Endocrine Abstracts

The mechanisms regulating aldosterone secretion in primary aldosteronism (PA) independently from the renin-angiotensin axis include diverse genetic and molecular mechanisms. One mechanism results from the activation of aberrantly expressed GPCR which are diverse and highly prevalent in adrenal tissues of patients with PA, either from aldosteronoma or bilateral adrenal hyperplasia. The levels of expression of GPCR vary greatly between different PA tissues particularly for ACTH ...

The mechanisms regulating cortisol production when ACTH of pituitary origin is suppressed in primary adrenal causes of Cushing’s syndrome (CS) include diverse genetic and molecular mechanisms. These can lead either to constitutive activation of the cAMP system and steroidogenesis or to its regulation exerted by the aberrant adrenal expression of several hormone receptors, particularly G-protein coupled hormone receptors (GPCR) and their ligands. Screening for aberrant exp...

Background: Twice-daily formulation of pasireotide, a pituitary-directed therapy, is approved for treatment of Cushing’s disease. Here we present data from a phase III study designed to evaluate the more convenient once-monthly long-acting release (LAR) formulation of pasireotide (approved for acromegaly) in patients with Cushing’s disease.Methods: Patients with persistent, recurrent, or de novo Cushing’s disease (not candidates for surger...

Background: 24-h mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC) levels are complementary parameters recommended for screening and monitoring treatment response in patients with Cushing’s disease (CD). In the published core period of the Phase III LINC 3 study (NCT02180217), therapy with osilodrostat (potent oral 11β-hydroxylase inhibitor) produced rapid, sustained reductions in mUFC and LNSC alongside improvements in clinical signs of hyper...

ARMC5 mutations are associated with PBMAH risks, but the ARMC5 action mechanism remains unknown. We discovered that ARMC5 was part of a novel ubiquitin ligase (E3) specific for RPB1, the largest Pol II subunit. ARMC5 deletion significantly reduced RPB1 ubiquitination and increased RPB1 accumulation. Surprisingly, the degradation of not only RPB1 but all the 12 subunits of Pol II was compromised in the absence of ARMC5, suggesting that this E3 acts on RPB1 and molecules in its ...

Introduction: A monthly, long-acting formulation of pasireotide normalized or reduced mean urinary free cortisol (mUFC) in most patients with Cushing’s disease (CD) in a multicentre, double-blind, Phase III study. The effects of long-acting pasireotide on signs and symptoms of CD are reported here.Methods: Patients with persistent/recurrent (n=123) or de novo (non-surgical candidates; n=27) CD and mUFC≥1.5–5xULN...

Introduction: In two Phase III studies (LINC3, NCT02180217; LINC4, NCT02697734), osilodrostat, (potent oral 11β-hydroxylase inhibitor), provided rapid, sustained reductions in mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC), alongside improvements in clinical signs of hypercortisolism and health-related quality of life (HRQoL), in Cushing’s disease (CD) patients. mUFC and LNSC are recommended for monitoring treatment response. We assessed wh...

Introduction: Phase II (LINC2, NCT01331239) and Phase III (LINC3, NCT02180217; LINC4, NCT02697734) studies showed that osilodrostat, a potent oral 11β-hydroxylase inhibitor, was an effective long-term treatment for Cushing’s disease patients. In this LINC programme pooled analysis, we examined how dose uptitration and adjustments during long-term maintenance can provide rapid, sustained mean urinary free cortisol (mUFC) control, and minimise AEs.<p class="abstext...

Background: In a large 12-month Phase III study, pasireotide led to rapid and sustained decreases in UFC and provided clinical benefit in patients with Cushing’s disease. Here, we report data following an open-label, open-ended extension.Methods: 162 patients with persistent/recurrent or de novo Cushing’s disease were randomized in the core study. 58 patients with mean UFC≤ULN or clinical benefit at month 12 entered the extension...

Introduction: Pasireotide normalized or reduced UFC in patients with Cushing’s disease in a large, 12-month study. This analysis evaluates the effects of pasireotide on the signs/symptoms of Cushing’s disease according to the degree of UFC control.Methods: Adult patients (n=162) with persistent/recurrent or de novo Cushing’s disease were randomized to pasireotide 600/900 μg s.c. bid. Dose titration (max: 1200 μg...