(CSEMP005) CLINICAL IMPROVEMENTS IN PATIENTS WITH CUSHING'S DISEASE RECEIVING OSILODROSTAT ACCORDING TO CONTROL OF URINARY AND LATE-NIGHT SALIVARY CORTISOL LEVELS: A POOLED ANALYSIS FROM LINC 3 AND LINC 4

Background: In two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734) of osilodrostat (a potent oral 11β-hydroxylase inhibitor) in patients with Cushing’s disease, rapid, sustained reductions in mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC) were observed, alongside improvements in clinical signs of hypercortisolism and indicators of health-related quality of life (HRQoL). mUFC and LNSC are recommended for monitoring treatment response. We assessed whether patients with both controlled mUFC+LNSC experienced greater improvements in clinical signs of hypercortisolism and HRQoL than with control of mUFC alone.

METHODS AND RESULTS: LINC 3 comprised a 48-week (W) core phase, including an 8W randomized-withdrawal period. LINC 4 included a 12W, double-blind, placebo-controlled period followed by 36W of open-label osilodrostat. Both studies had an optional extension period. mUFC (mean of 2–3 samples; normal range 11–138 nmol/24h) and LNSC (one sample; normal range ≤2.5 nmol/L) were measured by liquid chromatography-tandem mass spectrometry. Changes in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism and HRQoL were assessed in the pooled population by mUFC/LNSC control status: both controlled mUFC+LNSC (mUFC≤ULN [upper limit of normal]+LNSC≤ULN), controlled mUFC only (mUFC≤ULN+LNSC>ULN), and both uncontrolled mUFC+LNSC (mUFC>ULN+LNSC>ULN). Patients with controlled LNSC only (mUFC>ULN+LNSC≤ULN) were not analyzed as few patients had LNSC control without mUFC control. Patients in the core and extension phases of both studies with both mUFC and LNSC assessments were included. Data from patients receiving placebo during placebo-controlled periods were excluded. Of evaluable patients at baseline (n=160), 136 (85.0%) had both uncontrolled mUFC+LNSC. At W48 (n=133) and W72 (n=111), respectively, 59 (44.4%) and 54 (48.6%) patients had both controlled mUFC+LNSC, 49 (36.8%) and 44 (39.6%) had controlled mUFC only, and 19 (14.3%) and 11 (9.9%) had both uncontrolled mUFC+LNSC. Patients with both controlled mUFC+LNSC had greater percentage improvements from baseline to W72 in cardiovascular/metabolic-related parameters than patients with controlled mUFC only or both uncontrolled mUFC+LNSC (Table 1). Physical manifestations of hypercortisolism generally improved from baseline to W72 irrespective of mUFC/LNSC control. Patients with both controlled mUFC+LNSC or controlled mUFC only had the greatest improvement from baseline to W72 in HRQoL.

Conclusion: Patients with both controlled mUFC+LNSC or controlled mUFC only had the greatest improvements in cardiovascular/metabolic-related parameters and HRQoL. Improvements in most physical manifestations of hypercortisolism were observed irrespective of mUFC/LNSC control. Data are limited by small patient numbers in some groups. Both mUFC and LNSC normalization can improve long-term treatment outcomes in patients with Cushing’s disease.