Neurocrine Biosciences Reports Phase 3 Results of Therapy in Children with CAH

Rare Daily Staff

Neurocrine Biosciences reported that top-line data from its phase 3 CAHtalyst Pediatric Study evaluating the efficacy, safety, and tolerability of its experimental therapy crinecerfont in children and adolescents with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency met its primary endpoint.

Congenital adrenal hyperplasia (CAH) refers to a group of genetic conditions that result in an enzyme deficiency that alters the production of adrenal hormones which are essential for life. Approximately 95 percent of CAH cases are caused by a mutation that leads to deficiency of the enzyme 21-hydroxylase. In classic CAH, severe deficiency of this enzyme leads to an inability of the adrenal glands to produce cortisol and, in approximately 75 percent of cases, aldosterone. If left untreated, classic CAH can result in salt wasting, dehydration, and even death.

There are currently no non-glucocorticoid treatments approved by the U.S. Food and Drug Administration for classic CAH. Glucocorticoids, the current standard of care, are used not only to correct the endogenous cortisol deficiency but typically used at greater than physiologic doses (supraphysiologic) to try to suppress the high levels of corticotropin-releasing factor and adrenocorticotropic hormone that result in androgen excess. However, glucocorticoid treatment at supraphysiologic doses has been associated with serious and significant complications of steroid excess, including metabolic issues such as weight gain and diabetes, cardiovascular disease, and osteoporosis.

Additionally, long-term treatment with supraphysiologic GC doses may have psychological and cognitive impact such as changes in mood and memory. Androgen excess has been associated with abnormal bone growth and development in pediatric patients, female health problems such as acne, excess hair growth and menstrual irregularities, testicular rest tumors in males, and fertility issues in both sexes.

Crinecerfont is an oral, selective corticotropin-releasing factor type 1 receptor antagonist being investigated to help reduce and control excess adrenal androgens through a steroid-independent mechanism for the treatment of CAH due to 21-hydroxylase deficiency. Antagonism of CRF1 receptors in the pituitary has been shown to decrease adrenocorticotropic hormone levels, which in turn decreases the production of adrenal androgens and potentially the symptoms associated with classic CAH.

The CAHtalyst phase 3 global registrational study was designed to evaluate the safety, efficacy, and tolerability of crinecerfont in children and adolescents (2–17 years of age) with classic congenital adrenal hyperplasia due to 21-OHD. The study enrolled 103 female and male patients with CAH and consisted of a 28-week randomized, double-blind, placebo-controlled period followed by 24 weeks of open-label crinecerfont treatment and optional open-label extension. The study started in July 2021, and the open-label treatment portion is still ongoing.

The study demonstrates that lowering androgen levels enables lower, more physiologic dosing of glucocorticoids and thus could potentially reduce the complications associated with exposure to greater than normal glucocorticoid doses in patients with classic CAH.

Importantly and consistent with the results from the phase 3 CAHtalyst Adult study, crinecerfont treatment led to a statistically significant percent reduction from baseline in daily GC dose while maintaining androgen control at Week 28 versus placebo. Approximately 30 percent of participants receiving crinecerfont achieved a reduction to a physiologic GC dose while maintaining androgen control compared to 0% of participants receiving placebo. The study also met the other key secondary endpoint demonstrating a statistically significant decrease in serum 17-hydroxyprogesterone from baseline at Week 4 versus placebo.

Crinecerfont was generally well tolerated. During the double-blind, placebo-controlled period of the trial, the most common adverse events were headache, fever, vomiting, upper respiratory tract infection, and nasopharyngitis.  There were few serious adverse events, with none assessed as related to crinecerfont.

“The outstanding safety and efficacy results reported today for the CAHtalyst Pediatric study and last month for the CAHtalyst Adult study demonstrate the potential benefit of crinecerfont across all groups studied, including children, adolescents and adults,” said Kevin Gorman, CEO of Neurocrine Biosciences.

The data from the CAHtalyst Pediatric and Adult studies, including data from the open-label treatment periods, will support regulatory submissions to the FDA in 2024 and later to the European Medicines Agency. Additional information regarding the results from both phase 3 CAHtalyst studies will be provided at the company’s December 2023 Analyst Day and in a peer-reviewed medical journal.

Photo: Kevin Gorman, CEO of Neurocrine Biosciences