RARE Daily

FDA Grants Breakthrough Therapy Designation for Neurocrine’s Crinecerfont in CAH

December 6, 2023

Rare Daily Staff

The U.S. Food and Drug Administration granted Breakthrough Therapy designation to Neurocrine Biosciences for crinecerfont in congenital adrenal hyperplasia.

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% of CAH cases are caused by a mutation that leads to deficiency of the enzyme 21-hydroxylase (21-OHD). 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 FDA for classic CAH. Glucocorticoids (GCs), the current standard of care, are used not only to correct the endogenous cortisol deficiency but typically used at greater than physiologic (supraphysiologic) doses to try to suppress the high levels of corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH) 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. 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.

Corticotropin releasing factor (CRF) regulates the secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland. Crinecerfont is an investigational, oral, selective corticotropin-releasing factor type 1 receptor (CRF1) antagonist being developed to reduce and control excess adrenal androgens through a steroid-independent mechanism for the treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). Antagonism of CRF1 receptors in the pituitary has been shown to decrease adrenocorticotropic hormone (ACTH) levels, which in turn decreases the production of adrenal androgens and potentially the symptoms associated with classic CAH. Neurocrine’s data 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.

Breakthrough Therapy designation is a process developed by the FDA to expedite development and review of drugs that are intended to treat a serious condition and where clinical evidence indicates that the potential drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). Crinecerfont also received Fast Track and Rare Pediatric Disease designations in congenital adrenal hyperplasia.

The CAHtalyst phase 3 pediatric and adult global registrational studies were designed to evaluate the safety, efficacy, and tolerability of crinecerfont in children and adolescents (2–17 years of age) and adults (18 years of age and older) with CAH due to 21-OHD, respectively. Both studies met their primary and secondary endpoints. The CAHtalyst Pediatric study demonstrated a statistically significant decrease in serum androstenedione from baseline with crinecerfont at Week 4 over baseline, while both studies showed crinecerfont treatment led to statistically significant reductions in daily glucocorticoid from baseline while maintaining androgen control at Week 28 and Week 24, respectively.

Crinecerfont was generally well tolerated in the CAHtalyst phase 3 studies. The most common adverse events in the CAHtalyst Pediatric study were headache, fever, vomiting, upper respiratory tract infection, and nasopharyngitis, while the most common adverse events in the CAHtalyst Adult study were fatigue, headache, and coronavirus infection. Few serious adverse events were seen in either study, with none assessed as related to crinecerfont. Both studies achieved a >95 percent completion rate.

“The outstanding safety and efficacy results from the phase 3 CAHtalyst studies in pediatric and adult patients suggest that crinecerfont has the potential to represent a substantial improvement over current standard of care in CAH by controlling androgen levels and allowing for reduced steroid doses.,” said Eiry  Roberts, chief medical officer, Neurocrine Biosciences. “We remain on track to submit the new drug application in 2024.”

Photo: Eiry  Roberts, chief medical officer, Neurocrine Biosciences

Stay Connected

Sign up for updates straight to your inbox.