Levoketoconazole Effectively Treats Endogenous Cushing Syndrome in Phase 3 Trial

According to results of the phase 3 SONICS trial, levoketoconazole is a safe and effective treatment option for patients with Cushing syndrome.

Levoketoconazole, the 2S,4R enantiomer of ketoconazole, is a safe and effective treatment option for patients with Cushing syndrome, according to results of the phase 3 SONICS trial (ClinicalTrials.gov Identifier: NCT01838551), published in The Lancet Diabetes & Endocrinology.

Although ketoconazole is approved for treatment of endogenous Cushing syndrome by the European Medicines Agency and is used off label for this indication in the United States, the efficacy of the medication has never been investigated in a clinical trial. Levoketoconazole is an investigational drug in development for treatment of Cushing syndrome and, compared with ketoconazole, is a more potent inhibitor of the enzymes essential for cortisol production.

SONICS is a phase 3 single-group nonrandomized open-label international study with 3 phases: dose titration (2-21 weeks to achieve an effective and tolerable therapeutic dose, starting at 150 mg twice daily and increasing until mean 24-hour urinary free cortisol [UFC] normalization or maximal dose of 600 mg, twice daily), maintenance phase (6 months of treatment at the therapeutic dose), and extended evaluation (6 months of continued treatment; data not reported at this point).

The study cohort included adult patients (aged ≥18 years) with confirmed Cushing syndrome and a mean 24-hour UFC of ≥1.5 times the upper limit of the normal range.

The primary outcome was complete response rate, defined as the proportion of patients with mean UFC at or below the upper limit of normal at the completion of the 6-month maintenance phase, without an increase in dose at any time during maintenance therapy.

Of 94 patients who received at least 1 dose of the study medication, 80 patients had pituitary Cushing syndrome. Baseline mean UFC was 4.9 times the upper limit of the normal (243.3 µg/24 h). Mean UFC concentrations were reduced during the dose-titration phase, and 62 (81%) of 77 patients who entered the maintenance phase had a complete response.

At the end of the maintenance phase, 29 (31%) of 94 patients were classified as responders; the least-squares mean estimate of the proportion of responders was 0.30 (95% CI, 0.21-0.40 [P =.015]; vs null hypothesis of ≤0.20).

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Levoketoconazole was associated with improvements in biomarkers of cardiovascular risk (such as fasting blood glucose concentration, glycated hemoglobin, low-density lipoprotein cholesterol concentration, and body weight), as well as clinical signs of Cushing syndrome.

The most common adverse events included nausea (32%), headache (28%), peripheral edema (19%), hypertension (17%), fatigue (16%), and diarrhea (15%). There were 12 patients (13%) who discontinued levoketoconazole because of an adverse event, 9 (10%) who had 1 or more Fridericia-corrected QT value representing an increase of more than 60 ms from baseline, and 2 patients (2%) had 1 or more confirmed QT interval of more than 500 ms. The incidence of adrenal insufficiency was low (3%), possibly because the investigators were instructed to adjust the doses slowly.

The most common severe events (grade 3) were hypertension and increased alanine aminotransferase (ALT; 3 patients each). The researchers reported 1 life-threatening grade 4 event (depression).

ALT increases above the upper limit of the normal were documented in 39 (41%) of 94 patients, including 7 patients with a concentration between >3 and 5 times the upper limit of the normal and 3 patients with ALT >5 times the upper limit of normal. For the 10 patients (11%) with an ALT value >3 times the upper limit of normal, the highest ALT increases occurred by the visit in month 2 of the maintenance phase and were fully reversible; 8 of these patients discontinued from the study and 2 completed the maintenance phase, with no clinical sequelae noted for any patient.

The study had several limitations, including the open-label design, absence of a control group, and lack of direct efficacy comparison between ketoconazole and levoketoconazole.

“Twice-daily oral levoketoconazole 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,” concluded the researchers.

Disclosure: This clinical trial was supported by Strongbridge Biopharma. Please see the original reference for a full list of authors’ disclosures.

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Fleseriu M, Pivonello R, Elenkova A, et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing’s syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial [published online September 18, 2019]. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(19)30313-4