ECE2021 Audio Eposter Presentations Pituitary and Neuroendocrinology (113 abstracts)
11β-hydroxysteroid dehydrogenase type 1 (HSD-1) controls the intracellular cortisol pool that has access to cytosolic glucocorticoid and mineralocorticoid receptors. HSD-1 activity is elevated in patients with Cushings syndrome (CS).1 Patients with CS and constitutionally low HSD-1 activity showed no hypercortisolism-related symptoms despite very high 24-hour urine free cortisol.2, 3 A recent pilot trial of a HSD-1 inhibitor in patients with classical or mild CS showed positive trends on glycemic control and body habitus.4 SPI-62 is a potent, selective HSD-1 inhibitor. In four prior clinical trials once-daily SPI-62 dosing, without titration, was associated with few adverse events and substantially reduced intracellular cortisol.5-7 We have shown that in a double-blind, randomized, placebo-controlled, 6-week pilot trial in subjects with diabetes, SPI-62 was associated with clinically meaningful decreases on HbA1c, glucose, cholesterol, and triglycerides. Adult patients with ACTH-dependent CS will be randomized to receive SPI-62 followed by placebo, or placebo followed by SPI-62, in an upcoming international, multicenter clinical trial. Patients with urinary biomarker of HSD-1 activity (allotetrahydrocortisol + tetrahydrocortisol)/tetrahydrocortisone ≥ 1 will be eligible. Patients with recent radiation therapy or surgery, or planned surgery, for CS, and patients with pseudo-CS, cyclic CS, or exogenous CS will be excluded. Medical therapy for CS will be subject to washout before randomization, while medications intended to treat specific symptoms and comorbidities (except glucocorticoid or mineralocorticoid receptor antagonists) will be continued on stable regimens. Efficacy will be assessed based on glycemic control, body habitus, blood pressure, blood lipids, bone biomarkers, mood, cognition, and quality of life. Safety will be reported for all subjects who receive at least one dose of study drug and will include hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axis monitoring. This will be the first randomized placebo-controlled trial of a HSD-1 inhibitor in the treatment of CS.
1 Clin Endocrinol (1996) 45:605-611.
2 J Clin Endocrinol Metab (2002) 87:57-62.
3 Endocrine J (2008) 55:709-715.
4 Diabetalogia (2019) 62:S268-S269.
5 Clin Transl Sci (2019) 12:291-301.
6 J Nucl Med (2019) 60:1140-1146.
22 May 2021 - 26 May 2021