Osilodrostat dose impact on efficacy/safety in Cushing's disease: Large, pooled analysis of LINC 2, 3 and 4.

Objectives: Evaluate how osilodrostat dose and baseline mean urinary free cortisol (mUFC) affect treatment outcomes and provide evidence-based guidance on personalized medical treatment for patients with Cushing's disease.

Methods/design: Individual-patient data from the Phase II LINC 2 and Phase III LINC 3 and LINC 4 core and extension periods were pooled, excluding periods when patients received placebo (LINC 3 and LINC 4). Outcomes were evaluated in patients with available data across common time points.

Results: 229 patients were treated: starting osilodrostat dose 2mg twice daily, median average dose per patient 6.8mg/day for mean 113.7 weeks (standard deviation 73.1). mUFC control (not exceeding upper limit of normal) was achieved within 4-12 weeks in most patients and sustained throughout. Median time to first mUFC control was 35 days, longer with increasing baseline mUFC. Most common dose for first mUFC control was 4mg/day (33.2% of patients; median dose 10mg/day [range 2-60]). Adverse events (AEs) generally occurred more often during dose titration (baseline-week 12) than long-term treatment (week >12) but could occur at any time. AEs were manageable in most patients; n=37 (16.2%) discontinued because of AEs.

Conclusions: In this analysis of the largest and longest prospective interventional studies of an adrenal steroidogenesis inhibitor to date, osilodrostat provided rapid and sustained mUFC control, with dose decreases possible over the long term. AE frequency generally decreased over time, with no relationship with osilodrostat dose. Personalized adjustment of osilodrostat dose is important to optimize outcomes for patients with Cushing's disease.