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Endocrine Abstracts (2022) 81 RC13.1 | DOI: 10.1530/endoabs.81.RC13.1

ECE2022 Rapid Communications Rapid Communications 13: Adrenal and Cardiovascular Endocrinology 2 (8 abstracts)

HPA axis modulation by a potent inhibitor indicates 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) is a main source of cortisol that can bind intracellular receptors

David Katz 1 & Mark Mortier 2


1Sparrow Pharmaceuticals, Portland OR, United States; 2Emanate Biostats, Carlsbad CA, United States


Background: HSD-1 converts cortisone to cortisol in tissues in which cortisol excess is associated with morbidity including liver, adipose, bone, and brain. SPI-62 is a potent HSD-1 inhibitor in clinical development for treatment of Cushing’s syndrome and autonomous cortisol secretion, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibition.

Methods: We analyzed multiple dose trial1 data to characterize the contribution of HSD-1 to cortisol that can bind to intracellular receptors and HPA/HPG axis modulation by SPI-62. Data from subjects who received SPI-62 doses that achieved maximal liver HSD-1 inhibition were combined for analysis. ANCOVA models with treatment effect and baseline covariate were conducted; statistics are least squares mean [standard error].

Results: Compared to placebo (n=10), single SPI-62 doses (n=40) were associated with 24-hour urinary tetrahydrocortisol (2.27[0.134] v 4.44[0.269] mmol) and allotetrahydrocortisol (2.98[0.146] v 4.80[0.291] mmol) decreases, and tetrahydrocortisone (32.71[1.149] v 9.19[2.300] mmol) increase. Serum cortisol was decreased at 2-hours (152.2[11.64] v 226.6[24.00] nM) but not 4- or 12-hours post-dose. ACTH was increased at 4- and 12-hours (45.6[1.64] v 32.1[3.29]; 38.5[1.67] v 26.3[3.33] pg/ml) but not 2-hours post-dose. After 14 daily doses, SPI-62 was associated with 24-hour urinary tetrahydrocortisol (2.05[0.154] v 4.36[0.321] mmol), allotetrahydrocortisol (2.75[0.181] v 4.13[0.377] mmol), and tetrahydrocortisone (42.73[1.968] v 8.51[0.410] mmol) changes. ACTH was increased at pre-dose and 2-, 4-, and 12-hours post-dose (45.6[1.71] v 27.0[3.61]; 45.3[1.79] v 35.2[3.72]; 34.4[1.71] v 18.8[3.57]; 47.3[2.13] v 30.4[4.45] pg/ml). No differences on urinary cortisol or cortisone, serum cortisone, or CRH were observed after single or multiple doses. After multiple doses, SPI-62 was associated with increased DHEA-S (342.2[9.94] v 155.0[20.52] mg/dl) and, in females, testosterone (2.1[0.11] v 1.4[0.25] nM). No differences on aldosterone, estradiol, FSH, LH, progesterone, or SHBG were observed.

Discussion: SPI-62 resulted in ~40-50% decreases of urinary cortisol metabolites which indicate similar decrease of hepatocellular cortisol. Following a corresponding decrease, circulating cortisol homeostasis was restored rapidly by ACTH increase. Urinary cortisol was unaffected. SPI-62 is associated with moderate androgen increases that, to date, appear not associated with adverse effects. As HSD-1 contributes much of the intracellular cortisol that can access intracellular receptors, we hypothesize that HSD-1 inhibitors are potential treatments for conditions of cortisol excess such as Cushing’s syndrome and autonomous cortisol secretion.

Reference

1. Clin. Transl. Sci. 2019;12:291-301.

Volume 81

European Congress of Endocrinology 2022

Milan, Italy
21 May 2022 - 24 May 2022

European Society of Endocrinology 

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