SAT277 Intracellular Cortisol Control: An Approach To Reduce Cushing’s Syndrome Morbidity With Minimal Adrenal Insufficiency Risk?
Authors: Czerwiec Frank S , Katz David A , Stewart Paul M 
Published: October 2023

Abstract
Disclosure: F.S. Czerwiec: Employee; Self; Sparrow Pharmaceuticals, Inc. Stock Owner; Self; Sparrow Pharmaceuticals, Inc. D.A. Katz: Employee; Self; Sparrow Pharmaceuticals, Inc. Stock Owner; Self; Sparrow Pharmaceuticals, Inc. P.M. Stewart: Advisory Board Member; Self; Sparrow Pharmaceuticals, Inc. Consulting Fee; Self; Sparrow Pharmaceuticals, Inc.
Endocrinologists focus on circulating and excreted cortisol to diagnose and to assess severity and treatment response in Cushing’s syndrome (Cs), but tissue action that drives morbidity is mediated by cortisol binding to intracellular glucocorticoid (GC), mineralocorticoid, and non-genomic receptors. Patients with severe hypercortisolism and deficiency in 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) (an enzyme that generates active GC in target tissues) had no cortisol-related morbidity. Mice without the Hsd11b1 gene (which encodes HSD-1) or given a HSD-1 inhibitor were protected from glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, dermal atrophy, and trabecular bone loss associated with GC administration. The HSD-1 inhibitor AZD4017 prevented detrimental prednisolone effects on glycemic control and osteocalcin in a Phase 1 clinical trial. Although patients with cortisone reductase (i.e., HSD-1) deficiency show no signs or symptoms of adrenal insufficiency (AI), the theoretical possibility of AI in HSD-1 inhibitor treated patients has been raised. Healthy adults received the HSD-1 inhibitor SPI-62 or placebo for 14 days. Data after last dose were analyzed by ANCOVA with baseline as covariate. SPI-62 reduced 24h urinary cortisol metabolites (4.6 +/- 0.3 v 8.0 +/- 0.5 nmol), indicative of a 42% intrahepatocellular cortisol decrease. Results from other inhibitors support HSD-1 as the source of nearly half of intrahepatocellular cortisol in human. Morning serum (293.9 +/- 18.9 v 273.4 +/- 39.3 nM) and 24h urinary (100.7 +/- 6.9 v 89.6 +/- 14.0 nmol) cortisol did not differ between SPI-62 and placebo. No pattern of adverse events suggestive of AI has been observed in SPI-62, nor other HSD-1 inhibitor, clinical trials. Administration of a HSD-1 inhibitor to patients with GC excess could reduce Cs morbidity via reduction of cortisol or GC medication (e.g., prednisolone) available to intracellular receptors. Unlike current Cs treatments that are all associated with substantial AI risk, under HSD-1 inhibition ACTH-mediated cortisol secretion maintains normal circulatory cortisol available to enter cells and thus prevent AI. Data suggest that AI will not be an issue in patients treated with HSD-1 inhibitors. That prediction is under evaluation in Phase 2 clinical trials of SPI-62 in patients with ACTH-dependent Cs, autonomous cortisol secretion, and (together with prednisolone) polymyalgia rheumatica. Until more experience is gathered, caution in patients with modest autonomous cortisol secretion, suppressed ACTH, and atrophied adrenal tissue is advised. In situations that require GC rescue dosing during HSD-1 inhibitor administration, prodrug GCs (i.e., cortisone acetate, prednisone) will not be effective a. s they require HSD-1 for activation. Those patients require active agents (e.g., hydrocortisone, prednisolone).
Presentation: Saturday, June 17, 2023