SFEIES24 Plenary Orals Plenary Orals (2 abstracts)
Crinecerfont, a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, reduced excess adrenal androgens and enabled glucocorticoid dose reductions in adults with classic congenital adrenal hyperplasia: results from cahtalyst™
Richard J. Auchus 1 , Oksana Hamidi 2 , Rosario Pivonello 3 , Irina Bancos 4 , Gianni Russo 5 , Selma Witchel 6 , Andrea M. Isidori 7 , Patrice Rodien 8 , Umasuthan Srirangalingam 9 , Florian W. Kiefer 10 , Henrik Falhammar 11 , Debroah P. Merke 12 , Nicole Reisch 13 , Kyriakie Sarafoglou 14 , Gordon B. Cutler 15 , Julia Sturgeon 16 , Eiry Roberts 16 , Vivian H. Lin 16 , Jean L. Chan 16 & Robert Farber 16
1University of Michigan Medical School, Ann Arbor, USA; 2University of Texas Southwestern Medical Center, Dallas, USA; 3Università Federico II di Napoli, Naples, Italy; 4Mayo Clinic, Rochester, USA; 5IRCCS Ospedale San Raffaele, Milano, Italy; 6University of Pittsburgh School of Medicine, Pittsburgh, USA; 7Sapienza University of Rome, Rome, Italy; 8CHU d’Angers and Laboratoire MITOVASC, Université d’Angers, Angers, France; 9University College London Hospital, London, United Kingdom; 10Medical University of Vienna, Vienna, Austria; 11Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; 12National Institutes of Health Clinical Center and Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, USA; 13Medizinische Klinik und Poliklinik IV, LMU Klinikum München, Munich, Germany; 14University of Minnesota Medical School, Minneapolis, USA; 15Gordon Cutler Consultancy, LLC, Deltaville, USA; 16Neurocrine Biosciences, Inc., San Diego, USA
Introduction: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH), a genetic condition characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. This multinational Phase 3 study (CAHtalyst™) evaluated whether crinecerfont, an oral CRF1 antagonist, can reduce GC dose while maintaining androgen control in adults with CAH.
Methods: Adults (≥18yrs) with CAH on GC doses >13 mg/m2/d in hydrocortisone equivalents (HCe) and normal or elevated androstenedione were randomized (2:1) to crinecerfont 100 mg BID or placebo for 24wks. GC doses were maintained stable for 4wks, then reduced over 8wks to target of 8-10 mg/m2/d, followed by adjustment over 12wks to maintain androstenedione control (≤120% of baseline or ≤upper limit of normal).
Results: In 182 randomized participants (122 crinecerfont, 60 placebo), >95% completed 24-wk treatment. Mean±SD baseline GC dose was 17.6±4.9 mg/m2/d HCe (32±9 mg/d), with elevated pre-GC androstenedione (22±25 nmol/l) and 17-hydroxyprogesterone (287±268 nmol/l). At Wk4, crinecerfont-treated participants had significant least squares (LS) mean reductions in androstenedione (10.4 nmol/l) and 17 hydroxyprogesterone (-181.6 nmol/l) vs placebo (+1.6 nmol/l; LS mean difference [LSMD: -12.0 nmol/l; P < 0.0001] and 4.7 nmol/l [LSMD: -176.9 nmol/l; nominal P < 0.0001], respectively). At Wk24, there was greater GC dose reduction while maintaining androstenedione control with crinecerfont (-27% [-4.8 mg/m2/d]) vs placebo (-10% [ 2.5 mg/m2/d]; LSMD: -17%; P < 0.0001), with 63% vs 18% achieving physiologic dose ≤11 mg/m2/d with androstenedione control (P < 0.0001). Crinecerfont led to greater decreases vs placebo in body weight (-1.5% vs -0.1%, LSMD: -1.4%) and HOMA-IR (0.6 vs 0.4, LSMD: -0.3) at Wk24, and greater increases in bone turnover markers osteocalcin and CTx. Fatigue and headache were the most common adverse events.
Conclusions: Crinecerfont represents a novel treatment option to improve androgen control for patients with CAH. Participants on crinecerfont experienced reductions in androstenedione while GC dose was stable, enabling significant percent reductions in GC dose while maintaining androstenedione control.
Volume 104
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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