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

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 >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 mm(3) (−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.