Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

Abstract

Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study

“…Medical therapies, including pituitary-targeting agents, steroid synthesis inhibitors, and glucocorticoid receptor [GR] antagonists, are a treatment option for patients who are not candidates for surgery, and for patients with persistent or recurrent hypercortisolism after surgery who are unsuitable for, or unwilling to undergo, additional surgical procedures (12)(13)(14)(15).…”

Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach

“…Metyrapone inhibits 11β-hydroxylase and converting from 11-deoxycortisol to cortisol, results in reducing cortisol level. Metyrapone showed a revised estimated average remission rate of 75.9% ( 105 ) The frequently reported adverse events were hirsutism in women, dizziness, arthralgias, gastrointestinal disturbances, adrenal insufficiency, hypokalemia and peripheral edema ( 156 ).…”

Cushing’s Syndrome Effects on the Thyroid

“…Pasireotide (SOM 230) is a "second generation" SSTR ligand (SRL) with relevant affinity for SSTR1, SSTR2, SSTR3, and particularly for SSTR5 [58] that is able to induce a significant decrease in ACTH secretion through the activation of SSTR2 and SSTR5, expressed on the pituitary corticotroph cells [59]. Pasireotide is currently the only pituitarydirected drug with an official license by the European Medical Agency (EMA) and the American Food and Drug Administration (FDA) for the treatment of CD in patients for whom surgery is not an option or in case of persistent disease after surgery [60]. It is tempting to speculate that due to its effect on SSTR2 and SSTR5 on pituitary thyrotropes, pasireotide would inhibit TSH secretion and result in central hypothyroidism.…”

“…The steroidogenesis inhibitors are adrenal-directed drugs that induce a decrease in cortisol secretion through the inhibition of specific enzyme pathways [60]. The drugs available to date include metyrapone, ketoconazole, and mitotane.…”

“…The anti-steroidogenic activity of ketoconazole, which has been worldwide used as an off-label treatment in the management of CS during the last 30 years [60], is based on the inhibition of several steroidogenesis enzymes (cholesterol side-chain cleavage complex, 17,20-lyase, 11β-hydroxylase, 17β-hydroxylase), inducing a reduction in glucocorticoid, mineralocorticoid, and adrenal androgens synthesis [63]. Furthermore, this drug also acts on ACTH secretion, suggesting a possible double effect in the treatment of CD patients [60]. Ketoconazole may exert anti-thyroid activity, which has been demonstrated by in vitro and in vivo.…”