Long-term post-trial extension of osilodrostat therapy in selected Canadian patients with Cushing disease from the LINC 3 and LINC 4 programs

Background Long-term outcomes of selected patients who continue osilodrostat for Cushing disease after clinical-trial participation remain incompletely described. Methods We retrospectively analyzed a selected multicenter post-trial cohort of Canadian patients with Cushing disease previously enrolled in LINC 3 (NCT02180217) or LINC 4 (NCT02697734) who continued osilodrostat in the global roll-over study and, when applicable, in a Canadian investigator-initiated extension phase (ISS-CA-2023; NCT06131580). The dataset included 11 Canadian osilodrostat-exposed LINC participants who entered post-trial roll-over follow-up; 7 subsequently entered the Canadian investigator-initiated extension, whereas 4 discontinued during earlier follow-up for defined reasons. For longitudinal efficacy analyses, baseline and time zero were defined as first osilodrostat exposure in the parent LINC study; week 14 refers to week 14 after osilodrostat initiation. The main outcomes were time to first mean urinary free cortisol (mUFC) control, durability of control, long-term dose evolution, pituitary tumor surveillance, and safety. Results Eleven selected Canadian patients received continued osilodrostat, and all achieved first biochemical control after a median of 5 weeks (range: 2–12). Median mUFC decreased from 2.65 × ULN at parent-study baseline to 0.56 × ULN at week 14; these descriptive values were not used for inferential testing. Seven patients remained on therapy long term; at the last follow-up, six of seven had controlled mUFC after a median exposure of 98 months (range: 83 to 121). Maintenance doses varied widely, with a median last-visit dose of 6 mg/day (range: 0.125 to 40), and several patients required progressive down-titration over time. Hypocortisolism/adrenal-insufficiency events were common and generally managed with dose interruption or reduction and temporary glucocorticoid replacement. Clinically significant pituitary tumor enlargement leading to discontinuation and surgery occurred in two patients. Conclusion In this selected Canadian post-trial continuation cohort, osilodrostat was associated with rapid initial biochemical control and durable long-term control in many patients for up to 10 years. The findings support the feasibility of long-term individualized osilodrostat management in selected patients continuing therapy after LINC 3/LINC 4 participation, with ongoing need for dose adaptation and surveillance for adrenal insufficiency and pituitary tumor behavior.