Patients with classic adrenal hyperplasia (CAH) may be able to reduce their glucocorticoid (GC) doses with crinecerfont, a first-in-class corticotropin-releasing factor type 1 receptor antagonist, according to two studies recently published in The Journal of Clinical Endocrinology & Metabolism. Neurocrine Biosciences, Inc. funded the studies, and the company is marketing crinecerfont as CRENESSITY®.
The two papers — one focusing on adult care and the other pediatric care — present structured algorithms for reducing supraphysiologic glucocorticoid dosing, along with broader considerations for patient management in real-world practice. Two teams of expert endocrinologists convened for these studies, drafting companion pieces with recommendations for the adult and pediatric patients. “New and emerging non-glucocorticoid therapies for [CAH] can reduce adrenocorticotropic hormone-mediated androgen production, allowing for [GC] dose reductions,” the authors write.
“With the FDA approval of crinecerfont, the first non-GC adjunctive therapy to control androgens in patients with classic CAH, it is now possible for patients to reduce GCs to lower, more physiologic doses, potentially reducing the clinical complications associated with supraphysiologic GC treatment and excess androgens.”
Long-term supraphysiologic GC treatment can lead to multiple health comorbidities — adverse cardiovascular, metabolic, and skeletal outcomes. Dexamethasone especially, the authors point out, is associated with the most negative impacts on cardiometabolic health. “The increased risks of developing cardiometabolic comorbidities such as hypertension, cardiovascular disease, obesity, insulin resistance, and diabetes mellitus have been well documented in patients with CAH, especially those receiving higher GC doses,” the authors write.
But the reduction of GC doses is a tightrope and should be approached slowly; patients can experience GC withdrawal or adrenal insufficiency. Approaches to GC reduction should be individualized based on the patient’s therapeutic goals, cortisol needs, lifestyle preferences, and the clinician’s experience to set appropriate targets for clinical parameters, androgens, and GC dose regimen, the authors note.
Once patients start taking crinecerfont, laboratory measurements of androgen levels may be assessed around four weeks later to inform the approach to GC reduction, the authors write. “Appropriate target levels for androgens vary from patient to patient depending on age, sex, individual treatment goals, clinical markers of disease control, and timing of laboratory assessments,” the authors continue. Balancing the consequences of androgen excess with those of long-term supraphysiologic GC exposure has been an ongoing challenge in managing CAH, according to the authors. “With the FDA approval of crinecerfont, the first non-GC adjunctive therapy to control androgens in patients with classic CAH, it is now possible for patients to reduce GCs to lower, more physiologic doses, potentially reducing the clinical complications associated with supraphysiologic GC treatment and excess androgens,” they write. “This framework for reducing supraphysiologic GC doses in adult patients taking crinecerfont may become increasingly relevant as treatment of CAH shifts toward physiologic GC replacement with adjunctive control of adrenal androgens.”
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