Crinecerfont shows durable improvements in classic congenital adrenal hyperplasia and reduces glucocorticoid doses in phase-3 CAHtalyst trial
Presenter: Oksana Hamidi, DO, MSCS, UT Southwestern Medical Center, Dallas, TX
Crinecerfont improves weight-related outcomes and insulin resistance in adults with classic congenital adrenal hyperplasia: 2-year results from the CAHtalyst adult study. Presented June 14, 2026.
Patients taking crinecerfont, the first new therapy for classic congenital adrenal hyperplasia in about 70 years, had durable improvements in disease control and metabolic health and substantial reductions in glucocorticoid doses in up to 2 years of treatment in the phase-3 CAHtalyst trial. Improvements in weight and insulin resistance were clinically meaningful, and the drug was well tolerated, according to presenter Oksana Hamidi, DO, MSCS.
Congenital adrenal hyperplasia is a rare and severe genetic disorder of adrenal steroidogenesis, most commonly caused by 21-hydroxylase deficiency, that results in cortisol deficiency, androgen excess, and, in some patients, aldosterone deficiency. The disorder often requires lifelong glucocorticoid replacement therapy.
In 2024, the US Food and Drug Administration approved crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, as an adjunct to glucocorticoid replacement to control androgens in patients at least 4 years old with classic congenital adrenal hyperplasia.
“These patients have minimal choices when it comes to their treatment and often accept their fate,” said Dr. Hamidi. “Crinecerfont is a novel medication that allows these patients to reduce their glucocorticoid doses to physiologic levels and optimize their metabolic health.”
Multicenter phase-3 trial
CAHtalyst enrolled 182 participants 18 years and older with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency at 70 sites in 18 countries, including the United States. This phase-3 study consisted of a 24-week randomized, double-blind, placebo-controlled period, followed by a 6-month open-label period and an ongoing open-label extension. Study retention was high, according to the investigators, with 81% of participants completing at least 2 years of treatment.
To evaluate the long-term metabolic effects of treatment, investigators assessed body weight, body mass index, body composition, and insulin resistance using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) at 12 and 24 months.
Reshaping congenital adrenal hyperplasia therapy
Two-year results from the CAHtalyst study, presented at ENDO 2026, demonstrated crinecerfont’s durable benefits, with sustained reductions in glucocorticoid dose, body weight, body mass index, and insulin resistance at both 12 and 24 months.
The mean daily glucocorticoid dose in hydrocortisone equivalents was 17.6 mg/m2 at baseline, decreasing to 10.9 mg/m2 at 12 months and 10.6 mg/m2 at 24 months, a 38% decrease.
The mean body weight was 79.3 kg at baseline; at 12 and 24 months it was 1.8 kg lower. The mean body mass index at baseline was 29.8 kg/m2; at 12 and 24 months it was 0.7 kg/m2 lower.
The 103 (71%) of participants who were overweight or obese at baseline had reduced their body mass index by 0.9 kg/m2 at 12 months and were still at that level at 24 months. Among this subgroup, 39 (38%) achieved a 5% or greater reduction in weight. This subgroup also had mean decreases in fat mass exceeding that in lean mass.
The mean HOMA-IR score at baseline was 3.2, and 42% of participants had a score higher than 2.5, indicating insulin resistance. The mean score in the total group was 0.6 points lower at 12 and 24 months, and in the subgroup with insulin resistance at baseline it had decreased by 1.5 points at 12 months and 1.7 points at 24 months.
Crinecerfont was well tolerated, with only mild or moderate adverse reactions, most commonly headache and fatigue.
“Crinecerfont is revolutionizing this disease state and changing patients’ lives,” said Dr. Hamidi. “The changes we saw were statistically and clinically significant.”
Disclosures
None.
References
Hamidi O, Chalmers LJ, Falhammar H, et al. Crinecerfont improves weight-related outcomes and insulin resistance in adults with classic congenital adrenal hyperplasia: 2-year results from the CAHtalyst Adult Study. Presented at ENDO 2026, June 14, 2026, Chicago, IL. Presented at ENDO 2026, June 14, 2026, Chicago, IL.
Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2018; 103(11):4043–4088. doi:10.1210/jc.2018-01865