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Nevanimibe selectively targets adrenal steroidogenesis to treat serious orphan diseases

Millendo Therapeutics is currently advancing the development of nevanimibe (ATR-101) for the treatment of two orphan adrenal diseases: classic congenital adrenal hyperplasia (CAH) and endogenous Cushing's syndrome (CS). Both of these diseases are associated with an overactive adrenal cortex causing excess steroid production. Millendo believes that nevanimibe, a potentially first-in-class acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1) inhibitor, represents a novel, adrenal-specific approach that will address these diseases through the reduction of adrenal steroid production.

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

Millendo Therapeutics evaluated nevanimibe in a multicenter, single blind, intra-patient dose escalation Phase 2 clinical trial for the treatment of adult CAH. The trial's objectives were to evaluate the efficacy and safety of nevanimibe in this patient population. The trial, which assessed 5 escalating doses, alternated between 2 weeks of treatment with nevanimibe and 2 weeks with placebo to determine the effects of nevanimibe on adrenal steroid production. In the trial, Millendo observed nevanimibe to be associated with clear signs of clinical activity in seven of 10 treated patients, as measured by reductions in 17-hydroxyprogesterone (17-OHP), a key measure of disease control. Two patients experienced a reduction in 17-OHP levels to ≤2 times the upper limit of normal, the primary endpoint of the trial. Millendo also observed nevanimibe to have a rapid onset of action. Nevanimibe was reported to be well tolerated at all dose levels.

Millendo initiated a Phase 2b clinical trial of nevanimibe for the treatment of CAH in the third quarter of 2018; this trial is active with enrollment currently paused. For additional information, please visit www.clinicaltrials.gov and reference identifier number NCT03669549.

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.

nevanimibe diagram

Nevanimibe is also being studied in Cushing's syndrome (CS)

CS is a rare endocrine disease characterized by excessive cortisol production from the adrenal glands. The chronic cortisol excess in CS can cause weight gain, hypertension, diabetes, bone loss and a range of neurologic symptoms. With chronic exposure to higher than normal levels of cortisol, patients may also exhibit cognitive impairment and mood disorders. Millendo estimates that CS affects an estimated 20,000 people in the United States, with the medically managed target market being between 5,000 and 6,000 patients in the United States. CS most commonly affects people who are 20 to 50 years of age and women are affected three times more often than men.

Millendo’s approach to the treatment of CS is based on the same mechanism of action of nevanimibe, at similar dosing levels, that Millendo is exploring for the treatment of CAH. Due to its mechanism of action at the start of the steroidogenesis pathway, nevanimibe would be expected to treat endogenous Cushing's syndrome of any etiology (pituitary, adrenal, or ectopic).

Millendo is currently conducting a randomized, double-blind, placebo-controlled Phase 2 clinical trial to assess the safety and efficacy of nevanimibe in subjects with endogenous Cushing’s syndrome at clinical sites in the United States and United Kingdom. This trial, including both an open-label portion and a randomized double-blind placebo-controlled portion, is being conducted in up to 16 adults and is designed to provide dosing and efficacy information. Enrollment in the trial is ongoing.  For more information, please visit clinicaltrials.gov, identifier number NCT03053271.


  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 (12 pages)