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 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. Nevanimibe seeks to address these diseases through the reduction of adrenal steroid production.
Nevanimibe has shown clear biological activity in a Phase 2 proof-of-concept study in classic congenital adrenal hyperplasia (CAH)
Nevanimibe was evaluated in a multi-center, single-blind, multiple dose Phase 2 proof-of-concept clinical study to assess its efficacy, in addition to corticosteroids, in patients with classic congenital adrenal hyperplasia. The study, 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 steroids. In the first 10 patients, 7 demonstrated a clear biological effect 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 ≤2x the upper limit of normal, the primary endpoint, a result consistent with the short duration of treatment (2 weeks/dose level) and high baseline levels of 17-OHP. Nevanimibe also exhibited rapid onset of action with reductions in other key steroids and steroid precursors. Nevanimibe was well-tolerated at all dose levels.
Based on these positive results, Millendo is planning a subsequent clinical trial to assess longer periods of dosing and additional clinical endpoints.
First-in-class mechanism of action, highly adrenal-selective
Nevanimibe 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. Nevanimibe was chosen for its selectivity for ACAT1 over ACAT2. ACAT1 expression in the adrenals is 15x higher than in other tissues. 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 tested1
Nevanimibe is also being studied in Cushing’s syndrome
Preclinical studies showed that nevanimibe was well tolerated with demonstrated activity lowering cortisol levels in canines with naturally-occurring (endogenous) Cushing’s syndrome. These data, along with the demonstrated activity of nevanimibe in CAH patients, provide a strong basis for the development of nevanimibe in the treatment of Cushing’s syndrome. Due to its mechanism of action at the root 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 multi-center, randomized, double-blind, placebo-controlled Phase 2 clinical study to assess the safety and efficacy of nevanimibe in subjects with endogenous Cushing’s syndrome. Subjects will enter a 6-week open-label dose-titration period and then randomized in a double-blind fashion to either their current dose of nevanimibe or placebo for up to 4 weeks. For more information, please visit clinicaltrials.gov, identifier number NCT03053271.
Millendo has conducted a Phase 1 trial of nevanimibe as a potential new treatment option for patients with Adrenocortical Carcinoma (ACC). This study explored doses far higher than are currently being studied in Cushing’s syndrome or CAH trials and demonstrated good tolerability.