Endocrine Abstracts

Background: HSD-1, an intracellular enzyme, converts cortisone to cortisol in tissues where cortisol excess is associated with morbidity including liver, adipose, bone, brain, muscle, skin, and eye. SPI-62 is a potent and specific HSD-1 inhibitor in development for treatment of autonomous cortisol secretion (ACS) and Cushing’s syndrome, 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. Single and multiple SPI-62 doses decreased urinary cortisol metabolites indicating a similar decrease of hepatocellular cortisol in this important target tissue. After a corresponding transient decrease, circulating cortisol homeostasis was restored rapidly by ACTH increase which also resulted in a moderate adrenal androgen increase. SPI-62’s effects on ACTH and androgens did not result in adverse effects. Urinary free cortisol was not affected. The ACSPIRE trial will assess SPI-62 safety and efficacy in patients with dysregulated cortisol production due to ACS or adrenal Cushing’s syndrome (aCs) for the first time.

Methods: In this randomized, placebo-controlled, multinational, Phase 2 clinical trial, adult patients with ACS or aCs with otherwise benign adrenal adenomas, persistently elevated morning cortisol after verifiably adequate dexamethasone suppression, and at least two morbidities associated with hypercortisolism [A) insulin-resistance/type-2 diabetes mellitus, B) dyslipidemia, C) hypertension, or D) osteopenia] will be randomized to receive SPI-62 or placebo for 12 weeks. Subjects must have declined, delayed, or been deemed ineligible for adrenalectomy and not recently taken approved or experimental medical therapies for cortisol excess. Medical conditions or treatments likely to interfere with study assessments or subject safety are also excluded. Efficacy at 12-weeks is assessed by reduction of cortisol-associated morbidities of hyperglycemia and dyslipidemia while also examining, adiposity, hepatic steatosis, hypertension, inflammatory cytokines, osteopenia, muscle strength, cognition, sleep, and mood. Safety is assessed by adverse events, vital signs, ECGs, clinical laboratory analyses. Pharmacology is assessed by effects on HPA/HPG axis biomarkers and suppression of the urinary ratio of hepatic 5- and 3-steroid reductase metabolites of cortisol and cortisone (tetrahydrocortisol + allotetrahydrocortisol)/tetrahydrocortisone). Assessments include timed up-and-go and hand-grip strength tests, dual-energy x-ray absorptiometry, oral glucose tolerance test, continuous glucose monitoring, and 24-hour ambulatory blood pressure monitoring.

Results: This trial is ongoing; results are pending.

Discussion: This Phase 2 explores SPI-62 safety, HSD-1 inhibition, effects on HPA/HPG axes, and clinical effects in patients with ACS and aCs.