SFEBES2016 Poster Presentations Adrenal and Steroids (41 abstracts)
Characterization of clinical, biochemical and adrenal hormonal effects of ATR-101, a selective ACAT1 antagonist, in dogs with naturally-occurring Cushing’s syndrome
Stephen Hunt 1 , Michele Fritz 2 , William Schall 2 , N. Bari Olivier 2 , Rebecca Smedley 2 , Paul Pearson 3 , Marc Bailey 4 & Daniel Langlois 2
1Millendo Therapeutics, Inc., Ann Arbor, Michigan 48104, USA; 2Michigan State University College of Veterinary Medicine, East Lansing, Michigan 48824, USA; 3Pearson Pharma Partners, Westlake Village California 91362, USA; 4Integrated Nonclinical Development Solutions, Inc., Ann Arbor, Michigan 48103, USA.
Cushing’s syndrome (CS) in humans shares many similarities with its counterpart in dogs in terms of etiology (pituitary versus adrenal causes), clinical signs, and pathophysiologic sequelae. ATR-101 is a novel small molecule therapeutic currently in clinical development for the treatment of congenital adrenal hyperplasia and adrenocortical carcinoma in humans. ATR-101 is an adrenal-selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase 1). ACAT1 catalyzes cholesterol ester formation from cholesterol and long-chain fatty acyl-CoA and, in the adrenal cortex, is particularly important in creating a reservoir of substrate for steroid biosynthesis. Previous studies in healthy dogs have shown that ATR-101 decreases adrenal steroidogenesis at low doses and induces apoptosis at high doses. Treatment led to rapid, dose-dependent decreases in adrenocorticotropic hormone (ACTH) stimulated cortisol levels consistent with ATR-101-mediated inhibition of ACAT1. In this veterinary clinical study, we characterized the pharmacokinetics and investigated the clinical, biochemical and adrenal hormonal effects of ATR-101 in dogs with naturally-occurring CS after oral administration over a 2–4 week treatment period. In addition, adrenal gland histology and tissue drug concentrations were evaluated in dogs with adrenal-dependent disease. Companion dogs with naturally-occurring CS resulting from either pituitary (n=7) or adrenal (n=3) etiology were dosed orally over 2–4 weeks with each subject receiving two dose levels. Orally administered ATR-101 is well-tolerated, achieves exposures in a dose-dependent manner, distributes to the adrenal glands, and lowers post-ACTH stimulated cortisol levels regardless of underlying etiology in dogs with naturally-occurring CS. These results support the ongoing development of ATR-101 as a novel agent for treatment of endocrine disorders associated with adrenal steroid dysregulation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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