RF21 | PSAT100 HPA Axis Modulation by a Potent Inhibitor Indicates 11Beta-Hydroxysteroid Dehydrogenase Type 1 (HSD-1) Is a Significant Contributor to Cortisol Levels
Authors: Katz David , Mortier Mark 
Published: November 2022

Abstract

Background
HSD-1, an intracellular enzyme, converts cortisone to cortisol in target tissues in which cortisol excess is associated with morbidity including liver, adipose, bone, brain, muscle, skin, and eye. SPI-62 is a potent HSD-1 inhibitor in Phase 2 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 data from a multiple ascending dose trial (1) to characterize the contribution of HSD-1 to intracellular cortisol that can bind to intracellular receptors as well as HPA and HPG axis modulation by SPI-62. Data from all non-elderly subjects who received 10-50 mg SPI-62 (doses that achieved maximal liver HSD-1 inhibition) were combined for analysis. ANCOVA models with a treatment effect and baseline covariate were conducted; reported statistics are least squares means and standard errors.

Results
Compared to placebo (n=10), single doses of SPI-62 (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 24-hour urinary 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 at 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 at 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 (47.3[2.13] v 30.4[4.45]; 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] 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
Single SPI-62 doses 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 not affected. As other HSD-1 inhibitors, SPI-62 is associated with moderate androgen increases that, to date, appear not to be associated with adverse effects. As HSD-1 contributes much of the intracellular cortisol that can access intracellular receptors in target tissues for cortisol morbidity, we hypothesize that HSD-1 inhibitors have potential as treatments for conditions of cortisol excess such as Cushing's syndrome and autonomous cortisol secretion.

Reference
(1) Bellaire et al., Clin. Transl. Sci. 2019 May;12(3): 291-301.
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