Levoketoconazole Shows Promise for Endogenous Cushing's Syndrome

By Reuters Staff

September 30, 2019

NEW YORK (Reuters Health) - In patients with endogenous Cushing's syndrome, treatment with levoketoconazole led to sustained improvements in urinary free cortisol, "with an acceptable safety and tolerability profile," in the phase 3 SONICS study.

"The medical needs in Cushing's syndrome are very high despite the availability of approved treatments. Levoketoconazole might represent a useful therapeutic option for the medical treatment of Cushing's syndrome," Dr. Maria Fleseriu from Oregon Health and Science University in Portland and colleagues write in The Lancet Diabetes and Endocrinology, online September 18.

Endogenous Cushing's syndrome is a rare but serious endocrine disorder characterized by chronic overproduction of cortisol. Ketoconazole, which is often used to treat the disorder, is a racemic mix of two enantiomers (an L-form and a D-form), with essentially all of the cortisol-inhibiting action coming from the L-form. Levoketoconozole, a pure L-form of ketoconazole, is being developed by Strongbridge Biopharma, which funded the SONICS trial.

The non-randomized, open-label study enrolled 94 adults with confirmed Cushing's syndrome and a mean 24-hour urinary free cortisol (mUFC) of at least 1.5 times the upper limit of normal (ULN). The average mUFC at baseline was 671.4 nmol/24 h, which is 4.9 times the ULN.

Oral levoketoconazole was initiated at a dose of 150 mg twice daily and titrated upwards to a maximum of 600 mg twice daily to either normalize UFC or produce a therapeutic response, and then this dose was maintained for six months.

Of the 77 patients who advanced to the maintenance phase, 62 (81%) had mUFC normalize by the end of dose-titration phase.

At the end of the six-month maintenance phase, 29 (31%) of 94 patients had normalized UFC. The response rate was 49% in the 39 patients whose initial UFC was between two and less than five times the ULN.

"Additionally, levoketoconazole was associated with improvements in biomarkers of cardiovascular risk (such as fasting blood glucose concentration, HbA1c, LDL cholesterol concentration, and bodyweight), as well as clinical signs of Cushing's syndrome," the investigators report.

There were no unexpected safety signals. Nausea (32%) and headache (28%) were the most common adverse events.

Two patients had a QT interval (Fridericia corrected) of more than 500 ms, and three had suspected adrenal insufficiency. Thirty-nine (41%) of 94 patients had increases in the liver enzyme alanine aminotransferase (ALT) and in 10 (11%) patients ALT increased to three-times the ULN, but these effects were reversible when treated was stopped.

Four patients developed serious adverse events that were probably or definitely related to levoketoconazole; one had abnormal liver function test results, two had prolonged QT interval and one had adrenal insufficiency.

"An important limitation of our study is that we did not do a direct efficacy comparison between levoketoconazole and ketoconazole, and indirect comparison is problematic because of the absence of prospective studies assessing the efficacy of ketoconazole in Cushing's syndrome," the investigators note in their paper. The open-label design and absence of a control group are also limitations.

Commenting on the study in a linked editorial, Dr. Ashley Grossman of the University of Oxford, in the U.K., says "in the absence of a head-to-head trial, which is unlikely to be done, it is difficult to know whether levoketoconazole is indeed a real advance over racemic ketoconazole. Nevertheless, one would hope that more data will appear over time comparing the merits of the two formulations, and in any case such competition should be reflected in price competitiveness, to the benefit of health systems."

The study was funded by Strongbridge Biopharma. Several authors have financial relationships with the company.

SOURCE: http://bit.ly/2lbLBFJ

Lancet Diabetes Endocrinol 2019.