Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1

Congenital adrenal hyperplasia (CAH) is an inherited inability to synthesize cortisol in the
adrenal gland. More than 90% of cases are cause by deficiency of steroid 21-hydroxylase
(CYP21, also termed CYP21A2, P450c21), which is a cytochrome P450 enzyme located in the
endoplasmic reticulum. It catalyzes conversion of 17-hydroxyprogesterone (17-OHP) to
11-deoxycortisol, a precursor for cortisol, and progesterone to deoxycorticosterone, a
precursor for aldosterone. Aldosterone deficiency may lead to salt wasting with consequent
failure to thrive, hypovolemia, shock and if untreated, death in the first few weeks of life.
Because patients cannot synthesize cortisol efficiently, the adrenal cortex is stimulated by
corticotropin (ACTH) and overproduces cortisol precursors. Some of these precursors are
diverted to sex hormone biosynthesis, which may cause signs of androgen excess including
ambiguous genitalia in newborn females, rapid postnatal growth in both sexes, and accelerated
skeletal maturation and decreased adult height. Patients require supraphysiologic replacement
doses of glucocorticoids to suppress the adrenocorticotropic hormone (ACTH)-driven adrenal
androgen synthesis. Excessive glucocorticoids are associated with excessive weight gain and
slowing of linear growth. It would be desirable in pre-pubertal children to decrease the
exposure to excess glucocorticoids while avoiding the adverse effects of inappropriate
exposure to androgens. Abiraterone acetate is a prodrug of abiraterone, an irreversible
inhibitor of 17α hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]), a key enzyme
required for testosterone synthesis. This agent indeed suppresses adrenal androgen secretion
in adult women. In this Phase 1 study, the investigators will determine the minimum effective
dose of abiraterone acetate that normalizes androstenedione levels during the 7-day Treatment
Period.

Inclusion Criteria:

1. Pre-pubescent girls (age 2 years [12 kg minimum] to 8 years inclusive; skeletal age
<10 years) or boys (age 2 years [12 kg] to 9 years inclusive; skeletal age <11 years).

2. Confirmed classic 21-hydroxylase deficiency evident by genotype groups A, A1 or B or
clinical course (e.g., adrenal crisis with documented hyperkalemia and hyponatremia,
at diagnosis or during a later evaluation; ambiguous genitalia in females).
Documentation of one or both parents' genotypes may be required to confirm the
subject's genotype.

3. Requirement for standard of care fludrocortisone (any dose) and ≥10 mg/m2/day of
hydrocortisone for at least 1 month prior to the study consent.

4. Morning serum androstenedione concentrations >1.5 x ULN after 7 days of dosing with
doses of hydrocortisone required for physiologic replacement.

5. At least one parent (or other legally acceptable representative) must sign the
informed consent form before the performance of any study procedures, but both parents
must sign if both have parental rights. Children who are capable of providing assent
(typically 10 years of age and older) must sign an assent form before the performance
of any study procedures

Exclusion Criteria:

1. Evidence of central puberty: Tanner Stage >2 for breast development in girls or
testicular volume >4 mL in boys, or random LH >0.3 mIU/mL. Subjects with pubic and/or
axillary hair as the only sign of puberty onset will be allowed.

2. Current or history of hepatitis from any etiology, including history of active viral
hepatitis A, B, or C.

3. Patients with baseline hepatic impairment are excluded from this trial. To be eligible
for this protocol, patients must meet all of the following criteria:

AST, ALT and Total bilirubin < ULN Albumin > LLN No evidence of ascites No evidence of
encephalopathy

4. Abnormalities of liver function developing during the study

5. Abnormal renal function tests, defined as BUN or creatinine >1.5 ULN for age.

6. Significant anemia (hemoglobin < 12 g/dl). If documented to be due to iron deficiency,
subjects may be rescreened 3 months after this has been treated.

7. Clinically significant abnormality in the 12-lead electrocardiogram (ECG)

8. A history of a malabsorption syndrome.

9. Evidence of active malignancy.

10. Serious or uncontrolled co-existent disease, including active or uncontrolled
infection. Subjects may be rescreened after resolution of any such condition.

11. Concurrent medical condition or disease other than 21-hydroxylase deficiency that may
interfere with linear growth or that requires concomitant therapy that is likely to
interfere with study procedures or results.

12. Asthma or other condition requiring treatment with systemic corticosteroids within the
past 3 months. Asthma treatment with inhaled corticosteroids is permitted.

13. Treatment with potentially hepatotoxic medications (statins); strong inhibitors of
CYP3A4 (ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone,
saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), or CYP3A4
inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
phenobarbital). CYP2C8 substrates (rosiglitazone, pioglitazone, rapaglinide) and
CYP2D6 substrates (dextromethorphan, thioridazine) should be avoided

14. Treatment with medications to affect puberty or synthesis of sex steroids, including
gonadotropin releasing hormone agonists, aromatase inhibitors, or androgen receptor
blockers (e.g., flutamide, spironolactone). However, a gonadotropin releasing hormone
agonist may be started during the study for treatment-emergent central puberty without
disqualifying the subject

15. Treatment with growth hormone at enrollment or during the course of the study.

16. Known allergies, hypersensitivity, or intolerance to abiraterone acetate or its
excipients (refer to United States Prescribing Information).

17. Has received an investigational drug within 4 weeks of the planned first dose of study
drug or is currently enrolled in an investigational interventional study.

18. Any condition that, in the opinion of the investigator, would make participation not
be in the best interest (eg, compromise the well-being) of the subject or that could
prevent, limit, or confound the protocol-specified assessments.

19. Presence or history of cataracts.