Neurocrine Reports Positive Top-Line Data from Phase 3 Study of Crinecerfont in Adults with Congenital Adrenal Hyperplasia

Rare Daily Staff    

Neurocrine Biosciences reported positive top-line data from the phase 3 CAHtalyst Adult Study evaluating the efficacy, safety, and tolerability of crinecerfont in adults with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) refers to a group of genetic conditions that result in an enzyme deficiency that alters the production of adrenal hormones that are essential for life. Approximately 95 percent 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.

The phase 3 study met its primary endpoint at Week 24, demonstrating that treatment with crinecerfont resulted in a statistically significant percent reduction in daily glucocorticoid dose versus placebo while maintaining androgen control.

The study also met important key secondary endpoints, with a statistically significant decrease in androstenedione at Week 4 versus placebo. At Week 24, approximately 63 percent of patients on crinecerfont achieved a reduction to a physiologic GC dose versus approximately 18 percent on placebo.

Crinecerfont was generally well tolerated. The most common adverse events during the double-blind, placebo-controlled period of the trial were fatigue, headache, and coronavirus infection. There were few serious adverse events, with none assessed as related to crinecerfont.

“CAH patients suffer from a number of debilitating symptoms and have had suboptimal treatment options with existing standard of care for their whole lives. These data, along with data from the open label treatment period, will allow us to proceed with our regulatory submissions to the FDA in 2024 and European Medicines Agency afterwards,” said Kevin Gorman, CEO of Neurocrine Biosciences.

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 (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. 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 experimental, 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 CRF type 1 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.

“CAH is a difficult disorder to live with for patients and their caregivers, taking a huge toll physically and mentally,” said Eiry Roberts, chief medical officer at Neurocrine Biosciences. “For physicians, the current treatment paradigm is problematic, relying on glucocorticoids for a dual purpose: not only to address the underlying cortisol deficiency but typically at supraphysiologic doses to treat androgen excess resulting in well-known complications over the long-term. The CAHtalyst phase 3 Adult data bring us one step closer to a new approach to treating CAH with a therapy that has demonstrated the ability to substantially reduce glucocorticoid doses while maintaining or improving androgen control.”

Additional data from the phase 3 CAHtalyst study will be provided in a peer-reviewed medical journal or at a medical conference at a future date. Data from the phase 3 CAHtalyst Pediatric Study will be available, as planned, in early Q4 2023.

Photo: Kevin Gorman, CEO of Neurocrine Biosciences