osilodrostat and Pituitary-Neoplasms

Cushing disease (CD) is a very rare form of hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Clinical manifestations of CD can include central fat accumulation, arterial hypertension, glucose intolerance, skin atrophy with striae, and hypogonadism. Children are frequently diagnosed due to a growth stunt and excessive weight gain while classic cushingoid signs might be initially absent. Other children-specific presentations of CD are early or delayed puberty and hyperandrogenism in girls.. We present the main outcomes of clinical trials of osilodrostat (Isturisa®, Recordati) for CD, and its initial development as an aldosterone synthase inhibitor. Osilodrostat is indicated only when the surgical therapy of the pituitary adenoma is not an option or has not been curative; additionally, other steroidogenesis inhibitors were briefly summarized. Clinical trials of osilodrostat in children are lacking and we describe its potential role in the pediatric population.. Osilodrostat is the first adrenal steroidogenesis inhibitor to be European Medicines Agency- and United States Food and Drug Administration-approved (both in 2020) for the treatment of adults with Cushing syndrome/disease. Phase II and III clinical trials have shown its efficacy in normalizing 24-h urinary-free cortisol and a good safety profile. Osilodrostat's pharmacological properties and safety are currently being evaluated in a small Phase II trial (NCT03708900) - the first trial in the pediatric population (<18 years) with an estimated completion date in the year 2023.

Topics: Adenoma; Adult; Child; Cushing Syndrome; Female; Humans; Hydrocortisone; Imidazoles; Pituitary ACTH Hypersecretion; Pituitary Neoplasms

Cushing's disease (CD) is a rare endocrine disorder characterized by the overproduction of adrenocorticotropic hormone (ACTH) by pituitary adenoma followed by hypercortisolaemia with severe complications. Although transsphenoidal resection of the defined pituitary adenoma has been the treatment of choice for the past decades, it does not always result in long-term remission - 10-30% of cases show ineffective surgical treatment or tumour recurrence even after initial success. Pharmacological therapies for cortisol reduction are often required for those who either cannot undergo pituitary surgery or when the surgery has failed, and patients still present with the persistent disease. Osilodrostat is a potent oral steroidogenesis inhibitor that has lately been shown as an effective adjuvant therapy in the management of patients with CD. In this article, we review the recent reports on the efficacy and safety of osilodrostat in clinical settings.

Topics: Adenoma; Humans; Imidazoles; Neoplasm Recurrence, Local; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Pyridines

Hypercortisolism induced by Cushing disease causes high morbidity and mortality. The treatment of choice is pituitary surgery, but it often fails to achieve cure, and other treatment modalities (radiotherapy, bilateral adrenalectomy) may therefore be required. If these treatments are not effective or while waiting for their results, hypercortisolism should be controlled with drugs. The classical drug treatments are those that act by inhibiting cortisol secretion by the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate). The preliminary results of a new drug (LCI699) which is a potent enzyme inhibitor of cortisol secretion have been reported. A clinical trial of the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, has just been published. The drugs deserving more attention today are those with a direct action on the tumor by inhibiting ACTH secretion: somatostatin analogues (pasireotide), dopamine agonists (cabergoline), PPAR-γ, and retinoic acid. A special review is made of the available clinical trials with pasireotide and cabergoline.

Topics: Adenoma; Adrenocorticotropic Hormone; Animals; Cabergoline; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Ergolines; Etomidate; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Metyrapone; Mice; Mifepristone; Mitotane; Multicenter Studies as Topic; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; PPAR gamma; Pyridines; Rats; Somatostatin; Therapies, Investigational; Tretinoin

Endogenous Cushing's syndrome (CS) is a rare, multi-systemic condition resulting from chronic glucocorticoid excess sustained by a pituitary adenoma (Cushing's disease, CD), an adrenal adenoma or, less frequently, a neuroendocrine tumor. The optimal first-line option is surgery, but when it is contraindicated/refused, or in case of severe, life-threatening disease, medical treatment is a first-line choice. Osilodrostat (LCI699, Isturisa®) is a new, orally active adrenal steroidogenesis inhibitor currently approved by the FDA and EMA for the treatment of endogenous CS.. We illustrate the pharmacologic profile of osilodrostat and summarize the efficacy and safety of osilodrostat from the first phase I studies to the most recent evidence.. Osilodrostat acts as a potent, reversible inhibitor of 11β-hydroxylase (CYP11B1) and 18-hydroxylase (or aldosterone synthase, CYP11B2), counteracting both gluco- and mineralocorticoid production. According to the results of the LINC1, LINC2, and LINC3 studies and the preliminary findings of LINC4, osilodrostat offers an excellent efficacy in controlling hypercortisolism with a good tolerability. The non-negligible risk of adrenal insufficiency/steroid withdrawal symptoms, hypokalemia, and hyperandrogenism disorders, and the possibility, albeit rare, of pituitary tumor enlargement, require further confirmation and careful monitoring.

Topics: Adult; Cushing Syndrome; Humans; Imidazoles; Mixed Function Oxygenases; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Pyridines; Tablets