More than 90% of classic congenital adrenal hyperplasia (CAH) patients have defects in the cytochrome P450 enzyme steroid 21-hydroxylase, resulting in the inability to produce cortisol as well as the overproduction of androgens and androgen precursors such as 17-hydroxyprogesterone (17-OHP). Management of classic CAH can be challenging since patients are often unable to adequately balance the supraphysiologic doses of exogenous glucocorticoids required to suppress excess androgen production while avoiding the iatrogenic side effects of high-dose glucocorticoids. Nevanimibe hydrochloride, also known as ATR-101, is a novel, orally-administered adrenal-specific acyl-CoA:cholesterol acyltransferase-1 (ACAT1) inhibitor. Nevanimibe inhibits adrenal steroidogenesis by decreasing cholesteryl esters, the substrate required for steroid synthesis. This inhibition of adrenocortical steroidogenesis at an early step suppresses steroid production across all pathways (i.e., mineralocorticoid, glucocorticoid and androgens), resulting in improved control of hyperandrogenemia. In a previous Phase 2 study in patients with classic CAH and elevated 17-OHP levels (NCT02804178), nevanimibe decreased 17-OHP levels within 2 weeks of treatment. Millendo Therapeutics is now conducting a Phase 2b study to evaluate the efficacy and safety of nevanimibe in treating patients with classic CAH over a longer time period (NCT03669549). At approximately 12 sites in the EU, Israel, and Brazil, 2024 adult patients with classic CAH will be treated with nevanimibe at doses of 1000-2000 mg twice per day for 12 weeks. There are two patient cohorts: (1) patients with elevated 17-OHP and (2) patients with controlled levels of 17-OHP but requiring supraphysiologic dosing of glucocorticoids. During the screening period, patients who are on a high glucocorticoid dose and have suppressed 17-OHP levels may undergo a reduction in their supraphysiologic glucocorticoid dose to allow their 17-OHP levels to increase to > 4x the upper limit of normal (ULN). All eligible patients will be started on nevanimibe 1000 mg BID, and nevanimibe doses will be titrated based on 17-OHP levels. The primary efficacy endpoint is the proportion of patients who are able to achieve a reduction of 17-OHP to ≤ 2x ULN. Safety endpoints include the incidence of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), as well as values and changes from baseline in clinical laboratory tests, vital signs, physical examinations, and electrocardiogram parameters. Nevanimibe, an adrenal-specific ACAT1 inhibitor, presents a novel therapeutic approach to the treatment of classic CAH that may allow patients to more easily achieve balance between replacement glucocorticoid doses and control of hyperandrogenemia.
18 - 21 May 2019
European Society of Endocrinology