The purpose of this study is to evaluate the safety and tolerability of 1 mg osilodrostat therapy in patients with mild autonomous cortisol secretion (MACS), and to determine the impact on 24h urine steroid metabolome and circadian cortisol/cortisone concentrations

Inclusion Criteria:

• Provide written informed consent

• Stated willingness to comply with all study procedures and availability for the duration of the study

• Age ≥ 18 years

• Diagnosed with MACS

  • At least 2 abnormal post-dexamethasone cortisol results:

    i. 1 mg post-dexamethasone cortisol >1.8 mcg/dL or ii. 8 mg post-dexamethasone cortisol >1 mcg/dL

  • Historical dexamethasone suppression test results can be used if performed within 24 months prior to enrollment.

• Adrenal imaging phenotype consistent with benign disease (adrenal adenoma/s, macronodular or micronodular adrenal hyperplasia)

• At least one of the following comorbidities:

  • Obesity (BMI>30 kg/m2)
  • Dysglycemia
  • Dyslipidemia
  • Hypertension
  • Osteopenia
  • Osteoporosis
  • Fragility fractures

• Ability to take oral medication and be willing to adhere to the study intervention regimen

• For persons of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of ≤ 5% per year during the treatment period and for 1 month after the last dose of study treatment.

Exclusion Criteria:

• Planned alternative therapy for MACS during the study period

• Current use of oral exogenous glucocorticoid therapy

• Current use of opioid therapy >20 MME/day

• Planned use of oral exogenous glucocorticoid therapy

• Planned use of opioid therapy >20 MME/day

• Use of injectable glucocorticoid within the last 6 weeks or anticipated glucocorticoid use during the study period.

• Hypokalemia of hypomagnesemia at baseline visit

• Prolonged QTc on baseline ECG

• Concomitant therapy with medications likely to lead to drug-drug interactions (based on PI review).

• Investigator's judgement based on history/physical examination that a comorbidity or concomitant medication may impact the hypothalamic-pituitary-adrenal axis or steroid metabolome

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations that would limit compliance with study requirements

• Pregnancy or lactation

• Known allergic reactions to osilodrostat

• Suspected false positive post-dexamethasone cortisol results due to increased metabolism, poor absorption, or noncompliance with dexamethasone.

• Treatment with another investigational drug or other intervention within lower than specific therapy washout period