Androgen Reduction in Congenital Adrenal Hyperplasia

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. This Phase 2 will determine if, over 24 months, this treatment retards bone
age advancement and thus improves adult height prognosis. The present study is the first
clinical trial to explore the utility of abiraterone acetate as a means for decreasing daily
requirements for glucocorticoids in pre-pubertal children with 21-hydroxylase deficiency.

Inclusion Criteria:

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

- Confirmed classic 21-hydroxylase deficiency evident by genotype groups A, A1 or B, or
by clinical course.

- 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.

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

- Informed consent .

Exclusion Criteria:

- 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.

- Current or history of hepatitis from any etiology.

- Abnormal liver function tests (transaminases>3X ULN).

- Abnormal renal function tests (BUN or creatinine >1.5 ULN).

- Significant anemia (hemoglobin < 12 g/dl).

- Clinically significant ECG abnormality

- A history of a malabsorption syndrome.

- Evidence of active malignancy.

- Co-existent disease that may interfere with linear growth or that requires concomitant
therapy that is likely to interfere with study procedures or results.

- Treatment with potentially hepatotoxic medications, CYP2D6, strong inhibitors or
inducers of CYP3A4

- Treatment with medications to affect puberty or synthesis of sex steroids, including
gonadotropin releasing hormone agonists, aromatase inhibitors, or androgen receptor
blockers

- Treatment with growth hormone

- Known allergies, hypersensitivity, or intolerance to abiraterone acetate or its
excipients.