Crinecerfont Sustains Glucocorticoid Reduction, Improves Cardiometabolic Outcomes in Classic CAH

2-year data from the phase 3 CAHtalyst Adult Study suggest treatment with crinecerfont (Crenessity) enables durable reductions in glucocorticoid (GC) dosing while supporting improvements in weight, body composition, and insulin resistance among adults with classic congenital adrenal hyperplasia (CAH).¹

Presented at the Endocrine Society (ENDO) Annual Meeting 2026, the findings extend evidence supporting the December 2024 FDA approval of crinecerfont as an adjunct to GC replacement therapy for patients aged ≥4 years with classic CAH.¹

"We were able to take these supraphysiologic doses and maintain patients on physiologic replacement as early as 24 weeks, and that improvement was maintained even up to 24 months," said study presenter and investigator Oksana Hamidi, DO, associate professor in the division of endocrinology and metabolism at UT Southwestern Medical Center, in an interview with HCPLive. "It's not just a fluke. We saw a persistent, sustained, substantial reduction in glucocorticoid dose, and there was not a significant escape from that."

Durable Glucocorticoid Reduction Maintained Through 24 Months

The analysis included 182 adults with classic CAH enrolled in the CAHtalyst Adult Study (NCT04490915), a phase 3 randomized, double-blind, placebo-controlled trial with an ongoing open-label extension. Investigators evaluated changes in GC dose, body weight, body composition assessed by dual-energy X-ray absorptiometry, and insulin resistance through 24 months of treatment. At baseline, participants had a mean daily GC dose of 17.6 mg/m²/day hydrocortisone equivalents (HCe), corresponding to 32.3 mg/day.¹

Mean GC dose decreased by 37% from baseline to 10.9 mg/m²/day (19.9 mg/day) HCe at month 12 and remained reduced by 38% at month 24, reaching 10.6 mg/m²/day (19.4 mg/day) HCe. According to investigators, these reductions moved participants from clearly supraphysiologic GC exposure toward physiologic replacement levels.¹

Cardiometabolic Improvements Accompany GC Dose Reduction

At baseline, 71% of participants were overweight or obese, defined as a body mass index (BMI) ≥25 kg/m², and 42% had insulin resistance, defined as a homeostatic model assessment of insulin resistance (HOMA-IR) score >2.5. Mean reductions in body weight (-1.8 kg) and BMI (-0.7 kg/m²) observed at month 12 were maintained through month 24.¹

Among participants who were overweight or obese at baseline, 31% achieved >5% body weight reduction at month 12, increasing to 38% at month 24. Body composition analyses showed reductions in fat mass exceeded reductions in lean mass at both time points. By month 24, mean fat mass declined by 1.6 kg compared with a 0.8-kg reduction in lean mass.¹

Investigators also observed sustained improvements in insulin resistance. Mean HOMA-IR reductions from baseline were -0.6 at both months 12 and 24 across the overall study population. Among participants with insulin resistance at baseline, mean HOMA-IR reductions were -1.5 at month 12 and -1.7 at month 24.¹

Adults with classic CAH experience elevated rates of obesity, hypertension, dyslipidemia, and insulin resistance, although the relative contribution of chronic supraphysiologic GC exposure versus androgen excess remains an ongoing clinical question.

Hamidi noted many cardiometabolic complications observed in CAH, including increased fat mass, hypertension, osteoporosis, and insulin resistance, are commonly associated with excessive GC exposure, whereas accelerated bone growth and early puberty are more characteristic of uncontrolled androgen excess.

The findings suggest reductions in GC exposure can be achieved without sacrificing androgen control. As GC doses declined during treatment with crinecerfont, investigators observed concurrent improvements in weight, body composition, and insulin resistance.¹

"As we were able to lower glucocorticoids, while also maintaining control of androgens, we saw improvements in weight, improvements in BMI, favorable improvements in body composition with reduction in fat mass, improvement in lean mass, and improvements in insulin resistance," Hamidi said.

Safety and Clinical Considerations

Crinecerfont was generally well tolerated through 24 months, with investigators reporting no new safety signals during long-term treatment.¹

Investigators noted the study was not powered to detect differences between salt-wasting and simple virilizing forms of classic CAH. Hamidi also highlighted the importance of monitoring mineralocorticoid replacement in patients with salt-wasting disease, as reductions in hydrocortisone dosing may increase the need for fludrocortisone supplementation over time.

The open-label extension lacked a placebo comparator, limiting conclusions regarding the direct contribution of GC dose reduction to observed cardiometabolic improvements. However, the findings suggest long-term treatment with crinecerfont may enable sustained reductions in glucocorticoid exposure while supporting favorable cardiometabolic outcomes in adults with classic CAH.¹

Crinecerfont is a first-in-class oral corticotropin-releasing factor type 1 (CRF1) receptor antagonist that reduces adrenocorticotropic hormone-driven adrenal androgen production in classic CAH. The agent received FDA approval in December 2024 for patients aged ≥4 years based on results from the phase 3 CAHtalyst clinical program.³˒⁴

Editor’s Note: Hamidi reports relevant disclosures with Corcept Therapeutics, Neurocrine Biosciences, Xeris Pharma, Camurus, Crinetics Pharmaceuticals, and Recordati Rare Diseases.

References

1. 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: Endocrine Society Annual Meeting; June 14, 2026; Chicago, IL. Abstract ORF32-07.

2. 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

3. Neurocrine Biosciences. Neurocrine Biosciences announces FDA approval of CRENESSITY (crinecerfont), a first-in-class treatment for children and adults with classic congenital adrenal hyperplasia. Press release. December 13, 2024. https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-announces-fda-approval-crenessitytm

4. Auchus RJ, Hamidi O, Pivonello R, et al. Crinecerfont in classic congenital adrenal hyperplasia in adults. N Engl J Med. 2024;390(20):1865-1876. doi:10.1056/NEJMoa2313917