Can an innovative drug help kids with congenital adrenal hyperplasia reach normal height?

Children with congenital adrenal hyperplasia (CAH) often have elevated androgen levels, which leads to early puberty, accelerated bone maturation and short adult stature. Traditional glucocorticoid treatment, including hydrocortisone, is a Catch-22: It controls androgen levels, but high daily doses slows patients’ linear growth and puts them at risk for excess weight gain.

Researchers at Children’s Health℠ and UT Southwestern are working to improve on this: They’re leading a Phase I multicenter study to determine if abiraterone acetate, an oral androgen biosynthesis inhibitor, can safely lower patients’ androgen levels and reduce hydrocortisone doses.

“Kids do pretty well with hydrocortisone and fludrocortisone, but we’re hopeful that this new approach will lower patients’ exposure to excess androgens and glucocorticoids and, ultimately, improve their quality of life,” says Perrin White, M.D., Director of the Division of Pediatric Endocrinology at Children's Health and Professor at UT Southwestern. Dr. White is the principal investigator for the study.

CAH Reduces Patients’ Adult Heights

More than 90 percent of CAH cases are caused by 21-hydroxylase deficiency. Children with the disorder are unable to synthesize cortisol normally. This leads the adrenal cortex to overproduce cortisol precursors, which are then metabolized to androgen precursors and subsequently to testosterone.

Left untreated, CAH exposes patients to high levels of androgens and leads to rapid growth in childhood. Their bones mature faster than normal, causing the growth plates to close too early. Children with poorly controlled CAH tend to be tall children, but short adults.

The Catch-22 of CAH Treatment

Controlling androgen levels requires supraphysiological doses of hydrocortisone – generally 50 percent more than needed for other forms of adrenal insufficiency.

While treatment replaces cortisol and controls androgen levels, the high doses themselves may slow down growth. On average, patients with CAH will be around three inches shorter than their expected adult height.

Repurposing a Prostate Cancer Treatment

A few years ago, Dr. White and his colleagues began brainstorming ways to solve this. “We got the idea of short circuiting this problem by using a drug that would block the synthesis of all sex hormones,” he says.

This idea led them to abiraterone acetate, an FDA-approved treatment for prostate cancer that inhibits a key enzyme required for testosterone synthesis. The idea is that abiraterone acetate would minimize androgen secretion in patients with CAH. This, in turn, would slow down bone maturation, as well as reduce the amount of hydrocortisone needed.

“We would use this before a child is supposed to go through puberty,” Dr. White says. “Once they go into puberty, they need to make testosterone or estrogen. But prepubertal kids don't make a lot of sex hormones normally, so there's no problem with blocking it.”

Phase I Trial

Dr. White is the principal investigator for the multicenter Phase I study, which began recruiting participants – prepubescent children with classic 21-hydroxylase deficiency – in 2018.

The study aims to determine the minimum effective dose of oral abiraterone acetate that normalizes testosterone precursor levels. The 7-day treatment is an adjunct to approved CAH therapy (oral hydrocortisone and fludrocortisone).

The study completion date is slated for 2020. In Phase II, the researchers aim to determine if, over 24 months, the treatment slows bone age advancement and, ultimately, improves adult height prognosis.

Goal: Transform Endocrine Care

For Dr. White, this trial is part of a larger goal to transform care for children with endocrine disorders. He’s also leading studies on gene expression in white blood cells from children with either type 1 or type 2 diabetes mellitus. The endocrinology group is planning participation in two multicenter studies for patients with type 1 diabetes; one will test an advanced “bionic pancreas” insulin pump, and the other will use a new drug in patients with newly diagnosed diabetes in an attempt to slow the loss of insulin-producing cells in the pancreas.

The abiraterone acetate trial is currently recruiting participants. Learn more about the clinical trials program at Children’s Health, or refer a patient by calling 214-456-5136.

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