Inclusion Criteria:

Subjects must satisfy all following criteria at the Screening visit unless otherwise stated:

• Male or female aged 18 years or older.
• Able to provide written informed consent.
• Active and consistent cortisol excess:
• This is defined as UFC > upper limit of normal (ULN) based on at least 2 valid (i.e., complete)  24-hour urine samples collected during Screening. 
• Documented diagnosis of ACTH-dependent Cushing’s syndrome:
• This includes Cushing’s disease, ectopic ACTH secretion, and ectopic CRH secretion. Subjects may include newly diagnosed patients who have declined or are not considered candidates for surgery or patients with residual or recurrent disease after surgery in whom surgery or radiation are not planned within the next 6 months. Previous medical records will be used to support the diagnosis.
• At least 1 of the following will be considered satisfactory to establish the diagnosis:
• History of positive ACTH-staining pathology.
• History of documented, transient, AI after tumor removal requiring glucocorticoid replacement.
• ACTH level > 20 pg/mL with positive ACTH or cortisol response to CRH or desmopressin (DDAVP) stimulation in the presence of hypercortisolemia.
• Inferior petrosal sinus sampling with ACTH central:plasma gradient ≥ 2 before CRH or DDAVP or ≥ 3 after CRH or DDAVP.
• Presumptive Cushing’s disease based on presence of a pituitary tumor ≥ 6 mm along with positive ACTH or cortisol response to CRH or DDAVP stimulation or an overnight or high-dose (8 mg) dexamethasone suppression of cortisol, performed and interpreted according to locally recognized standards of diagnosis.
• In the absence of any of the above, an individual might be eligible if ectopic ACTH-dependent Cushing’s syndrome was otherwise confirmed via adequate testing consistent with the local standards of care. Such cases must be discussed with and explicitly approved by the Medical Monitor and Sponsor, and the specific diagnostic criteria used to establish the diagnosis of ACTH-dependent Cushing’s syndrome must be documented.
• Willing to comply with reproductive precautions.
• Current evidence of Cushing’s morbidities of hyperglycemia, dyslipidemia, hypertension, or osteopenia.
• Defined by having at least 2 of the below criteria, ideally including both “a” and “b”, but including at least 1 of “a” or “b”. At the Medical Monitor’s discretion, any 2 of the 4 criteria may be allowed.
• Diagnosis of insulin-resistance/pre-diabetes or type 2 diabetes: Including patients on stable diabetic treatment, but excluding those ethically requiring further or frequent therapy adjustments.
  • Type 2 diabetes is defined as a current HbA1c ≥ 6.5% but ≤ 9.5% (otherwise excluded), fasting blood glucose (FBG) > 126 mg/dL, or 2 hr OGTT ≥ 200 mg/dL;
  • Pre-diabetes is defined as current HbA1c < 6.5 but > 5.7%, FBG > 100 to 125 mg/dL, or 2-hour OGTT 140 to 199 mg/dL;
  • Insulin-resistance may also be defined by abnormal HOMA-IR < 2.5 or by CGM data (e.g., mean glucose, glycemic variability, time in range, estimated HbA1c).
• Diagnosis of dyslipidemia: This is evidenced by history of total cholesterol level of ≥ 6.2 mmol/L (240 mg/dL) or triglycerides of ≥ 5.2 mmol/L (200 mg/dL) Current total cholesterol may be < 6.2 mmol/L, and current triglycerides may be < 5.2 mmol/L, if controlled with allowed lipid-lowering therapy.
• Diagnosis of hypertension: Incident hypertension should be brought under control and stabilized prior to randomization at Day 1. Subjects with hypertension which is reasonably, but sub-optimally managed by standard therapy at baseline (systolic blood pressure [SBP] > 140 but < 180 or DBP > 90 but < 120 mmHg) qualify.
• Diagnosis of osteoporosis or osteopenia: Osteoporosis (Z-score ≤ -2.0) or osteopenia (T-score ≤ -1.0) or history or evidence of minimal-traumatic or osteoporotic fracture treated with lifestyle modification with mineral or vitamin supplementation or stable approved osteoporosis therapies.

