Endocrine Abstracts

ATR-101 is a selective Acyl-CoA: cholesterol acyltransferase 1 (ACAT1) inhibitor in development for the treatment of diseases of the adrenal cortex including rare endocrine diseases, such as congenital adrenal hyperplasia (CAH) and Cushing’s syndrome (CS), and in adrenocortical carcinoma (ACC). ATR-101 has been shown to inhibit adrenal steroidogenesis at low doses and cause apoptosis at high doses. To better understand the adrenal-specific effects of ATR-101, in vivo, a 13-week toxicity study was carried out in dogs. Groups of four male and four female beagle dogs received vehicle or ATR-101 at 3, 10 or 30 mg/kg by gavage dosed twice daily (BID) for 91 days (total daily doses of 6, 20 and 60 mg/kg per day). Additionally, two dogs from the vehicle and high dose cohorts were observed in a 28 day recovery period. Due to clinical signs indicative of adrenal insufficiency beginning on Day 20, the 30 and 10 mg/kg BID groups were reduced to 20 mg/kg BID and 7.5 mg/kg BID, respectively, and received replacement glucocorticoid and mineralocorticoid therapy with marked clinical improvement. Twice daily oral administration of ATR-101 for 91 days at doses of 3, 10/7.5, and 30/20 mg/kg/BID to dogs did not result in any early deaths. Systemic exposure to ATR-101 was similar between males and females, and increased with increasing dose in a greater than dose proportional manner. Clinical signs and clinical chemistry changes were predominantly secondary to adrenal insufficiency as sequelae of the intended pharmacology of ATR-101. Increases in endogenous ACTH levels and decreases in post ACTH-stimulation serum cortisol levels, and adrenal weight and the cortical atrophy were consistent with the expected pharmacological effects. The NOAEL, excluding effects secondary to the intended pharmacology, was 10/7.5 mg/kg BID. These results support the development of ATR-101 for treatment of endocrine disorders caused by adrenocortical hormone dysregulation.