Endocrine Abstracts

Introduction: Phase II (LINC2, NCT01331239) and Phase III (LINC3, NCT02180217; LINC4, NCT02697734) studies showed that osilodrostat, a potent oral 11β-hydroxylase inhibitor, was an effective long-term treatment for Cushing’s disease patients. In this LINC programme pooled analysis, we examined how dose uptitration and adjustments during long-term maintenance can provide rapid, sustained mean urinary free cortisol (mUFC) control, and minimise AEs.

Methods: Data from 229 patients enrolled in LINC2, LINC3 (both mUFC>1.5x the upper limit of normal [ULN]) and LINC4 (mUFC>1.3xULN) were pooled and analysed. Placebo treatment periods were excluded. In LINC2, patients started open-label osilodrostat 2 mg twice daily (bid), with dose increases every 2 weeks (W) if mUFC>ULN. In LINC3, patients started open-label osilodrostat 2 mg bid, with dose increases every 2W until W12 if mUFC>ULN, then every 4W thereafter. In LINC4, patients were randomised to osilodrostat 2 mg bid or placebo (W1–W12), then increased every 3W until W12 if mUFC>ULN and every 3W thereafter. Maximum dose was 30 mg bid in all studies (reduced from 50 mg bid in LINC2 core phase). Dose adjustments were permitted during the extensions based on efficacy/tolerability.

Results: Median (min–max) osilodrostat exposure was 100W (1–351). Median (min–max) dose was 6.8 mg/day (1–47); dose needed to achieve mUFC control varied widely. Median time to first mUFC control: all patients, 35 days (D; 95% confidence interval [CI]:34–41); by baseline mUFC severity: <2xULN, 28D (95% CI:17–34); 2–5xULN, 40D (95% CI:34–42); >5xULN, 52D (95% CI:41–56). Median time to first AE of special interest (AESI) was 12W (95% CI:10–15); AESIs occurred at different osilodrostat doses. Fewer hypocortisolism-related (baseline to W12, 23%; W12–48, 24%; W48–72, 8%; W72–≤ W351, 20%) and adrenal hormone precursor accumulation-related AEs (baseline to W12, 36%; W12–48, 37%; W48–72, 14%; W72–≤ W351, 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]; adrenal hormone precursor accumulation-related [n=3]).

Conclusions: Osilodrostat provided sustained mUFC control in all 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, but AESIs were less frequent during long-term treatment than dose uptitration and were mostly manageable without stopping treatment. Personalised therapy during dose titration and lifelong monitoring are needed to optimise clinical outcomes.