Exclusion Criteria

Subjects will be excluded from the study if they satisfy any of the following criteria at the Screening visit unless otherwise stated:

• Recent or planned Cushing’s surgery: Surgery for Cushing’s within the past 6 weeks or planned within 24 weeks after randomization.
• Use of medications for Cushing’s syndrome within the washout periods prior to randomization.
• Recent Cushing’s radiotherapy: Any fractionated radiation therapy for Cushing’s within the past 2 years, or conventional radiation therapy within 4 years.
• History of bilateral adrenalectomy.
• History of pseudo-Cushing’s syndrome.
• History of cyclic Cushing’s syndrome.
• Exogenous hypercortisolism or factitious Cushing’s syndrome.
• History of non-ACTH-dependent hypercortisolism:
• This includes that caused by a known inherited syndrome (e.g., McCune Albright syndrome, Carney complex) but not including multiple endocrine neoplasia type 1 where diagnostic testing has led to a diagnosis of Cushing’s disease (79%) while excluding autonomous adrenal Cushing’s syndrome (21%).
• High risk of Nelson’s syndrome: Current evidence of macroadenoma with, or at risk of, optic nerve or vital structure compression, e.g., tumor showing aggressive growth within 2 mm of optic chiasm or with evidence of blood-vessel encroachment.
• Uncontrolled Cushing’s morbidities of hyperglycemia, dyslipidemia, hypertension, or osteopenia:
• Including evidence of chronic, poor glycemic control (HbA1c > 9.5%), symptomatic dyslipidemia (e.g., hypercholesterolemia with recent (< 1 year) cerebro- or cardiovascular events, hypertriglyceridemia with pancreatitis), persistent uncontrolled hypertension (systolic blood pressure > 180 mmHg or DBP > 120 mmHg), or recent (< 1 year) osteoporotic fracture ethically requiring additional medical intervention.
• Use of drugs likely to interfere with study assessments:
• These include chronic systemic corticosteroids, thiazolidinediones, 5-alpha-reductase inhibitors, certain drugs that affect cognitive testing (e.g., oxybutynin or opioids) within 12 weeks prior to the first dose of study drug. See concomitant medications section for recommendations regarding use of certain other allowed medications.
• Uncontrolled hypothyroidism or hyperthyroidism: Free thyroxine should be in normal range and stable, whether endogenous or on levothyroxine replacement [> 8 weeks] and without elevated thyroid-stimulating hormone.
• Moderate or severe renal impairment: Defined by an estimated glomerular filtration rate (GFR) repeatedly < 60 mL/min or confirmed by measured GFR < 60 mL/min.
• Medically significant liver disease.
• Including cirrhosis, chronic active hepatitis, chronic persistent hepatitis, or subjects with serum total bilirubin > 1.5 × ULN (unless previously diagnosed with benign Gilbert’s disease) or serum ALT or AST >3 × ULN.
• Medically significant cardiovascular or ECG abnormalities:
• This includes patients with recent (< 1 year) myocardial infarction or stroke, orthostatic or vasovagal syncope, QT interval corrected (QTc) intervals > 500 ms, or evidence of significant, life-threatening arrhythmia or bradycardia (HR < 45 bpm).
• History of idiopathic thrombocytopenic purpura.
• History of adrenal carcinoma.
• Recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: Positive test for infection within the past 4 weeks or hospitalization for coronavirus disease 2019 (COVID-19) within the past 6 months.
• History of cancer within 3 years other than ectopic ACTH from an unidentified source, non-melanoma skin cancer, thyroid cancer, or early-stage prostate cancer.
• If stable and requiring hormone-suppressive therapy, patients with prostate cancer may be included at Medical Monitor discretion, however their data may be excluded in assessment of SPI-62 effects on HPA and HPG axes).
• Any major surgery, or significant post-operative sequelae, within 1 month prior to informed consent or planned during the trial.
• Pregnant, lactating, or planning fertility in the next 6 months and unwilling to adhere to approved contraceptive use or abstinence.
• Participation in any clinical trial within 1 month prior to informed consent (or longer for biologic and long-lasting experimental therapies).
• Receipt of blood products within 2 months prior to Screening.
• Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening. Subjects are not to donate blood, plasma, or platelets during the study.
• Poor peripheral venous access.
• Any other current or prior medical condition expected to interfere with the conduct of the study or the evaluation of its results.

Eligibility last updated 2/23/22. Questions regarding updates should be directed to the study team contact.