ORF35-03 - Osilodrostat Improves Health-Related Quality of Life in Cushing's Disease: Analysis of Patient-Reported Outcomes from the Phase III LINC 3 and LINC 4 Studies

Introduction: Cushing’s disease (CD) is a rare disorder of cortisol excess. LINC 3 (NCT02180217) and LINC 4 (NCT02697734) assessed the impact of osilodrostat, an 11β-hydroxylase inhibitor, on health-related quality of life (HRQoL) in patients with CD.

Methods: LINC 3: 26-week (W) open-label osilodrostat, 8W randomised withdrawal phase, 14W open-label osilodrostat; LINC 4: 12W double-blind, placebo-controlled period, 36W open-label osilodrostat. Mixed-effect models and paired t-tests evaluated changes from baseline in Cushing’s Quality of Life (CSQoL), Beck Depression Inventory II (BDI-II) and EuroQol Five Dimensions Five Levels (EQ-5D-5L) total and domain/item scores. Class t-tests were used for correlation analysis. Decreases in BDI-II score and EQ-5D-5L domain score indicate improvement. Minimal clinically important differences (MCIDs) were defined as changes of: CSQoL, 10.1 points; BDI-II, 17.5%; EQ-5D-5L, 0.037–0.069. Patient data from baseline to W72 were pooled; LINC 4 placebo-arm data were excluded. Data are reported as mean change from baseline unless otherwise stated.

Results: 185 patients were included (mean baseline total scores: CSQoL, 44.0; BDI-II, 15.6; EQ-5D-5L, 0.7). CSQoL total score significantly increased over time by: W12: 7.72, n=154; W26: 11.45, n=160; W48: 13.36, n=152; W72: 15.32, n=128 (all P≤0.001), reaching the MCID at W26. All CSQoL item scores significantly improved from baseline to W72 (P <0.05), with the largest changes in bruising, sleep and body image (W72: 0.93, 0.81 and 0.74, respectively; all P<0.001); future worry, bruising and body image were most impaired at baseline. BDI-II total score significantly improved from baseline by: W12: −19.0%, n=154; W26: −34.2%, n=160; W48: −36.0%, n=153; W72: −41.2%, n=128 (all P<0.001), reaching the MCID at W12. All BDI-II item scores but one improved over time, with the largest absolute changes at W72 in items with the greatest burden at baseline (loss of energy, −0.46; sleep changes, −0.59; fatigue, −0.49; all P<0.001). EQ-5D-5L utility score significantly improved from baseline after W26 by: W12: 0.02, n=154; W26: 0.04, n=160; W48: 0.06, n=153; W72: 0.08, n=128 (P <0.01 for W26–72), reaching the MCID range at W26. The most improved EQ-5D-5L domains at W72 were pain/discomfort (−0.42), anxiety/depression (−0.35) and mobility (−0.35; all P<0.001), with pain/discomfort and anxiety/depression most impaired at baseline. HRQoL total scores were strongly intercorrelated: CSQoL–BDI‑II, r=–0.74; CSQoL–EQ‑5D-5L, r=0.67; BDI‑II–EQ‑5D-5L, r=–0.68; P< 0.001.

Conclusions: Osilodrostat significantly improved HRQoL with clinically meaningful, long-term improvements observed across all reported HRQoL instruments. Including the LINC 3 placebo data may underestimate the treatment effect. The data reinforce evidence of osilodrostat’s early and sustained impact on HRQoL in patients with CD.