Supplemental Data. Supplement to: Abiraterone Acetate to Lower Androgens in Classic 21-Hydroxylase Deficiency

Transcription

1 Supplemental Data Supplement to: Abiraterone Acetate to Lower Androgens in Classic 21-Hydroxylase Deficiency Richard J. Auchus, Elizabeth O. Buschur, Alice Y. Chang, Gary D. Hammer, Carole Ramm, David Madrigal, George Wang, Martha Gonzalez, Xu Steven Xu, Johan W. Smit, James Jiao, and Margaret K. Yu Division of Metabolism, Diabetes, & Endocrinology, University of Michigan, Ann Arbor, MI (R.J.A., E.O.B., G.D.H., C.R., D.M.); Division of Endocrinology, Metabolism, Diabetes and Nutrition, Mayo Clinic, Rochester, MN (A.Y.C.); Janssen Research & Development, Raritan, NJ (G.W., M.G., X.S.X., J.J.); Janssen Research & Development, Beerse, Belgium (J.W.S.); and Janssen Research & Development, Los Angeles, CA (M.K.Y.).

2 SUPPLEMENTAL DATA Table of contents SUPPLEMENTAL TABLE 1. Inclusion and exclusion criteria... 3 SUPPLEMENTAL TABLE 2. CYP21A2 genotypes, hydrocortisone (HC) and 9α-fludrocortisone acetate (FCA) doses, and serum androstenedione (AD) values at screening... 4 SUPPLEMENTAL TABLE 3. Baseline characteristics of six participants... 5 SUPPLEMENTAL TABLE 4. Safety measures and adverse events... 6 SUPPLEMENTAL FIG. 1. Schematic diagram of study protocol.... 7

3 SUPPLEMENTAL TABLE 1. Inclusion and exclusion criteria Inclusion criteria Premenopausal women, aged > 18 years Receiving a hormonal contraceptive agent from the time of entry into the study until 3 months after the completion of the study Confirmed classic 21-hydroxylase deficiency by CYP21A2 genotypes associated with classic congenital adrenal hyperplasia Morning serum androstenedione concentration after at least 6 days of hydrocortisone and 9αfludrocortisone acetate at study-defined doses greater than or equal to 1.5 times the upper limit of normal No coexisting medical conditions that would preclude participation Liver, renal, or electrocardiogram assessments without clinically significant abnormalities as deemed by the investigator Willingness to adhere to the protocol Exclusion criteria History of bilateral adrenalectomy Current or history of active or chronic hepatitis Any active infection Unable to fast or history of malabsorption syndrome Evidence of active malignancy Serious or uncontrolled coexistent nonmalignant disease, including active and uncontrolled infection Receiving systemic glucocorticoids for any reason other than for the treatment of 21- hydroxylase deficiency Any disorders requiring treatment with anticonvulsants Subjects of child-bearing potential who are not willing to use a method of birth control with adequate barrier protection Pregnant or breast-feeding Planned surgery prior to the end of the study Received an investigational drug or device within 4 weeks of the planned first dose of abiraterone acetate Any condition that would make participation not in the best interest of the participant as deemed by the investigator Genotypes associated with nonclassic 21- hydroxylase

4 SUPPLEMENTAL TABLE 2. CYP21A2 genotypes, hydrocortisone (HC) and 9α-fludrocortisone acetate (FCA) doses, and serum androstenedione (AD) values at screening Participant Genotype* HC (mg) FCA (mg) AD (ng/dl) In2G/conv Q318X/Q318X vs del del/conv R483P/del rescreen In2G/F306+1nt conv/conv vs del rescreen In2G/In2G del/del rescreen rescreen rescreen I172N/conv I172N/I172N I172N+R356W/ I172N+R356W vs del In2G/I172N MWF In2G/Q318X In2G/conv *conv, large gene conversion; vs del indicates test cannot distinguish homozygous or hemizygous for mutation or conversion, no functional CYP21A2 gene present. HC doses are AM-noon-PM, approximately 08:00 12:00 06:00. FCA doses are AM-PM, approximately 08:00 08:00; MWF, Monday, Wednesday, Friday. To convert androstenedione to nmol/liter, multiply by

5 SUPPLEMENTAL TABLE 3. Baseline characteristics of six participants Baseline characteristic N = 6 Age y Median 36 Range Body mass index* Median 36.7 Range Race (n) Caucasian 6 Comorbidities (n) Hypertension 0 Diabetes mellitus 1 Impaired glucose tolerance 1 Baseline laboratory data Serum 17OHP ng/dl Median Range Serum androstenedione ng/dl Median 764 Range Serum testosterone ng/dl Median 113 Range Serum potassium mmol/l Median 4.2 Range Abbreviations: 17OHP, 17-hydroxyprogesterone. *The body mass index is the weight in kilograms divided by the square of the height in meters. Conversion factors to nmol/liter: multiply 17OHP by , androstenedione by , and testosterone by

6 SUPPLEMENTAL TABLE 4. Safety measures and adverse events Safety measure and AE Median (range) Median systolic blood pressure, mmhg Day 8, 100 mg/d abiraterone treatment period 112 (94 123) Day 8, 250 mg/d abiraterone treatment period 114 ( ) Diastolic blood pressure, mmhg Day 8, 100 mg/d abiraterone treatment period 73 (65 92) Day 8, 250 mg/d abiraterone treatment period 71 (54 81) Serum potassium, mmol/liter Day 8, 100 mg/d abiraterone treatment period 4.3 ( ) Day 8, 250 mg/d abiraterone treatment period 3.8 ( ) PRA, ng/ml/h Day 1, 100 mg/d abiraterone treatment period 6.3 ( ) Day 8, 100 mg/d abiraterone treatment period 7.0 ( )* Day 1, 250 mg/d abiraterone treatment period 9.5 ( ) Day 8, 250 mg/d abiraterone treatment period 5.4 ( )* Serum alanine aminotransferase, IU/l Day 8, 250 mg/d abiraterone treatment period 15 (9 40) Serum creatinine, mg/dl Day 8, 250 mg/d abiraterone treatment period 0.85 ( ) Abbreviations: PRA, plasma renin activity. To convert PRA to ng/liter/s multiply by To convert creatinine to µmol/liter, multiply by *No clinically meaningful change and no suppressed (< 0.6) PRA values on day 8 of either treatment period; sample size too small and range too wide to perform formal statistical comparison.

7 SUPPLEMENTAL FIG. 1. Schematic diagram of study protocol.