Randomized Trial of Osilodrostat for the Treatment of Cushing Disease

Context: Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. Objective: We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11 beta hydroxylase inhibitor, compared with placebo in patients with Cushing disease. Methods: LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:11 period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion >= 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC <= ULN at week 12. The key secondary endpoint was the proportion achieving mUFC <= ULN at week 36 (after 24 weeks' open-label osilodrostat). Results: Seventy-three patients (median age, 39 years (range, 19-671; mean/median mUFC, 3.1 x ULN/2.5 x ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC <= ULN (odds ratio 43.4; 95% CI 71, 343.2; P < 0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC <= ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (375% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). Conclusion: Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.