PMON160 Improvements in Clinical Signs of Hypercortisolism and Quality of Life According to Urinary and Late-Night Salivary Cortisol Levels in Patients with Cushing's Disease Treated with Osilodrostat
Authors: Biller Beverly M K , Fleseriu Maria , Pivonello Rosario , Feelders Richard A , Lacroix Andre , Auchus Richard J , Piacentini Andrea , Pedroncelli Alberto M , Newell-Price John 
Published: November 2022

Abstract

Objective
Cushing's disease (CD) is a debilitating disorder of chronic hypercortisolism. Assessment of 24h mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC) is recommended for screening and monitoring treatment response. In the published core period of the Phase III, LINC 3 study (NCT02180217), osilodrostat therapy (a potent oral 11β-hydroxylase inhibitor) produced rapid, sustained reductions in both mUFC and LNSC alongside improvements in clinical signs of hypercortisolism and health-related quality of life (HRQoL) in patients with CD. Here we explored cardiovascular/metabolic-related parameters, physical features and HRQoL according to mUFC and/or LNSC control.

Methods
LINC 3 (core period) enrolled 137 adults with CD and mUFC &gt;1.5x upper limit of normal (ULN), who received open-label osilodrostat up to 48-week (W) (starting dose: 2 mg twice daily [bid]; maximum: 30 mg bid); eligible patients were randomized in an 8W placebo-controlled, withdrawal period (W26–34). mUFC (three sample average; normal 11–138 nmol/24h [4–‍50 µg/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), CushingQoL and Beck Depression Inventory-II (BDI-II) scores were also evaluated. Data were recorded at baseline, regularly throughout, and at W48. Analyses are presented for patients with both mUFC and LNSC assessments, defined as: both mUFC+LNSC controlled (mUFC≤ULN+LNSC≤ULN), only mUFC controlled (mUFC≤ULN+LNSC&gt;ULN), only LNSC controlled (mUFC&gt;ULN+LNSC≤ULN) and both mUFC+LNSC uncontrolled (mUFC&gt;ULN+LNSC&gt;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. Patients with both mUFC+LNSC controlled had generally greater mean improvements from baseline to W48 in cardiovascular/metabolic-related parameters than those with only mUFC or LNSC controlled or both mUFC+LNSC uncontrolled, respectively: weight, –5.9, –3.3, –2.2 and –‍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, –16.9, –4.8, –15.0, –11.0 mg/dL; and HbA1c, –0.4, –0.3, –0.9, –0.0%. CushingQoL/BDI-II scores improved from baseline to W48 irrespective of mUFC and/or LNSC control. The proportion of patients with improved physical manifestations of hypercortisolism (facial rubor, striae, fat pads, bruising, hirsutism [females], muscle atrophy) was greatest in patients with both mUFC+LNSC controlled or only mUFC controlled.

Discussion
At W48, over half the evaluable patients had both mUFC+LNSC controlled following osilodrostat treatment. Improvements in clinical signs of hypercortisolism and HRQoL occurred irrespective of mUFC and/or LNSC control; however, for some clinical outcomes, improvements were greater in patients with both mUFC+LNSC controlled. Findings are limited by small patient numbers in some groups. mUFC and LNSC are complementary parameters used to assess disease control and patients with both mUFC+LNSC controlled have better outcomes.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.