ESPE Abstracts (2016) 86 S9.3

Recent Advances in CAH: Treatments Saving GC Exposure

Richard Auchus


Background: Glucocorticoid therapy in 21-hydroxylase deficiency (congenital adrenal hyperplasia, CAH) both replaces the cortisol deficiency and reduces adrenal androgen production. Androgen control, however, often requires supraphysiologic and/or nocturnal glucocorticoid exposure. Chronic treatment in this manner contributes to long-term complications observed in CAH cohorts, including high rates of obesity, low bone density, glucose intolerance, skin fragility, and excess mortality. While cortisol replacement remains mandatory, alternative non-glucocorticoid agents to control androgen excess are desirable.

Objective and hypotheses: We have explored 2 conceptually distinct approaches to lower adrenal androgen production in phase I trials: blockade of androgen synthesis and antagonism of corticotropin-releasing factor (CRF) action.

Method: The first study included 6 women with classic CAH and serum androstenedione (AD) >1.5x the upper limit of normal (>12 nmol/l). These participants received 100 mg and 250 mg of the CYP17A1 (17-hydroxylase/17,20-lyase; P450c17 or P450 17A1) inhibitor abiraterone acetate (AA) for 6 consecutive days in sequential cycles of 100 or 250 mg/d. The second study employed a fixed-sequence single dose of 0, 300, or 600 mg of the CRF type 1 receptor antagonist NBI-77860 in 8 women with classic CAH.

Results: In the AA study, mean first-morning AD for days 6 and 7 normalized in 5 of 6 participants at 250 mg/d. First-morning AD normalized in all participants on day 7 at 250 mg/d, and AD remained normal 2 to 8 h on day 6 at both doses. Testosterone (T) and its metabolites fell in parallel; hypertension and/or hypokalemia were not observed. In the NBI-77860 study, reductions of adrenocorticotropin and 17-hydroxyprogesterone were conclusively demonstrated in half of participants. Responses strongly correlated with drug exposure, providing evidence of target engagement.

Conclusion: These studies demonstrate proof-of-concept for combination therapies using physiologic glucocorticoid dosing plus an agent to attenuate androgen production. Long-term studies of these and related drugs in children and adults with CAH are necessary to determine if these strategies are superior to conventional glucocorticoid therapy alone.

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