Levoketoconazole therapy for Cushing's syndrome

Cushing's syndrome is defined by a persistent or cyclical increase in blood cortisol concentrations. The professional diagnosis is based on two or more positive tests: low dose dexamethasone suppression, late-night salivary cortisol, or 24-hour urinary free cortisol.

Surgery is the treatment of choice, which often leads to a permanent cure. However, not infrequently, the source of hypercortisolism cannot be identified, or surgical intervention is not sufficient. In such circumstances, medical therapy is preferred over watchful waiting.

SONICS was a phase 3, open-label, non-randomized clinical trial. Its investigators tested the utility of levoketoconazole in normalizing urinary cortisol levels in 94 adults with uncontrolled Cushing's syndrome.

After full dose titration and 6-month maintenance therapy, about 30% of patients achieved the desired outcome, as defined by normalized urinary cortisol concentrations. The rate of adverse events was not insignificant: nausea 32%, headaches 28%, study discontinuation 13%, and increased liver enzyme in 11% of participants.

Although the study results are not stupendous, they are meaningful and provide additional options for patients with refractory or uncontrolled Cushing's syndrome.


Also see:

Cushing’s Syndrome







Levo-ketoconazole is a ketoconazole stereoisomer in development for treatment of Cushing's syndrome and has not been assessed previously in a clinical trial in patients with Cushing's syndrome. We aimed to investigate the efficacy and safety of levoketoconazole in patients with endogenous Cushing's syndrome.


SONICS is a phase 3, multicentre, open-label, non-randomised, single-arm study in which we recruited adults (≥18 years) with confirmed Cushing's syndrome and a mean 24-h urinary free cortisol (mUFC) of at least 1.5 times the upper limit of normal from 60 hospital and community sites in 19 countries (15 countries in Europe, and Canada, Israel, Turkey, and the USA).

Patients were treated with oral levoketoconazole in a 2–21 week incremental dose-titration phase starting at 150 mg twice daily (150 mg increments until mUFC normalisation, maximum 600 mg twice daily) and a 6-month maintenance phase.

  • Primary outcome was the proportion of patients with mUFC normalisation at end of maintenance, without dose increase during the maintenance phase (in the intention-to-treat population).

Prespecified adverse events of special interest were potential liver toxicity, corrected QT prolongation, and adrenal insufficiency.


Between July 30, 2014, and June 30, 2017, 201 individuals were screened and 94 patients were enrolled and received at least one dose of study medication. Of the 94 patients, 80 (85%) had pituitary Cushing's syndrome.

Mean mUFC at baseline was 243.3 μg/24 h) which is 4.9 times the upper limit of normal. Of the 77 patients who advanced to the maintenance phase, 62 (81%) had mUFC normalisation by end-of-dose titration.

  • At the end of the 6-month maintenance phase, 29 (31%) of 94 patients were responders; the least-squares mean estimate of the proportion of responders was 0.30 (P ≤0.20).

The most common adverse events in the 94 patients were nausea (32%) and headache (28%). Adverse events led to study discontinuation in 13% of 94 patients. Two patients had a QT interval (Fridericia corrected) of more than 500 ms, and three patients had suspected adrenal insufficiency.

Alanine aminotransferase reversibly increased to more than three times the upper limit of normal in ten (11%) patients. Four patients had serious adverse events that were considered probably or definitely related to the study drug: abnormal liver function test results (n=1), prolonged QT interval (n=2), and adrenal insufficiency (n=1). One person died from colon carcinoma unrelated to study medication.


Twice-daily oral LEVO-ketoconazole treatment led to sustained improvements in urinary free cortisol, with an acceptable safety and tolerability profile.

Levoketoconazole might represent a useful therapeutic option for the medical treatment of Cushing's syndrome.