MON-015 - Phase IV Study to Assess the Efficacy and Safety of Osilodrostat in Patients with Hypertension Caused by Cushing'S Syndrome with Mean Urinary Free Cortisol ≤2X the Upper Limit of Normal: LINC CARE Study Design

Introduction: Cushing’s syndrome (CS) is characterized by cortisol excess and is associated with a high burden of comorbidities, such as hypertension (HTN) and diabetes mellitus (DM), across various CS etiologies and severities. Results from a pooled analysis of two Phase III studies (LINC 3 and LINC 4) indicate that 66.7% and 47.4% of patients (pts) with Cushing’s disease and mean urinary free cortisol (mUFC) ≤2x the upper limit of normal (ULN) had HTN and dysglycemia at baseline (BL), respectively. However, research often overlooks mild CS cases, despite the notable cardiometabolic risk. As shown in analyses of LINC 3 and LINC 4, osilodrostat, a potent 11β-hydroxylase and aldosterone synthase inhibitor, can decrease blood pressure (BP) and glycemic parameters in pts with CS and comorbid HTN and/or DM. LINC CARE (NCT07247162) will assess the efficacy and safety of osilodrostat in pts with HTN caused by CS.

Methods: This double-blind, randomized, placebo-controlled study will enroll ~63 CS pts (aged ≥18 years) with uncontrolled HTN despite medication (systolic blood pressure [SBP] ≥135 mmHg or diastolic blood pressure [DBP] ≥85 mmHg) and with mUFC >1–≤2x ULN across ~75 sites (USA, Canada, Latin America, Europe). After a ≤3-week (W) screening period, the 30W study will comprise an 18W dose-titration and a 12W dose-maintenance phase. Pts will be randomized (2:1 ratio) to receive osilodrostat 1 mg once daily (evening) or matching placebo. In the dose-titration phase, treatment will be titrated every 3W based on serum cortisol levels and clinical treatment response. Pts will then enter a dose-maintenance phase and continue on the same dose received at the end of dose titration. Primary endpoint: proportion of pts with mUFC ≤ULN at W30. Key secondary endpoint: proportion of BP responders (≥5 mmHg reduction in mean SBP and/or DBP assessed by ambulatory blood pressure monitoring) at W30. Other secondary endpoints (assessed at W21 and W30 unless otherwise specified): proportion of responders in glycemia (≥25% reduction in glucose from BL during oral glucose tolerance test in pts with BL glycated hemoglobin ≥6%) and body weight (≥5% decrease from BL); change from BL in SBP, glycemic parameters, and antihypertensive and antidiabetic medication; change in body weight and proportion of pts with mUFC ≤ULN over time; and occurrence of adverse events, including hypocortisolism. Exploratory endpoints at W21/W30: proportion of composite cardiometabolic responders (in ≥1 of BP, glycemia, or weight); proportion of pts with morning serum cortisol ≤50 nmol/L (≤1.8 µg/dL) after low-dose dexamethasone suppression test; and change from BL in diurnal/nocturnal BP pattern, DBP, 24-hour urinary adrenal steroid metabolome, salivary cortisol, and cortisone pattern, and quality of life.

Conclusion: LINC CARE will provide evidence on osilodrostat efficacy, safety and dosing in pts with HTN caused by CS and with mUFC ≤2x ULN.

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