12429 Overnight Metyrapone Therapy In Patients With Mild Autonomous Cortisol Secretion (MACS): An Open Label Phase 2 Interventional Study
Authors: Ferreira E Y , Saini J , Larson J , Atkinson E , Powell C , Nevin S , Fell V , Bancos I 
Published: October 2024

Disclosure: E.Y. Ferreira: None. J. Saini: None. J. Larson: None. E. Atkinson: None. C. Powell: None. S. Nevin: None. V. Fell: None. I. Bancos: Grant Recipient; Self; HRA Pharmaceuticals. Research Investigator; Self; HRA Pharmaceuticals.

Context: Mild autonomous cortisol secretion (MACS) is the most prevalent hormonal abnormality demonstrated in 20-45% of patients with adrenal adenomas. MACS is associated with increased prevalence and incidence of cardiovascular morbidity, frailty, fragility fractures, psychiatric and sleep disorders, as well as increased mortality. Bilateral MACS due to bilateral adrenal adenomas or macronodular adrenal hyperplasia is seen in around 20% of patients with MACS. Management of patients with unilateral MACS who are not surgical candidates or do not desire adrenalectomy, and management of patients with bilateral MACS is challenging. Safe and effective medical therapy is urgently needed in these patients. Objective: 1) assess safety and tolerability of overnight metyrapone therapy in patients with MACS, 2) evaluate the impact of overnight metyrapone on steroid profiling and circadian cortisol secretion and 3) determine the efficacy of overnight metyrapone on metabolic and bone parameters, mood, sleep, cognition, quality of life, frailty and senescence biomarkers. Methods: This open-label, phase 2 interventional single-center study using overnight metyrapone opened for enrollment in December 2023 (NTC06106295) and plans to enroll 30 patients with MACS. Eligible participants include adults with adrenal adenoma or macronodular adrenal hyperplasia and MACS, and at least one comorbidity attributed to hypercortisolism. Metyrapone is administered overnight at 250 mg to 1000 mg. Duration of the study is 6 months (main study) and up to 42 months for extension study. Primary endpoint is incidence of treatment related adverse events. Key secondary endpoints include: glucocorticoid/androgen ratio, morning/evening cortisol curve, metabolic parameters (change in blood pressure, hyperglycemia, weight), frailty index and senescence biomarkers. Results: Between December 15th 2023 and April 6th, 7 patients with MACS (4, 57% women) enrolled at a median age of 62 years (IQR 56-68). Median BMI was 29 kg/m2(IQR 25-34). Post-dexamethasone cortisol was 3.1 mcg/dL (IQR 2.4-6.2), corticotropin (ACTH) was 7.3 pg/mL (IQR 5-20), and dehydroepiandrosterone-sulfate (DHEAS) was 73 mcg/dL (IQR 59-86). Median hypercortisolism clinical severity score was 9 (IQR 2-11) and biochemical severity score was 3.5 (IQR 2-5). Prevalence of hypertension (57%), dysglycemia (67%), dyslipidemia (86%), depression (57%), anxiety (43%), and bone disease (70%) was high. In 7 participants, median frailty index was 0.2 (IQR 0.2-0.4), and 3 (43%) were considered frail (frailty index &gt;0.25). As of April 6th, 2024, no major treatment-related adverse events were reported, and no patient discontinued therapy. Conclusion: Results of this study will characterize safety and tolerability of overnight metyrapone in patients with MACS and evaluate the impact of overnight metyrapone on MACS-associated comorbidities.

Presentation: 6/1/2024