Baseline characteristics of adults with classic congenital adrenal hyperplasia enrolled in CAHtalyst, a phase 3 study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Richard Auchus; Oksana Hamidi; Rosario Pivonello; Irina Bancos; Selma Witchel; Andrea Isidori; Patrice Rodien; Umasuthan Srirangalingam; Florian Kiefer; Henrik Falhammar; Deborah Merke; Nicole Reisch; Julia Sturgeon; Eiry Roberts; Vivian Lin; Jean L Chan; Robert Farber

doi:10.1530/endoabs.99.P423

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Endocrine Abstracts (2024) 99 P423 | DOI: 10.1530/endoabs.99.P423

ECE2024 Poster Presentations Adrenal and Cardiovascular Endocrinology (95 abstracts)

Baseline characteristics of adults with classic congenital adrenal hyperplasia enrolled in CAHtalyst, a phase 3 study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Richard Auchus ¹ , Oksana Hamidi ² , Rosario Pivonello ³ , Irina Bancos ⁴ , Selma Witchel ⁵ , Andrea Isidori ⁶ , Patrice Rodien ^7,8 , Umasuthan Srirangalingam ⁹ , Florian Kiefer ¹⁰ , Henrik Falhammar ¹¹ , Deborah Merke ^12,13 , Nicole Reisch ¹⁴ , Julia Sturgeon ¹⁵ , Eiry Roberts ¹⁵ , Vivian Lin ¹⁵ , Jean L Chan ¹⁵ & Robert Farber ¹⁵

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¹University of Michigan Medical School, Ann Arbor, USA; ²University of Texas Southwestern Medical Center, Department of Internal Medicine, Dallas, USA; ³University of Naples Federico II, Napoli, Italy; ⁴Mayo Clinic, Rochester, USA; ⁵University of Pittsburgh School of Medicine, Pittsburgh, USA; ⁶Sapienza University of Rome, Roma, Italy; ⁷Mitovasc, Angers, France; ⁸Angers University Hospital Center, Angers, France; ⁹University of College London, London, UK; ¹⁰Medical University of Vienna, Wien, Austria; ¹¹Karolinska Institute, Stockholm, Sweden; ¹²NIH Clinical Center, Bethesda, USA; ¹³Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, USA; ¹⁴Ludwig Maximilian University of Munich, München, Germany; ¹⁵Neurocrine Biosciences, San Diego, USA

Objectives: To describe the baseline characteristics of individuals enrolled in CAHtalyst (NCT04490915), a randomized, double-blind, placebo-controlled, Phase 3 study evaluating the safety and efficacy of crinecerfont (a corticotropin-releasing factor type 1 receptor [CRF₁] antagonist) in adults with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD).

Methods: The study included adults (age ≥18 years) with classic 21OHD. Key eligibility criteria included glucocorticoid dose >13 mg/m²/day in hydrocortisone equivalents (HCe; conversion factors: 4× for predni[so]lone, 60× for dexamethasone) adjusted for body surface area (BSA) with stable dose for ≥1 month prior to screening, and normal or elevated androstenedione (A4). Baseline demographics and characteristics were summarized descriptively in all randomized participants.

Results: Of 182 enrolled participants, 51% were men and 90% were White. Mean (±S.D.) age was 30.8±9.9 years (range: 18–58 years), mean BSA was 1.8±0.2 m², and mean body mass index (BMI) was 29.8±7.0 kg/m² (with BMI ≥30 kg/m² in 47% of participants). The mean total daily glucocorticoid dose was 17.6±4.9 mg/m²/day (32.3±9.3 mg/day) HCe, with 57% on hydrocortisone alone, 30% on a predniso(lo)ne-containing regimen, and 13% on a dexamethasone-containing regimen. In addition, 86% of participants were on fludrocortisone (mean dose: 136±72 μg/day). Mean (±S.D.) hormone concentrations prior to the morning glucocorticoid dose were as follows: adrenocorticotropic hormone, 264±317 pg/ml; 17-hydroxyprogesterone, 9467±8829 ng/dl; A4, 620±729 ng/dl; testosterone (T) in females, 86±85 ng/dl; A4/T in males, 2.2±2.4; follicle-stimulating hormone in males, 6.3±9.4 IU/l; and luteinizing hormone in males, 4.6±5.0 IU/l. Among the 90 females, 42 (47%) reported a history of hirsutism; of the 66 females of childbearing potential not on hormonal or intrauterine contraception, 35 (53%) reported a history of amenorrhea or menstrual irregularities. Among the 92 males, 44 (48%) reported a history of testicular adrenal rest tumors (TARTs) while 53 (58%) had evidence of TARTs by ultrasound prior to study entry. Comorbidities included osteopenia (15%), hypertension (10%), osteoporosis (5%), and diabetes mellitus (2%).

Conclusion: In a Phase 3 trial evaluating crinecerfont (a CRF₁ antagonist) in adults with classic 21OHD, clinical evidence of glucocorticoid and androgen excess (e.g., high prevalence of obesity, hirsutism [females], and TARTs [males]) were observed at baseline. Androgens and other steroid biomarkers were elevated despite treatment with supraphysiological doses of glucocorticoids. These findings emphasize the urgent need for novel glucocorticoid-sparing treatments for this chronic condition.