Therapeutic efficacy and safety of newly approved FDA drug levoketoconazole in cushing syndrome: a systematic review.

BACKGROUND

Cushing syndrome is a severe endocrinopathy due to chronic hypercortisolism with etiology that includes the administration of exogenous glucocorticoids, pituitary adenomas, ectopic ACTH-producing tumors, and adrenal tumors. Expressed as central obesity, hypertension, glucose intolerance, and psychiatric symptoms, it greatly affects the QoL and has a high association with morbidity and mortality.

AIM: This systematic review summarizes data from clinical trials to compare the effectiveness and safety of a newly approved drug, levoketoconazole, for the treatment of Cushing syndrome.

METHODOLOGY: An extensive search was conducted in PubMed, Google Scholar, and the Cochrane Library for terms related to the effectiveness and safety of levoketoconazole in Cushing syndrome. Selected studies included phase 2 and phase 3 interventional trials enrolling adult patients (≥18 years) with confirmed endogenous Cushing syndrome (ECS). Outcomes of interest included mean urinary free cortisol (mUFC), clinical signs and symptoms, quality of life measures, and adverse events. Risk of bias was assessed using the Cochrane Collaboration Risk of Bias Tool.

RESULTS

Six interventional studies were included. In the SONICS phase 3 trial, 62% of patients achieved normalization of mUFC at the end of the 6-month maintenance phase, with sustained biochemical and clinical benefits during extended evaluation. During the randomized withdrawal phase of the LOGICS trial, loss of mUFC response occurred in 95.5% of patients switched to placebo compared with 40.5% of patients who continued levoketoconazole treatment (P = 0.0002), demonstrating maintenance of biochemical control with active therapy. Common adverse events included nausea, headache, hypokalemia, and fatigue. Serious drug-related adverse events were uncommon but clinically relevant, including hepatotoxicity, QT prolongation, and adrenal insufficiency.

CONCLUSION

Levoketoconazole significantly lowers cortisol levels and alleviates clinical manifestations in patients with Cushing syndrome with reasonable safety. There is a need to perform a periodic checkup of the liver function and adrenal insufficiency. Additional long-term research is needed to strengthen its place in treatment plans.