Endocrine Abstracts

Background: 24-h mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC) levels are complementary parameters recommended for screening and monitoring treatment response in patients with Cushing’s disease (CD). In the published core period of the Phase III LINC 3 study (NCT02180217), therapy with osilodrostat (potent oral 11β-hydroxylase inhibitor) produced rapid, sustained reductions in mUFC and LNSC alongside improvements in clinical signs of hypercortisolism in patients with CD. Here, we explored these improvements by mUFC and/or LNSC control.

Methods: The core LINC 3 study enrolled 137 adults with CD and mUFC >1.5xULN who received open-label osilodrostat over 48 weeks (W; starting dose: 2 mg twice daily; maximum: 30 mg twice daily); eligible patients were randomised in an 8W placebo-controlled, withdrawal period (W26–34). mUFC (three-sample average; normal 11||138 nmol/24h) and LNSC (single sample; normal ≤2.5 nmol/l) were assessed centrally by liquid chromatography-tandem mass spectrometry. Cardiovascular/metabolic-related parameters, physical features (rating: 0=absent; 1=mild; 2=moderate; 3=severe), and CushingQoL and Beck Depression Inventory II (BDI-II) scores were also evaluated. Data were recorded at baseline and regularly until W48. Analyses are presented for patients with both mUFC and LNSC assessments, defined as: both mUFC+LNSC controlled, only mUFC controlled, only LNSC controlled, and both mUFC+LNSC uncontrolled. Control was defined as ≤ULN.

Results: Of evaluable patients at baseline (n=87), 74 (85.1%) had both mUFC+LNSC uncontrolled. At W48, 38 patients (54.3%) had both mUFC+LNSC controlled, 21 (30.0%) had only mUFC controlled, 3 (4.3%) had only LNSC controlled, and 8 (11.4%) had both mUFC+LNSC uncontrolled. Mean improvements from baseline to W48 in cardiovascular/metabolic-related parameters were generally greater in patients with both mUFC+LNSC controlled than patients with only mUFC or LNSC controlled or both mUFC+LNSC uncontrolled, respectively: weight, ||5.9, ||3.3, ||2.2, –3.8 kg; systolic blood pressure, ||14.4, ||8.0, ||7.4, ||3.0 mmHg; diastolic blood pressure, –8.6, ||4.8, ||8.2, ||4.0 mmHg; fasting plasma glucose, ||0.9, ||0.3, ||0.8, ||0.6 mmol/l. CushingQoL/BDI-II scores improved from baseline to W48 irrespective of mUFC and/or LNSC control. Patients with both mUFC+LNSC controlled or only mUFC controlled had the greatest proportion with improved physical manifestations of hypercortisolism (facial rubor, striae, fat pads, bruising, hirsutism [females], muscle atrophy).

Discussion: After 48W of osilodrostat treatment, most evaluable patients had both mUFC+LNSC controlled or only mUFC controlled. Improvements in clinical signs of hypercortisolism and health-related quality of life occurred irrespective of mUFC and/or LNSC control; however, improvements were greater in patients with both mUFC+LNSC controlled for some clinical outcomes.