(CSEMP013) OSILODROSTAT DOSING CONSIDERATIONS IN CUSHING'S DISEASE: A POOLED ANALYSIS OF 229 PATIENTS ACROSS LINC 2, LINC 3 AND LINC 4

Background: The LINC program (Phase II, LINC 2 [NCT01331239]; Phase III, LINC 3 [NCT02180217] and LINC 4 [NCT02697734]) showed that osilodrostat, a potent oral 11β-hydroxylase inhibitor, was an effective long-term treatment for patients with Cushing’s disease. This pooled analysis of the LINC program examined how optimal outcomes could be achieved with dose uptitration and adjustments during long-term maintenance therapy to provide rapid, sustained mean urinary free cortisol (mUFC) control and minimize adverse events (AEs).

METHODS AND RESULTS: The LINC program enrolled patients with Cushing’s disease (LINC 2 and LINC 3: mUFC >1.5 x upper limit of normal [ULN]; LINC 4: mUFC >1.3 x ULN). Individual patient data were pooled and analyzed. Data from patients receiving placebo during placebo-controlled periods were excluded. Osilodrostat dose schedule is summarized in Table 1. Dose adjustments were permitted during the extension periods based on efficacy/tolerability. In total, 229 patients were included in the analyses. Median (min–max) osilodrostat exposure was 100 weeks (1–351). Median (min–max) dose was 6.8 mg/day (1–47); dose needed to achieve mUFC control varied widely between patients. Patients with lower baseline mUFC values achieved control of mUFC faster than patients with higher baseline mUFC values and required a lower median average osilodrostat dose overall (Table 2). Median time to first AE of special interest (AESI) was 12 weeks (95% CI: 10–15); AESIs occurred at different osilodrostat doses. Fewer AEs related to hypocortisolism (baseline to week 12, 23%; weeks 12–48, 24%; weeks 48–72, 8%; weeks 72–351, 20%) and adrenal hormone precursors (baseline to week 12, 36%; weeks 12–48, 37%; weeks 48–72, 14%; weeks 72–351, 18%) occurred during long-term maintenance than dose titration. AESIs were mostly manageable with dose interruption and/or additional therapy, with few patients discontinuing treatment (hypocortisolism related, n=8; related to accumulation of adrenal hormone precursors, n=3).

Conclusion: Osilodrostat provided sustained mUFC control in all three studies; time to control was shorter with lower baseline mUFC values. Median daily osilodrostat dose was low but varied widely. Dose titration differed between studies; however, AESIs were less frequent during long-term treatment than during the dose-uptitration phases and were mostly manageable without stopping treatment. Personalized therapy during dose titration and lifelong monitoring are needed to optimize clinical outcomes in patients with Cushing’s disease.