pasireotide, and investigational agents such as relacorilant and ACTH receptor antagonists.

Beyond Mifepristone: Enzyme Inhibitors, Pituitary-targeted Agents, and Emerging Therapies

In this segment, Richard Auchus, MD, broadens the discussion beyond mifepristone to review other medical therapies targeting cortisol synthesis and pituitary drivers of Cushing syndrome. He begins with metyrapone, a relatively weak 11β-hydroxylase inhibitor that has been used off label for many years. Metyrapone requires high total daily doses (often 1–3 g or more) divided three or four times a day, making it more suitable for inpatient settings where rapid titration and close monitoring are feasible. The newer 11β-hydroxylase inhibitor osilodrostat is highlighted as approximately 1000 times more potent, dosed once or twice daily in milligram rather than gram quantities, but with an attendant risk of overtreatment and adrenal insufficiency if not carefully managed—considerations that make endocrinology oversight essential.

Dr Auchus then reviews steroidogenesis inhibitors that have been used chronically, including ketoconazole and levoketoconazole. Ketoconazole, long employed off label for Cushing syndrome, is limited by a black box warning regarding hepatotoxicity and by the risk of QT prolongation. Levoketoconazole, the more potent 2S,4R stereoisomer, allows roughly half the dose and twice-daily rather than three-times-daily dosing, potentially improving tolerability and adherence. For pituitary-dependent Cushing disease, pasireotide—a somatostatin analog targeting somatostatin receptor subtype 5—can be useful, but is ineffective in ACTH-independent forms such as adrenal adenomas, reinforcing the importance of accurate etiologic classification before selecting therapy.

Finally, Ralph DeFronzo, MD, and Dr Auchus discuss emerging and investigational therapies. Relacorilant, a selective glucocorticoid receptor modulator that does not significantly block progesterone receptors, has completed major trials (GRACE and GRADIENT) and may avoid some gynecologic adverse effects seen with mifepristone, such as endometrial thickening and bleeding. Additional pipeline agents include ACTH receptor antagonists (eg, agents targeting melanocortin 2 receptor) for ACTH-dependent disease. Together, these agents expand the therapeutic landscape, providing multiple pharmacologic “Plan A, B, C, and D” options for patients who are not surgical candidates, have persistent or recurrent disease after surgery, or have non-neoplastic hypercortisolism. The segment underscores that, unlike in past decades, clinicians now have a diverse toolkit to tailor therapy to disease etiology, severity, and patient-specific risk profiles.

DeFronzo and Auchus underscore the magnitude of metabolic benefit with mifepristone, the complexity of managing withdrawal and electrolyte issues, and the importance of specialist support and education for primary care physicians.

Practical Use of Mifepristone and the Need for Endocrinology–Primary Care Collaboration

In this segment, Ralph DeFronzo, MD, elaborates on the practical magnitude of benefit observed with mifepristone in hypercortisolism, particularly in patients enrolled in trials like CATALYST. He reiterates that beyond the approximately 1.5–percentage point drop in hemoglobin A1c, patients experienced average weight loss of roughly 5 kg and a 5.1-cm reduction in waist circumference—changes that translate to meaningful alterations in body habitus. From a diabetes-management perspective, such improvements, combined with marked reductions in insulin dose, signal a fundamental shift in the underlying pathophysiology rather than incremental pharmacologic fine-tuning.

However, Dr DeFronzo and Richard Auchus, MD, candidly describe real-world barriers to safe and confident use of mifepristone, particularly in primary care. DeFronzo recounts an early CATALYST patient who developed glucocorticoid withdrawal symptoms, sought care from a primary physician unfamiliar with the trial, and was advised to stop the medication over concerns about adrenal crisis. This anecdote highlights how lack of familiarity with withdrawal phenomena and the expected rise in serum cortisol can lead to premature discontinuation or misinterpretation of adverse effects. Managing hypokalemia via spironolactone and other supportive strategies requires an understanding of the drug’s mechanistic profile and a proactive approach to monitoring.

To address these challenges, the faculty advocate for close collaboration between primary care and endocrinology. Primary care clinicians are best positioned to recognize high-risk patients—those with refractory diabetes and hypertension on multiple agents—whereas endocrinologists bring experience in interpreting hormone tests, managing cortisol-directed therapies, and counseling patients through withdrawal symptoms. Dr DeFronzo notes that manufacturers of mifepristone sponsor support programs that can help guide dosing, monitoring, and side-effect management for clinicians new to the therapy. Collectively, the speakers argue that a team-based model, with clear referral pathways and shared care, is essential to realizing the full potential of mifepristone in broader hypercortisolism management.

Richard Auchus, MD, PhD

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