Endocrine Abstracts

Introduction: In two Phase III studies (LINC3, NCT02180217; LINC4, NCT02697734), osilodrostat, (potent oral 11β-hydroxylase inhibitor), provided rapid, sustained reductions in mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC), alongside improvements in clinical signs of hypercortisolism and health-related quality of life (HRQoL), in Cushing’s disease (CD) patients. 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, compared to control of mUFC alone.

Methods: LINC3 comprised a 48-week (W) core phase, including an 8W randomised-withdrawal period. LINC4 included a 12W, double-blind, placebo-controlled period followed by 36W of open-label osilodrostat. Both studies had an optional extension. mUFC (mean of 2–3 samples; normal range [NR] 11–138 nmol/24h) and LNSC (one sample; NR ≤ 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≤ upper limit of normal [ULN]+LNSC≤ ULN), controlled mUFC (mUFC≤ ULN+LNSC>ULN) and both uncontrolled mUFC+LNSC (mUFC>ULN+LNSC>ULN). Patients with controlled LNSC (mUFC>ULN+LNSC≤ ULN) were not analysed as few patients had LNSC control without UFC control. Patients in core and extension phases with both mUFC and LNSC assessments were included. Placebo treatment periods were excluded.

Results: 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, 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 or both uncontrolled mUFC+LNSC, respectively: fasting plasma glucose, –5.0%, –4.8%, 1.9%; glycated haemoglobin, –5.1%, –4.8%, –1.3%; weight, –6.5%, –6.5%, –4.5%; waist circumference, –7.2%, –6.3%, –4.9%. Physical manifestations of hypercortisolism generally improved from baseline to W72 irrespective of mUFC/lNSC control. Patients with both controlled mUFC+LNSC or controlled mUFC had the greatest improvement from baseline to W72 in HRQoL.

Conclusions: Patients with both controlled mUFC+LNSC or controlled mUFC 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 normalisation can improve long-term treatment outcomes in CD patients.