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ATR-101 selectively targets the adrenals to treat serious orphan diseases

Millendo Therapeutics is currently advancing the development of ATR-101 for the treatment of several orphan adrenal diseases: classic congenital adrenal hyperplasia (CAH), endogenous Cushing’s syndrome (CS) and adrenocortical carcinoma (ACC). Each of these are diseases that result from an overactive adrenal cortex, causing either excess steroid production and/or over-proliferation. ATR-101 seeks to address these diseases through the reduction of adrenal steroid production at low doses and induction of apoptosis in adrenocortical cells at higher doses.

First-in-class mechanism of action, highly adrenal-selective

ATR-101 is a potent and selective inhibitor of ACAT1 (acyl-CoA:cholesterol acyltransferase 1), an enzyme that catalyzes the transformation of free cholesterol to cholesterol ester. In the adrenals, cholesterol esters serve as a substrate reservoir for steroid biosynthesis. ATR-101 was chosen for its selectivity for ACAT1 over ACAT2. ACAT1 expression in the adrenals is 15x higher than in other tissues. In preclinical studies, ATR-101 was found to be preferentially distributed to the adrenals. Combined, these yield the highly directed adrenal effects of ATR-101.

ATR-101 reduces adrenal steroidogenesis

ATR-101 inhibits ACAT1, which reduces the reservoir of cholesterol esters in the adrenals. Cholesterol is the starting point for adrenal steroidogenesis, so this reduced level of substrate lowers adrenal steroid output. This activity has been demonstrated at relatively low doses in in vivo preclinical studies, where ATR-101 significantly reduced the levels of all adrenal steroids and steroid intermediates tested.

ATR-101 is currently in Phase 2 for the treatment of endocrine diseases of adrenal steroid excess

Several serious diseases result from the abnormal production of adrenal steroids. Millendo seeks to address classic congenital adrenal hyperplasia (CAH) and endogenous Cushing’s syndrome (CS). In both diseases, overproduction of specific adrenal steroids causes significant complications, and ATR-101 is being evaluated in both diseases to reduce adrenal steroid output. Millendo is currently conducting a Phase 2 clinical trial in the treatment of CAH. For more information, please visit clinicaltrials.gov, identifier number NCT02804178.

Orally administered ATR-101 was well tolerated with demonstrated activity lowering cortisol levels in canines with naturally-occurring (endogenous) Cushing’s syndrome. These data provide a strong basis for the development of ATR-101 in the treatment of Cushing’s syndrome. Due to its mechanism of action at the root of the steroidogenesis pathway, ATR-101 would be expected to treat endogenous Cushing's syndrome of any etiology (pituitary, adrenal, or ectopic). Millendo is currently conducting a Phase 2 clinical trial in the treatment of endogenous CS. For more information, please visit clinicaltrials.gov, identifier number NCT03053271.

Higher doses of ATR-101 are being investigated in ACC

While low doses of ATR-101 primarily inhibit steroidogenesis, higher exposures of ATR‑101 result in selective apoptosis of adrenocortical cells. In vitro studies in human H295R adrenocortical cancer cells have shown that ATR-101-mediated apoptosis is caused by inhibition of ACAT1 with subsequent disruption of cholesterol homeostasis leading to triggering of the unfolded protein response and, ultimately, adrenocortical apoptosis1. Millendo is investigating ATR-101 in an ongoing Phase 1 trial as a potential new treatment option for patients with adrenocortical carcinoma. For more information, please see clinicaltrials.gov, identifier number NCT01898715.


  1. LaPensee CR, et. al. ATR-101, a selective and potent inhibitor of acyl-CoA acyltransferase 1, induces apoptosis in H295R adrenocortical cells and in the adrenal cortex of dogs. Endocrinology. 2016 May;157(5):1775-88. (PMID: 26986192)