Phase 3 Clinical Trial Shows Benefits of a New Treatment for Children With Congenital Adrenal Hyperplasia

When it comes to caring for children with congenital adrenal hyperplasia (CAH), avoiding the side effects of traditional treatments has long been a challenge. But in a recent phase 3 clinical trial, a new drug called crinecerfont showed safety and efficacy in children with classic CAH, the severe form of this condition. This constitutes a major therapeutic breakthrough for CAH.

CAH is the most common cause of primary adrenal insufficiency in children, affecting the hormone-producing adrenal glands. Individuals with CAH lack an enzyme required to synthesize key hormones such as cortisol, which is needed for responding to stress and illness. Patients with CAH are missing cortisol but can produce male hormones, or androgens, in abundance when steroid biosynthesis is disrupted. Dysregulating the balance of hormones can set children on an abnormal growth trajectory, and can lead to health complications later in life, such as fertility issues.

“Children with classic CAH are traditionally treated with hydrocortisone to replace cortisol and to decrease excess androgens,” says Mimi Kim, MD, MSc, Co-director of the Congenital Adrenal Hyperplasia Clinic and an investigator in the Center for Endocrinology, Diabetes and Metabolism at Children’s Hospital Los Angeles. Dr. Kim is also second author on the new study. “But we often give higher doses of glucocorticoids in order to maintain hormone balance across an individual’s lifetime,” she explains. “This makes crinecerfont and this class of drug a novel, adjunctive therapy in patients with CAH to decrease androgen excess and glucocorticoid doses in patients with CAH.”

Dr. Kim is nationally recognized for her work in CAH, having recently won the 2024 prize for Best Original Research Paper from Hormone Research in Paediatrics and the Pediatric Endocrine Society (PES). The prize was awarded for a study published with several CHLA collaborators, which found that infants with CAH already had significant differences in brain structure compared to healthy infants. The early impact of CAH on children further highlights the need for a new treatment that could help to modulate hormone levels more effectively and reduce the impacts of glucocorticoid therapy and hormone imbalances on an individual with CAH over the course of a lifetime.

Discovering crinecerfont’s potential

Prior phase 2 trials had shown that an oral drug called crinecerfont—a corticotropin-releasing factor type 1 receptor antagonist—could lower levels of the steroid hormone androstenedione in patients with CAH. “Controlling androgen levels such as the level of androstenedione is an important part of disease control and maintaining a healthy hormone balance in the body,” says Dr. Kim. Based on the results of the phase 2 trials, the phase 3 trial was launched.

The randomized clinical trial was conducted at 37 academic medical centers across the US, Canada and Europe. Of 103   children with classic CAH, 69 were assigned to receive crinecerfont and 34 received a placebo for 28 weeks. 100 participants remained in the trial after 28 weeks. A stable dose of glucocorticoid was maintained for 4 weeks and was adjusted as long as participants’ androstenedione levels were controlled.

At 4 weeks, mean androstenedione levels were significantly reduced in the crinecerfont group but slightly increased in the placebo group. After 28 weeks, there was an 18% decrease in the mean glucocorticoid dose among the crinecerfont group (while androstenedione control was maintained) but a 5.6% increase in the placebo group. The most common adverse events experienced by participants were headaches, increased body temperature and vomiting.

“We found that crinecerfont was more effective than placebo and that children treated with crinecerfont had fewer adverse effects,” says Dr. Kim.

Limitations and future considerations

Dr. Kim is eager to continue researching this new class of drugs further. “It is exciting to see in this trial how significantly crinecerfont can advance care for patients with CAH,” she says. “A longer trial with additional clinical outcomes for patients will be be illuminating moving forward.”

This study was published in the New England Journal of Medicine and was sponsored by Neurocrine Biosciences.