Randomized Trial of Osilodrostat for the Treatment of Cushing Disease

Abstract

Context: Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal.

Objective: We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease.

Methods: LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks' open-label osilodrostat).

Results: Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC ≤ ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P < 0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC ≤ ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%).

Conclusion: Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.

Keywords: 11β-hydroxylase; Cushing disease; hypercortisolism; osilodrostat.

Figure 1.

(A) Study design and dosing schedule and (B) timing of study visits, 24-hour UFC collection, and dose adjustments during the LINC 4 study. Three urine samples drawn at 24-hour intervals were collected by patients at screening, within 7 days prior to day 1, and immediately prior to the week 12 visit (primary endpoint). Two 24-hour urine samples were collected immediately prior to each of the other visits (ie, at weeks 2, 5, and 8). Dose matching and adjustments were managed by independent endocrinologists. *Dose adjustments to normalize mUFC or to address safety concerns were permitted. Dose-titration sequence: 2 mg twice daily →5 mg twice daily →10 mg twice daily →20 mg twice daily (maximum dose in double-blind period) →30 mg twice daily (maximum dose in open-label period). Doses of < 2 mg twice daily (1 mg twice daily, 1 mg every day, 1 mg every other day) were allowed if necessary; ^†All patients on doses of ≥ 2 mg twice daily started open-label osilodrostat 2 mg twice daily at week 12, while patients on < 2 mg twice daily continued with their most recent dose. Abbreviations: bid, twice daily; IE, independent endocrinologist; mUFC, mean urinary free cortisol; qd, every day; qod, every other day.

Figure 2.

Patient disposition flow chart. *Patient was randomly allocated to osilodrostat but did not receive any study treatment because of a serious AE (grade 4 pituitary apoplexy that required hospitalization prior to receiving any study drug) that was not considered related to treatment. Abbreviation: AE, adverse event.

Figure 3.

(A) Intrapatient changes in mUFC from baseline to week 12 and (B) proportion of randomized patients with mUFC ≤ ULN up to week 12. ULN for mUFC is 138 nmol/24 hours (50 μg/24 hours). For panel A, each vertical set of data points represents 1 patient and is shown in order of decreasing baseline mUFC. Six patients randomized to osilodrostat and 4 patients randomized to placebo had mUFC ≤ 1.3 × ULN at baseline; however, mUFC was > 1.3 × ULN at screening (ie, patients met the eligibility criterion). Abbreviations: mUFC, mean urinary free cortisol; ULN, upper limit of normal.

Figure 4.

Mean mUFC at time points up to weeks 12 and 48 by randomized treatment group. Dashed horizontal line indicates ULN for mUFC: 138 nmol/24 hours (50 μg/24 hours). Abbreviations: mUFC, mean urinary free cortisol; ULN, upper limit of normal.