Endocrine Abstracts

Background: Osilodrostat (potent oral 11β-hydroxylase inhibitor) provided rapid normalisation of mean urinary free cortisol (mUFC) in Cushing’s disease (CD) patients during the 48-week (W) core period of LINC 4 (NCT02697734) and was well tolerated. We report long-term efficacy and safety results from the LINC 4 core and extension phases.

Methods: 73 adults with CD and mUFC >1.3 upper limit of normal (ULN) were enrolled. LINC 4 comprised a 12W, randomised, double-blind, placebo-controlled period followed by 36W of open-label osilodrostat. At W48, patients could continue receiving open-label osilodrostat during an optional extension. Dose adjustments were permitted based on efficacy/tolerability (open-label range, 1–30 mg bid). Efficacy/safety are reported for all patients unless otherwise stated (excludes W1–12 data for placebo recipients).

Results: 65/73 patients completed the core phase; 60 entered the extension. Median (range) osilodrostat exposure from core baseline to study end was 87.1 (2–127) W; median (IQR) average dose was 4.6 (3.7–9.2) mg/day. 15 patients discontinued osilodrostat, 7 after W48 (6 because of adverse events [AEs]). The proportion of patients with normal mUFC (≤138 nmol/24 h) was 68.5% (n=50/73) at W48, 61.5% (n=40/65) at W72 and 72.4% (n=42/58) at extension end-of-treatment (EOT). Median mUFC decreased from 2.5ULN (core baseline) to 0.5ULN (W48 and W72) and 0.4ULN (EOT). Median late-night salivary cortisol decreased from 2.8ULN (core baseline) to 1.2ULN (W48 and W72) and 1.1ULN (EOT). Most common AEs overall were decreased appetite (46.6%), arthralgia (45.2%), fatigue (39.7%), nausea (37.0%), headache (34.2%) and dizziness (30.1%). AEs related to hypocortisolism and accumulation of adrenal hormone precursor occurred in 28.8% (21/73) and 61.6% (45/73) of patients overall, less frequently in the extension than the core. Most were grade 1/2 and resolved with dose reduction/interruption and/or concomitant medication. After W48, one patient experienced an AE of hirsutism. Median adrenocorticotropic hormone increased from 1.1ULN (core baseline) to 3.0ULN (W48), 3.6ULN (W72) and 3.5ULN (EOT). Median change (95%CI) in pituitary tumour volume (by MRI) from core baseline to last assessment was 4.0 (−24.1, 169.8) mm³; AEs related to pituitary tumour enlargement led to discontinuation in 2 and 0 patients during the core and extension. No trend was observed between tumour volume change and osilodrostat dose.

Conclusion: Osilodrostat provided long-term control of cortisol production during LINC 4. Fewer AEs related to hypocortisolism and accumulation of adrenal hormone precursors occurred during the extension than the core. Osilodrostat is an effective and well-tolerated long-term treatment option for CD patients.