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Hamidi reviews 2-year CAHtalyst data showing crinecerfont enabled sustained glucocorticoid reductions to physiologic range in adults with classic congenital adrenal hyperplasia.
Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency requires lifelong glucocorticoid replacement to suppress adrenocorticotropic hormone (ACTH) and control adrenal androgen excess. The fundamental clinical challenge is that achieving androgen control typically demands supraphysiologic glucocorticoid doses, which carry substantial toxicity. Patients are at risk for exogenous Cushing syndrome, cardiometabolic complications, and reduced quality of life from high-dose, multi-daily regimens.
00:00:07 - Study Overview
00:00:39 - Key Findings
00:01:27 - Physiological Dosing
00:02:29 - Discontinuation of Dexamethasone, Hydrocortisone Reduction
00:03:58 - Long-Term Adherence and Tolerability
00:04:54 - Impact on Downstream CAH Effects
00:05:56 - Excitement Versus Reality
The physiologic replacement range for hydrocortisone is approximately 15 to 20 mg/day, yet many adults with classic CAH are managed on doses nearly double that threshold.
Crinecerfont, a first-in-class corticotropin-releasing factor type 1 (CRF1) receptor antagonist, offers a mechanistically distinct approach. By blocking CRF from activating the CRF1 receptor, crinecerfont reduces ACTH drive and adrenal androgen production, potentially enabling GC dose reduction without sacrificing androgen control. In December 2024, the agent received US Food and Drug Administration approval as an adjunct to physiologic glucocorticoid replacement in classic CAH.
2-year data from the CAHtalyst Adult Study presented at the American Association of Clinical Endocrinology (AACE) Annual Meeting 2026 by Oksana Hamidi, DO, an associate professor in the division of endocrinology and metabolism at the University of Texas Southwestern Medical Center, extend previously reported findings supporting the FDA approval. The trial enrolled 182 adults taking supraphysiologic glucocorticoid doses at baseline, with a mean daily dose of approximately 32 mg/day. By week 24, crinecerfont-treated participants achieved a least-squares mean glucocorticoid reduction of 27% versus 10% with placebo (LSMD, -17%; 95% CI, -24% to -10%; P <.0001).
Results showed that reduction was sustained through month 24, with mean glucocorticoid doses stabilizing at approximately 19.4 mg/day (10.6 mg/m²/day). Of note, the proportion of participants achieving a glucocorticoid dose within the physiologic range held at approximately 70% from month 12 through month 24.
Reductions in treatment burden were also documented. Among patients on hydrocortisone with > 2 doses per day, 62% reduced their dosing frequency by ≥ 1 dose per day. Of those on dexamethasone-containing regimens, 75% became dexamethasone-free. Cumulatively, actual glucocorticoid exposure over 2 years was 8010 mg/m² versus a projected 12,152 mg/m² had patients remained on their baseline dose.
“Patients who have classic CAH oftentimes require multiple medications per day, multiple doses per day, so it is a big challenge for them to live on a clock and constantly have reminders on their watches and calendars to keep taking their glucocorticoids, otherwise they lose control of their androgens,” Hamidi explained. “By reducing the doses, say, from 3 times a day dosing to 2 times a day dosing, I strongly believe that that improves patients' overall quality of life, but also their sense about their disease control and allows them to be more consistent with their medication.”
Safety data across the full 2-year period showed no new signals, with most adverse events rated mild or moderate and few discontinuations. Hamidi noted that as glucocorticoid doses are lowered, clinicians should ensure patients are equipped with sick-day guidance and injectable glucocorticoids for adrenal crisis prevention.
The trial's retention rate of > 80% over 2 years reflects sustained patient engagement that Hamidi described as exceeding her expectations and as evidence that patients were seeing the outcomes they had hoped for.
Editors’ note: Hamidi reports relevant disclosures with Corcept Therapeutics, Neurocrine Biosciences, Adaptyx, Camurus, Crinetics Pharmaceuticals, and Recordati Rare Diseases, Inc.
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