PMON162 Osilodrostat Provides Sustained Clinical Benefits and Improves Health-Related Quality of Life in Patients with Cushing's Disease: Results from the Phase III LINC 4 Study

BACKGROUND: Cushing's disease (CD) is a serious disorder associated with increased cardiovascular morbidity and mortality, and reduced patient quality of life (QoL), because of hypercortisolism. We report long-term effects of osilodrostat, a potent 11β-hydroxylase inhibitor, on cardiovascular/metabolic-related risk factors, physical features of hypercortisolism and QoL in CD patients following the core and extension phases of the LINC 4 study (NCT02697734). METHODS: LINC 4 comprised a 12-week (W), randomized, double-blind, placebo-controlled period, 36W of open-label osilodrostat, and an optional extension phase in adults with CD and mUFC >1.3xULN. 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 or discontinued treatment. Cardiovascular/metabolic-related parameters, physical features of hypercortisolism (rating: 0=absent; 1=mild; 2=moderate; 3=severe), and CushingQoL score were evaluated at core baseline, every 2, 4, 12 or 24W (depending on study phase/parameter) and at the end-of-treatment extension (EOT) visit. Change from baseline is provided for patients with assessments at core baseline, W48 and EOT. RESULTS: Of the 65 patients completing W48, 60 entered the extension. Median (range) osilodrostat exposure from core baseline to study end: 87.1 (2–127) W; median (IQR) average dose: 4.6 (3.7‍–‍9.2) mg/day. Mean changes (95% CI) in cardiovascular/metabolic-related parameters from core baseline to W48 and EOT, respectively, included decreases in systolic (−9.7 [−14.9, −4.6] mmHg; −12.4 [−17.4, −7.4] mmHg; baseline: 131.5 mmHg) and diastolic (−4.2 [−7.3, −1.2] mmHg; −5.6 [−8.9, −2.4] mmHg; baseline 87.5 mmHg) blood pressure, fasting plasma glucose (−3.1 [−6.8, 0.6] mg/dL; −3.5 [−8.5, 1.4] mg/dL; baseline: 95.3 mg/dL) and cholesterol (−0.5 [−0.8, −0.2] mmol/L; −0.6 [−0.9, −0.3] mmol/L; baseline: 5.5 mmol/L). Improvements (mean change [95% CI]) from core baseline to W48 and EOT also occurred for weight (–4.3 [–5.9, –2.6] kg; –6.8 [–8.8, –4.8] kg; baseline: 78.3 kg) and waist circumference (–4.5 [–6.0, –3.1] cm; –7.6 [–9.6, –5.6] cm; baseline: 102.8 cm). Physical features of hypercortisolism improved (severity reduced) or remained stable from core baseline to EOT in most patients (respectively): ecchymosis (21% [n=10/48]; 79% [n=38/48]), striae (26%; n=12/46; 72% [n=33/46]), hirsutism in females (29% [n=11/38]; 61% [n=23/38]), muscle weakness (33% [n=16/49]; 61% [n=30/49]), facial rubor (48% [n=23/48]; 46% [n=22/48]), central obesity (55% [n=27/49]; 37% [n=18/49]), and fat pads (dorsal: 58% [n=28/48]; 31% [n=15/48]; supraclavicular: 65% [n=32/49]; 35% [n=17/49]). CushingQoL score improved from core baseline to W48 and EOT (mean change [95% CI]: 12.0 [8.2, 15.9]; 17.1 [12.5, 21.7]; baseline: 51.8). CONCLUSION: Most cardiovascular/metabolic-related parameters continued to improve during long-term osilodrostat treatment. Additionally, most physical features of hypercortisolism, including hirsutism, either improved or remained stable, and CushingQoL score improved. Osilodrostat is an effective treatment that may alleviate disease burden for many patients with CD. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.