OR27-3 Long-Term Results from the Phase III LINC 4 Study: Osilodrostat Maintained Normal Mean Urinary Free Cortisol in Patients with Cushing's Disease, with a Favorable Safety Profile
Authors: Auchus Richard J , Belaya Zhanna , Bex Marie , Feelders Richard A , Heaney Anthony P , Paul Michaela , Pedroncelli Alberto M , Snyder Peter J , Turcu Adina F , Witek Przemysław , Gadelha Mônica 
Published: November 2022

Abstract

Background
Osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid and sustained normalization of mean urinary free cortisol (mUFC) in patients with Cushing's disease (CD) 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 combined.

Methods
73 adults with CD and mUFC &gt;1.3× the upper limit of normal (ULN) were enrolled. LINC 4 comprised a 12W, randomized, double-blind, placebo-controlled period followed by 36W of open-label osilodrostat. At W48, patients could enter an optional extension. Dose adjustments were permitted based on efficacy/tolerability (range during open-label treatment 1–30 mg bid). LINC 4 ended when all patients transitioned to a separate long-term safety study (not reported) or discontinued treatment. Efficacy/safety are reported for all patients unless otherwise stated, and excludes data collected during W1–12 for placebo recipients.

Results
Of the 65 patients who 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 average (IQR) 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/24h [50 µg/24h]) was 68.5% (n=50/73) at W48, 61.5% (n=40/65) at W72 and 72.4% (n=42/58) at the end-of-treatment extension (EOT) visit. Median mUFC decreased from 2.5×ULN (core baseline) to 0.5×ULN (W48 and W72), to 0.4×ULN (EOT). Median late-night salivary cortisol decreased from 2.8×ULN (core baseline) to 1.2×ULN (W48 and W72), to 1.1×ULN (EOT).The most common AEs during the entire study were decreased appetite (46.6%), arthralgia (45.2%), fatigue (39.7%), nausea (37.0%), headache (34.2%) and dizziness (30.1%). Hypocortisolism- and adrenal-hormone-precursor-accumulation-related AEs occurred in 28.8% (21/73) and 61.6% (45/73) of patients during the entire study, less frequently in the extension than the core. Most were grade 1/2 and resolved with dose reduction/interruption and/or concomitant medication. During the extension, hirsutism and acne were reported as AEs by 1 and 0 patients, respectively.Median ACTH increased from 1.1×ULN (core baseline) to 3.0×ULN (W48), to 3.6×ULN (W72), to 3.5×ULN (EOT). Median change (95% CI) in pituitary tumor volume (assessed by MRI) from core baseline to last available assessment was 4.0 mm3 (−24.1–169.8); pituitary-tumor-enlargement-related AEs led to drug discontinuation in 2 and 0 patients during the core and extension, respectively. No trend was observed between tumor 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 during the core. Osilodrostat is an effective and well-tolerated long-term treatment option for CD patients.
Presentation: Tuesday, June 14, 2022 10:15 a.m. - 10:30 a.m.