• Richard J Auchus, Oksana Hamidi, Rosario Pivonello, Irina Bancos, Gianni Russo, Selma F Witchel, Andrea M Isidori, Patrice Rodien, Umasuthan Srirangalingam, Florian W Kiefer, Henrik Falhammar, Deborah P Merke, Nicole Reisch, Kyriakie Sarafoglou, Gordon B Cutler, Julia Sturgeon, Eiry Roberts, Vivian H Lin, Jean L Chan, Robert H Farber, and CAHtalyst Adult Trial Investigators.
• From the Departments of Pharmacology and Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, and the Endocrinology and Metabolism Section, Medicine Service, Lieutenant Colonel Charles S. Kettles Veterans Affairs Medical Center - both in Ann Arbor (R.J.A.); the Division of Endocrinology and Metabolism, University of Texas Southwestern Medical Center, Dallas (O.H.); Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples (R.P.), the Department of Pediatrics, Endocrine Unit, IRCCS San Raffaele Scientific Institute, Endo-ERN Center for Rare Endocrine Conditions, Milan (G.R.), and the Department of Experimental Medicine, Sapienza University of Rome, Rome (A.M.I.) - all in Italy; the Division of Endocrinology and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester (I.B.), and the Departments of Pediatrics and Experimental and Clinical Pharmacology, Divisions of Endocrinology and Genetics and Metabolism, University of Minnesota Medical School, Minneapolis (K.S.) - both in Minnesota; the Division of Pediatric Endocrinology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh (S.F.W.); the Department of Endocrinology, Diabetology, and Nutrition, Endo-ERN Center for Rare Endocrine Conditions, Centre Hospitalier Universitaire d'Angers and Laboratoire Physiopathologie Cardiovasculaire et Mitochondriale, Université d'Angers, Angers, France (P.R.); the Departments of Endocrinology and Diabetes, University College London Hospital, London (U.S.); the Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna (F.W.K.); the Department of Molecular Medicine and Surgery, Karolinska Institutet, and the Department of Endocrinology, Karolinska University Hospital, Stockholm (H.F.); the National Institutes of Health Clinical Center and Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD (D.P.M.); the Department of Endocrinology, Internal Medicine IV, Ludwig Maximilians Universität München, Munich, Germany (N.R.); Gordon Cutler Consultancy, Deltaville, VA (G.B.C.); and Neurocrine Biosciences, San Diego, CA (J.S., E.R., V.H.L., J.L.C., R.H.F.).
• N. Engl. J. Med. 2024 Aug 8; 391 (6): 504514504-514.

BackgroundAdrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH.MethodsIn this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control.ResultsAll 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups.ConclusionsAmong patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.).Copyright © 2024 Massachusetts Medical Society.

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