Neurocrine Biosciences announced that the US Food and Drug Administration (FDA) approved Crenessity^™ (crinecerfont) on Dec. 13, 2024, about two weeks ahead of its anticipated decision date. Both the oral capsule and solution formulation are approved to control androgen levels in adults and pediatric patients with classic congenital adrenal hyperplasia (CAH), together with glucocorticoids. Crenessity is a first-in-class selective corticotropin-releasing factor type 1 receptor (CRF₁) antagonist that works by reducing the excessive production of androgens, allowing for lower doses of glucocorticoids. Recommended dosing for adults is 100mg twice daily with a meal and for pediatric patients is weight-based twice daily with a meal. It is expected to be available in approximately one week and cost information will be known at that time. For full prescribing information, please click here.

At a Glance

• Brand Drug: Crenessity^™(crinecerfont)
• Manufacturer: Neurocrine Biosciences
• Date Approved: Dec. 13, 2024
• Indication: Adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients four years of age and older with classic CAH
• Dosage Forms Available: 25mg, 50mg, and 100mg capsules, 50mg/mL oral solution
• Launch Date: Expected to be available in approximately one week.
• Estimated Annual Cost: Cost information is expected to be available at launch.
• CAH is a rare, genetic endocrine disorder that affects the adrenal glands, which produce cortisol in response to stress or illness and produces mineralocorticoids, such as aldosterone, which regulate sodium and potassium levels. The adrenal glands also affect the sex hormone, testosterone, which is needed for growth and development. The estimated prevalence is 1/10,000; therefore, approximately 30,000 patients in the US have CAH.
• An autosomal recessive disorder, 21-hydroxylase deficiency (21-OHD), is caused by the lack of 21-hydroxylase enzyme required for cortisol synthesis and accounts for approximately 95% of CAH cases. This enzyme deficiency leads to low cortisol and aldosterone levels that cause symptoms such as low appetite, nausea, dizziness, and fatigue. An adrenal crisis can be life-threatening, and patients may have symptoms such as low blood pressure, low blood sugar, dehydration, vomiting,  diarrhea, and shock. Additionally, because androgens, the precursor to cortisol, are still being produced, this excess androgen can result in salt wasting, dehydration, and death.
• There is no curative treatment option for CAH, but the goal is to lower the androgens the body is over-producing and replace mineralocorticoids (fludrocortisone) and glucocorticoids (GCs; e.g., betamethasone, prednisolone, prednisone, hydrocortisone, dexamethasone, methylprednisolone). GCs correct the endogenous cortisol deficiency, but the doses used are higher than the cortisol replacement needed to lower the levels of adrenocorticotropic hormone (ACTH) and adrenal androgens. These high doses of GCs can cause serious adverse effects including weight gain, diabetes, cardiovascular disease, and osteoporosis. Crenessity is intended to be used as an add-on therapy with glucocorticoids to help reduce daily doses.
• The CAHtalyst Pediatric and Adult Phase III trials are published in the New England Journal of Medicine (NEJM). In the adult study, participants received a dose of 100mg twice daily or a placebo. At week 24, the change in the glucocorticoid dose was −27.3% in the crinecerfont group and −10.3% in the placebo group (−17.0%; P<0.001). A physiologic glucocorticoid dose was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont but increased with placebo (P<0.001). In the pediatric study, children two years to 17 years of age underwent randomization to a dose of 25mg (body weight of 10kg to <20kg), 50mg (body weight of 20kg to <55kg), or 100mg (body weight of ≥55kg) or matching placebo twice daily, with morning and evening meals. At week 28, the mean glucocorticoid dose had decreased by 18.0% with crinecerfont but increased by 5.6% with placebo (−23.5%; P<0.001). At week 4, the androstenedione level was substantially reduced in the crinecerfont group but increased in the placebo group (P<0.001). Both studies achieved lower steroid doses and decreased androgen levels for the treatment group.
• Crenessity carries a warning for acute adrenal insufficiency or adrenal crisis with inadequate concomitant glucocorticoid therapy. It is recommended not to reduce the glucocorticoid dose below the dose required for cortisol replacement. In both Phase III studies, crinecerfont was well tolerated with the most common adverse events being headache, fever, fatigue, arthralgia, abdominal pain, and upper respiratory tract infection.
• In Phase III development for CAH, Neurocrine Biosciences is developing chronocort an oral, modified-release hydrocortisone designed to mimic natural circadian rhythm throughout the day. Spruce Biosciences’ tildacerfont is an oral CRF₁ antagonist in Phase II studies for the treatment of CAH.