Endocrine Abstracts

Background: Cushing’s disease (CD) is associated with hypercortisolism-induced cardiovascular morbidity and mortality and impaired patient quality of life (QoL). We report long-term effects of osilodrostat (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), randomised, double-blind, placebo-controlled period, 36W of open-label osilodrostat, and an optional extension in adults with CD and (mUFC >1.3x upper normal limit). Dose adjustments were permitted based on efficacy/tolerability (open-label range, 1–30 mg bid). Cardiovascular/metabolic-related parameters, physical features of hypercortisolism (rating: 0=absent;1=mild;2=moderate;3=severe), and CushingQoL scores were evaluated at core baseline, every 2, 4, 12 or 24W (depending on study phase/parameter) and at extension end-of-treatment (EOT). Change from baseline is provided for patients with assessments at core baseline, W48 and EOT.

Results: Of 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] and −12.4 [−17.4,−7.4] mmHg; baseline: 131.5 mmHg) and diastolic (−4.2 [−7.3,−1.2] and −5.6 [−8.9,−2.4] mmHg; baseline 87.5 mmHg) blood pressure, fasting plasma glucose (−3.1 [−6.8,0.6] and −3.5 [−8.5,1.4] mg/dl; baseline: 95.3 mg/dl) and cholesterol (−0.5 [−0.8,−0.2] and −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 occurred for weight (||4.3 [||5.9,||2.6] and ||6.8 [||8.8,||4.8] kg; baseline: 78.3 kg) and waist circumference (||4.5 [||6.0,||3.1] and ||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 (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]); 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] and 17.1 [12.5.21.7]; baseline: 51.8).

Conclusion: Alongside cortisol control, most cardiovascular/metabolic-related parameters continued to improve during long-term osilodrostat treatment. Additionally, most physical features of hypercortisolism, including hirsutism, improved or remained stable, and CushingQoL score improved. Osilodrostat is an effective treatment that may alleviate disease burden for many CD patients.