Cushing syndrome

Phase 3 trial confirms the effectiveness of osilodrostat in Cushing disease

This is the first phase 3 study of any medical therapy (osilodrostat) to include a placebo-controlled period in patients with Cushing disease.

Osilodrostat is a potent novel steroidogenesis inhibitor that inhibits 11-beta-hydroxylase, the enzyme that catalyses the final step of cortisol synthesis in the adrenal cortex.

It is approved worldwide for the treatment of patients with Cushing disease who are candidates for medical therapy.

LINC-3 is a prospective, multicenter phase 3 study with a double-blind, randomized withdrawal phase.

The study had an open-label, single-arm stage for 24 weeks to titrate and determine the therapeutic dose of osilodrostat. Patients who met criteria were then randomly assigned, in a double-blind manner, to continue osilodrostat at the same therapeutic dose or to receive a matching placebo for 8 weeks (withdrawal phase; weeks 26 to 34). In the final stage (weeks 35 to 48), all participants were given open-label osilodrostat.

The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (i.e., mean 24-hour urinary free cortisol concentration at or below the upper limit of normal) at the end of the randomized stage (week 34).

• 137 patients were enrolled to receive open-label osilodrostat.

• 71 (52%) patients were eligible for the randomized stage at week 26

  • osilodrostat (n=36)

  • placebo (n=35); 1 patient in this group discontinued due to an adverse event.

• At week 34, significantly more patients who continued osilodrostat treatment maintained a complete response, without a dose increase above the level at week 26, versus those who were on placebo

  • 31 (86%) of 36 vs. 10 (29%) of 34 (odds ratio [OR] 13.7, 95% CI 3.7 to 53.4; P <0.0001).

Secondary endpoints included the proportion of participants who had a complete response at the end of week 24 and week 48, cardiovascular-related parameters, and patient-reported outcomes. At the end of week 48, 91 (66%) enrolled patients had a complete response. Most patients (82%) completed the 48-week study, and the rate of discontinuations due to adverse events was low (13%).

Hypocortisolism-related adverse events were reported in 70 (51%) of patients during the study (mostly occurring and resolved during the dose-titration period). Other commonly reported adverse events were nausea (57 [42%]), headache (46 [34%]), and fatigue (39 [28%]).

The study concluded that osilodrostat rapidly reduces mean UFC concentrations and cortisol production and sustains this reduction alongside improvements in clinical signs of hypercortisolism without unexpected side-effects.

Osilodrostat is the only steroidogenesis inhibitor approved in both Europe and the US for use in patients with Cushing disease. This paper confirmed its efficacy as first-line medical therapy after surgery in most patients with this disease.

See Management: approach

See Management: treatment algorithm

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