title: Single-Dose Study of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Women With 21-Hydroxylase Deficiency.
abstract: BACKGROUND
  Treatment of 21-hydroxylase deficiency (21OHD) is difficult to optimize. Normalization of excessive ACTH and adrenal steroid production commonly requires supraphysiologic doses of glucocorticoids.
  
  
  OBJECTIVE
  We evaluated the safety and tolerability of the selective corticotropin releasing factor type 1 (CRF1) receptor antagonist NBI-77860 in women with classic 21OHD and tested the hypothesis that CRF1 receptor blockade decreases early-morning ACTH and 17α-hydroxyprogesterone (17OHP) in these patients.
  
  
  METHODS
  The study enrolled eight classic 21OHD females, ages 18-58 years, seen at a single tertiary referral university setting.
  
  
  METHODS
  This was a phase Ib, single-blind, placebo-controlled, fixed-sequence, single-dose trial. During three treatment periods separated by 3-week washout intervals, patients sequentially received placebo, NBI-77860 300 mg, and NBI-77860 600 mg at 10 pm; glucocorticoid therapy was withheld for 20 hours. We evaluated ACTH, 17OHP, androstenedione, and testosterone as well as NBI-77860 pharmacokinetics over 24 hours.
  
  
  RESULTS
  Dose-dependent reductions of ACTH and/or 17OHP were observed in six of eight subjects. Relative to placebo, NBI-77860 led to an ACTH and 17OHP reduction by a mean of 43% and 0.7% for the 300 mg dose, respectively, and by 41% and 27% for the 600 mg dose, respectively. Both NBI-77860 doses were well tolerated.
  
  
  CONCLUSIONS
  The meaningful reductions in ACTH and 17OHP following NBI-77860 dosing in 21OHD patients demonstrate target engagement and proof of principle in this disorder. These promising data provide a rationale for additional investigations of CRF1 receptor antagonists added to physiologic doses of hydrocortisone and fludrocortisone acetate for the treatment of classic 21OHD.
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: Adina F
authors.initials: AF
authors.lastname: Turcu
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Spencer-Segal
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Farber
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: Rosa
authors.initials: R
authors.lastname: Luo
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Ramm
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: David
authors.initials: D
authors.lastname: Madrigal
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: Tim
authors.initials: T
authors.lastname: Muth
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: O'Brien
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine (A.F.T., J.L.S.-S., C.A.R., D.M., T.M., R.J.A.), and Department of Pharmacology (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Neurocrine Biosciences (R.H.F., R.L., D.E.G., C.F.O.), San Diego, California 92130.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D053961:Azabicyclo Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008875:Middle Aged; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013997:Time Factors; D055815:Young Adult; D000099052:CRF Receptor, Type 1
chemical_list: D053961:Azabicyclo Compounds; C556497:NBI 77860; D010069:Oxadiazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D019326:17-alpha-Hydroxyprogesterone; D000324:Adrenocorticotropic Hormone