ESPEYB17 8. Adrenals Clinical Trials - New Treatments (1 abstracts)
To read the full abstract: Lancet Diabetes Endocrinol. 2019; 7(11): 855-865. PMID: 31542384A.
Endogenous Cushings syndrome is a rare, serious endocrine condition characterized by chronic overproduction of cortisol (1). It is most often caused by a pituitary adenoma (i.e. Cushings disease), while other causes include ectopic ACTH secretion or primary adrenal neoplasia (2). Patients with Cushings syndrome have increased mortality, mainly as a result of cardiovascular complications. Surgical removal of the underlying lesion is first-line therapy, sometimes preceded by preoperative medical treatment (13). Medical treatments aim to suppress the excessive ACTH or cortisol production or to decrease cortisol activity (1). Few medications have been evaluated in well-designed prospective studies. Ketoconazole, an azole antifungal drug that inhibits steroidogenesis, is approved for the treatment of endogenous Cushings syndrome in Europe and is used off-label in the USA. However, although ketoconazole can reduce urinary free cortisol concentrations in patients with endogenous Cushings syndrome, its use is often limited by side-effects, such as hepatotoxicity and QT interval prolongation, as well as the potential for drug interactions. Levoketoconazole, the 2S,4R enantiomer of ketoconazole, decreases cortisol synthesis via potent inhibition of several enzymes in the steroidogenic pathway and might have lower risk of hepatotoxicity and an improved side-effect profile relative to ketoconazole (4).
This phase 3 multicentre, single-arm, non-randomised, open-label study (SONICS, Registration no: NCT01838551) investigated the efficacy, safety and tolerability of twice-daily oral levoketoconazole in patients with endogenous Cushings syndrome. Ninety four patients with Cushings syndrome [80 (85%) with pituitary Cushings disease] were studied prospectively and received at least one dose of levoketoconazole. Patients were treated with oral levoketoconazole in a 221 week incremental dose-titration phase starting at 150 mg twice daily (150 mg increments until mean 24-hour UFC normalization to a maximum of 600 mg twice daily) and a 6-month maintenance phase. Levoketoconazole normalized 24-h UFC concentrations after 6 months of maintenance therapy (without a dose increase after establishing a therapeutic dose) in 31% of patients. In addition, it was associated with improvements in cardiovascular disease risk factors, as well as normalization of cortisol concentrations in some patients. Levoketoconazole was generally well tolerated, with no unexpected safety signals identified.
Therefore, levoketoconazole might represent a useful therapeutic option for the medical treatment of Cushings syndrome. Although Cushings syndrome is rare in children and adolescents, levoketoconazole might represent a useful therapeutic option when surgery is delayed, contraindicated or unsuccessful, given the reported acceptable safety and tolerability profile.
References:
1. Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushings syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 280731.
2. Creemers SG, Ho and LJ, Lamberts SW, Feelders RA. Cushings syndrome: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother 2015; 16: 182944.
3. Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A. Advances in the medical treatment of Cushings syndrome. Lancet Diabetes Endocrinol 2019; 7: 30012.
4. Auchus RJ, Wu Y, Liu J. 2S,4R-ketoconazole is the relevant enantiomer of ketoconazole for cortisol synthesis inhibition: steroidogenic P450s inhibition involves multiple mechanisms. Endocr Rev 2018; 39 (2 suppl): SUN-410 (abstr).