LB-OR-1 Marked Androgen Reduction in Adult Women With Classic 21-Hydroxylase Deficiency (21OHD) Treated With Abiraterone Acetate (AA) Added to Physiologic Hydrocortisone (HC) and Fludrocortisone (FC)

Program: Late-Breaking Abstracts
Session: LB-OR-Late-Breaking Oral Session
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 11:30 AM
Room 122 (Moscone Center)
Richard Joseph Auchus*1, Elizabeth Osborne Buschur1, Gary D Hammer1, Alice Yoonju Chang2, Carole Andrea Ramm1, David Anthony Madrigal1, George Wang3, Martha Gonzalez3, Steven Xu3, Hans Smit4, Italo Poggesi5 and Margaret K. Yu6
1University of Michigan, Ann Arbor, MI, 2Mayo Clinic, Rochester, MN, 3Janssen Research & Development, Raritan, NJ, 4Janssen Research & Development, Beerse, Belgium, 5Jan-Cilag, Cologno Monzese, Italy, 6Janssen Research & Development, Los Angeles, CA
In the treatment of women with congenital adrenal hyperplasia due to 21OHD, control of androgen excess without iatrogenic Cushing syndrome remains an elusive goal. Recent cohort studies show that glucocorticoid overtreatment is common in adults with 21OHD, leading to comorbidities and impaired quality of life, but therapeutic alternatives to glucocorticoids for androgen excess management are lacking. AA is a potent inhibitor of cytochrome P450c17 (CYP17A1) used in combination with prednisone for prostate cancer treatment. We hypothesized that AA added to physiologic HC and FC would correct androgen excess in women with 21OHD without causing hypertension and hypokalemia.

This phase 1 open-label, multiple-dose, intrasubject, sequential dose-escalation study enrolled 6 women with classic 21OHD and serum androstenedione (AD)>1.5× normal (>345 ng/dL), who were taking 20 mg/d HC plus FC. AA oral suspension was taken for 6 days, starting at 100 mg QAM with dose escalations after ≥7-day washouts, until >80% of participants had normalization (<230 ng/dL) of the morning AD before HC and AA, mean of AD on Days 6 and 7 (mAD, primary end point). Secondary end points include 17-hydroxyprogesterone, total testosterone (T), urine androsterone and etiocholanolone glucuronides (T metabolites), electrolytes, and safety.

At 100 mg/d AA, mAD normalized in 50% of participants, with a reduction from a median baseline of 764 ng/dL to median mAD of 254 ng/dL. The primary end point was met at 250 mg/d AA, as mAD normalized in 5/6 (83%) participants, with a decrease from a median baseline of 664 ng/dL to mAD of 126 ng/dL. After the Day 6 AA dose, AD fell to a median nadir of 66 and 38 ng/dL by 8 h at 100 and 250 mg/d, respectively. Serum T and urine T metabolites fell in parallel to AD. At 250 mg/d AA, T decreased from a median baseline of 89 ng/dL to a median of 28 ng/dL (69% fall) for mean of T on Days 6 and 7 (mT). AA exposure was strongly and significantly negatively correlated with mAD and mT. The correlation coefficients between AUC24and mAD and mT were -0.73 (p=0.007) and -0.72 (p=0.008), respectively. The one participant who did not normalize mAD had the lowest drug exposure, without evidence of dose proportionality. AA was safe and well tolerated. No adverse events of hypertension or hypokalemia were observed.

Based on data generated in this dose-escalation study, AA added to replacement HC and FC normalizes androgen excess in this population of women with 21OHD.

Disclosure: RJA: Principal Investigator, Jansen Pharmaceuticals. CAR: Investigator, Jansen Pharmaceuticals. DAM: Investigator, Jansen Pharmaceuticals. GW: Owner, Johnson &Johnson, Employee, Janssen Research & Development. MG: Employee, Jansen Pharmaceuticals. SX: Employee, Janssen Research & Development, Owner, Johnson &Johnson. HS: Employee, Johnson &Johnson, Owner, Johnson &Johnson. IP: Employee, Jansen Pharmaceuticals. MKY: Employee, Janssen Research & Development, Owner, Janssen Research & Development. Nothing to Disclose: EOB, GDH, AYC

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: Janssen Research & Development
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