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• W4387337581 abstract "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 individuals 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). The LINC program enrolled individuals 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 participant data were pooled and analyzed. Data from individuals receiving placebo during placebo-controlled periods were excluded. The osilodrostat dose schedule is summarized in Table 1. Dose adjustments were permitted during the extension periods based on efficacy/tolerability. In total, 229 individuals 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 participants. Individuals with lower baseline mUFC values achieved control of mUFC faster than individuals 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 individuals discontinuing treatment (hypocortisolism related, n=8; related to accumulation of adrenal hormone precursors, n=3). Osilodrostat provided sustained mUFC control in all 3 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 individuals with Cushing’s disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT)" @default.
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• W4387337581 date "2023-10-01" @default.
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• W4387337581 title "OSILODROSTAT DOSING CONSIDERATIONS IN CUSHING'S DISEASE: A POOLED ANALYSIS OF 229 INDIVIDUALS ACROSS LINC 2, LINC 3, AND LINC 4" @default.
• W4387337581 doi "https://doi.org/10.1016/j.cjca.2023.06.398" @default.
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