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Nevanimibe for congenital adrenal hyperplasia

Nevanimibe selectively targets adrenal steroidogenesis

Nevanimibe was observed to be associated with clear signs of clinical activity in a Phase 2 clinical trial for the treatment of adult CAH

Potentially first-in-class mechanism of action, highly adrenal-selective

Nevanimibe is a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase 1 (ACAT1), 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. Nevanimibe was chosen for its selectivity for ACAT1 over ACAT2 because ACAT1 expression in the adrenals is 15 times higher than in other tissues1. In preclinical studies, nevanimibe was found to be preferentially distributed to the adrenals. Combined, these attributes yield the highly directed adrenal effects of the compound.

Nevanimibe reduces adrenal steroidogenesis

Nevanimibe 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 nevanimibe significantly reduced the levels of all adrenal steroids and steroid intermediates tested2.
References
  1. SOAT1 sterol O-acyltransferase 1, Gene ID: 6646 Internet. The Human Protein Atlas, version 18 [cited 20 Aug 2018]. Available from: https://www.ncbi.nlm.nih.gov/gene/6646
  2. Langlois DK, Fritz MC, Schall WD, Bari Olivier N, Smedley RC, Pearson PG, et al. ATR-101, a selective ACAT1 inhibitor, decreases ACTH-stimulated cortisol concentrations in dogs with naturally occurring Cushing’s syndrome. BMC endocrine disorders. 2018;18(1):24 Available from: https://www.ncbi.nlm.nih.gov/pubmed/29720169
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