CRF1 and ACTH antagonists in patients with classic 21-hydroxylase deficiency

Abstract

Supraphysiological replacement doses of glucocorticoids are commonly used in 21-hydroxylase deficiency (21OHD) to be able to control the adrenal androgen and steroid precursor production. By reducing the ACTH production by blocking the corticotropin-releasing factor type 1 receptor (CRF1) or the ACTH receptor more physiological glucocorticoid doses can be used. Melanocortin type 2 receptor (MC2R, or ACTH receptor) antagonist block ACTH on the adrenals and has a similar effect. These three novel principles have been used in drug development and are currently in different phases. The data from the largest randomized controlled phase 3 trial in 21OHD have recently been published showing that crinercerfont, an orally administered CRF1 antagonist, has very good effect in controlling the adrenal androgens and steroid precursors while lowering the glucocorticoids into the physiological range. The competitor tildercerfont, another CRF1 antagonist, did not show convincing results in one of their randomized control phase 3 trials which was prematurely terminated. Atumelnant (CRN04894), a MC2R antagonist has just presented the initial results from an open-label, dose-finding phase 2 study in patients with 21OHD with encouraging results while Lu AG13909, an ACTH receptor antagonist, currently is trialed in a phase 1 study in patients with 21OHD.