Osilodrostat Is an Effective and Well-Tolerated Treatment for Cushing’s Disease (CD): Results From a Phase III Study With an Upfront, Randomized, Double-Blind, Placebo-Controlled Phase (LINC 4)

Background: In a prior Phase III, randomized-withdrawal study, osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid and sustained normalization of mean urinary free cortisol (mUFC) in most patients (pts) with CD. Now, we report efficacy and safety results from another Phase III study of osilodrostat in pts with CD that included an upfront, double-blind, randomized, placebo-controlled phase (LINC 4: NCT02697734). Methods: Adults with CD with mUFC >1.3 x ULN were randomized 2:1 to osilodrostat 2 mg bid or matching placebo for a 12-week (W) double-blind period, with dose adjustments at W2, 5 and 8 (range 1-20 mg bid) based on efficacy and tolerability; dose matching and adjustments were managed by independent endocrinologists. From W12 to W48, all pts received open-label osilodrostat, with dose adjustments permitted (range 1-30 mg bid). At W48, pts could enter an optional extension. Primary endpoint: proportion of randomized pts in each arm who received ≥1 treatment dose with mUFC ≤ULN at W12. Results: 73 pts were randomized and received osilodrostat (n=48) or matching placebo (n=25; baseline median [range] mUFC 2.5 x ULN [0.7-12.5] vs 2.2 x ULN [0.2-18.9]). 77% of osilodrostat recipients achieved mUFC ≤ULN at W12 vs 8% of placebo recipients (OR 43.4; 95% CI 7.1-343.2; P<0.0001). At W36, 81% (95% CI 69.9-89.1) of osilodrostat recipients had mUFC ≤ULN (key secondary endpoint). Median time to first controlled mUFC response was 35 days (95% CI 34‒52) for pts randomized to osilodrostat. Median duration of osilodrostat exposure at data cut-off (Feb 25, 2020) was 71.7 vs 62.3 weeks for pts randomized to osilodrostat and placebo (median [IQR] dose 4.7 [3.8-9.0] vs 6.0 mg/day [3.7-9.7]). Up to W12, 3 osilodrostat pts discontinued, 1 because of an AE (arthralgia), vs 0 with placebo. The most common (≥30%) AEs occurring by W12 were decreased appetite (38% osilodrostat vs 16% placebo), arthralgia (35% vs 8%) and nausea (31% vs 12%). AEs related to hypocortisolism and adrenal-hormone-precursor accumulation occurred in 15% vs 0% and 44% vs 36% of osilodrostat and placebo pts; most were grade 1/2 and resolved with dose reduction/interruption and/or concomitant medication. During the overall study period, the most common (≥30%) AEs occurring on osilodrostat treatment were arthralgia (45%), decreased appetite (45%), fatigue (38%), nausea (37%) and headache (33%). Improvements in cardiovascular- and metabolic-related parameters, including systolic and diastolic blood pressure and HbA(1c), were observed with osilodrostat treatment at W12 and W48. Conclusion: Osilodrostat was superior to placebo at normalizing mUFC levels at W12 (77% vs 8%). Improvements in mUFC levels were sustained at W36. Few pts discontinued because of AEs; hypocortisolism-related AEs were infrequent and manageable. We conclude that osilodrostat is a highly effective and well-tolerated treatment for pts with CD.