Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

Abstract

Introduction: Endogenous Cushing's syndrome (CS) is a rare, life-threatening endocrine disorder that is caused by chronic exposure to cortisol overproduction. Levoketoconazole (Recorlev), a 2S, 4R stereoisomer of ketoconazole, is a steroidogenesis inhibitor under investigation for the treatment of CS. Areas covered: This review covers the pharmacology, efficacy, and safety of levoketoconazole for the treatment of patients with endogenous CS. Expert opinion: Based on the preclinical and clinical pharmacology findings, levoketoconazole appears to be the relevant enantiomer of ketoconazole for inhibition of steroidogenesis, with more potent inhibition of both cortisol and androgen synthesis relative to ketoconazole racemate and the 2R, 4S stereoisomer dextroketoconazole. Results from the phase III SONICS study showed that levoketoconazole was effective in normalizing cortisol levels and improving biomarkers of cardiovascular risk in a significant percentage of patients. In addition, treatment with levoketoconazole showed improvements in subjective clinical assessments of clinician-rated CS clinical signs and symptoms, patientreported quality of life, and depression symptom severity. Testosterone levels decreased significantly in women. Levoketoconazole had an acceptable safety profile with no unexpected safety signals. The favorable pharmacology, efficacy, and safety profile of levoketoconazole supports its use as medical therapy for CS, if approved.

Osilodrostat — an emerging drug for the medical management of Cushing’s disease

“…Due to these initial promising results, the FDA recently accepted for review the application for levoketoconazole in the treatment of CD. However, more time is needed to compare its safety profile with ketoconazole [23].…”

Treatment of Cushing’s syndrome with osilodrostat: practical applications of recent studies with case examples

“…The phase 3 SONICS study evaluating efficacy and safety of levoketoconazole reported no study withdrawals due to tumor growth with no change in tumor size in most patients through 12 months on treatment [ 12 , 25 ]. In this study, mean ACTH concentrations in the 80 patients with CD increased during dose titration and remained elevated through the maintenance phase.…”

“…Baseline evaluation needed before medication start This example patient provides a good illustration of the steps to be taken before initiating osilodrostat. Obtaining potassium and magnesium levels and ECG measurements are critical both before initiating treatment, as a baseline, and during treatment with osilodrostat; this is also true with other adrenal steroidogenesis inhibitors, such as metyrapone [10,16] and levoketoconazole [12,17] or with the glucocorticoid receptor blocker mifepristone [11], to monitor for the development of low potassium or prolonged QTc on ECG. For patients starting specifically on osilodrostat, an ECG should be performed at baseline and 1 week after initiating therapy to ensure there is no QTc prolongation (although this is uncommon, as described later), in addition to checking for hypokalemia or hypomagnesemia and, if present, correcting these before beginning treatment.…”

“…As with other helpful reviews that describe practical considerations for use of mifepristone [ 11 ], levoketoconazole [ 12 ], and pasireotide [ 13 , 14 ], the objective of this narrative review is to address clinical considerations and recommendations [ 1 ] when using osilodrostat for patients with CD, ectopic CS, or adrenal CS by providing illustrative example case studies.…”

Cushing’s disease: adrenal steroidogenesis inhibitors

“…Moreover, based on remission rates, osilodrostat appears to have the highest efficacy, followed by metyrapone, ketoconazole and levoketoconazole. A direct comparison between the racemic ketoconazole and the selective levoketoconazole is not available at clinical levels; however, experimental studies seem to suggest that levoketoconazole displays a higher potency in inhibiting adrenal enzymes compared to dextroketoconazole and to racemic ketoconazole, potentially allowing lower doses of levoketoconazole to achieve the same efficacy of ketoconazole [ 28 , 29 ]. Moreover, levoketoconazole showed a lower potency toward liver enzymes inhibition compared to dextroketoconazole, suggesting an improved safety profile of levoketoconazole on liver function [ 28 ].…”