Mario Maldonado, MD, Global Head of Clinical Development for Endocrinology at Recordati Rare Diseases, discusses Recordati’s presentations at ENDO 2025.
LINC6 Clinical Trial
LINC 6 is an ongoing, prospective observational study evaluating the long-term safety and efficacy of osilodrostat over 3 years in 205 adult patients with Cushing’s disease (CD) and non-pituitary Cushing’s syndrome (non-PCS). Osilodrostat is a potent 11β-hydroxylase inhibitor. Results were presented from a 2 year interim analysis.
Treatment-related adverse events were reported 91 times in 34 patients with CD and 14 times in 9 patients with non-PCS, most being mild to moderate. The most common treatment-related adverse events in patients with CD were adrenal insufficiency, diarrhea, dizziness, fatigue, and nausea. In patients with non-PCS the most common adverse events were adrenal insufficiency, hypokalemia, abnormal hormone cortisol level, dizziness, hirsutism, joint stiffness, musculoskeletal stiffness, and nervous system disorder.
A total of 17 patients with CD reported 29 serious adverse events, while 10 patients with non-PCS reported 16 serious adverse events. Patients with CD and non-PCS reported 21 and 9 hypocortisolism-related adverse events, 16 and 6 adrenal hormone precursor accumulation-related adverse events, and 3 and 0 arrhythmogenic potential/QT interval prolongation-related adverse events, respectively. Patients with CD had 3 pituitary tumor enlargement-related adverse events. At month 3, mUFC and LNSC were normal in 73.9% and 56.3% of pts. By month 6, mUFC and LNSC were normal in 63.0% and 30.4% of pts.
Osilodrostat Rollover Study
The LINC rollover study was an open-label, multicenter trial evaluating long-term safety and efficacy of osilodrostat in patients with CD. A total of 127 participants were included after completing either the LINC 2, LINC 3, or LINC 4 clinical trial extension phase.
All patients experienced at least one adverse event, with 86.6% considered treatment related. The most common adverse events were nausea, adrenal insufficiency, and fatigue. Serious adverse events were reported in 44.9% of participants, with 8.7% considered treatment related. The most common serious adverse event was adrenal insufficiency. Additionally, adverse events related to accumulation of adrenal hormone precursors were reported in 65.4%, hypocortisolism in 55.9%, pituitary tumor enlargement in 8.7%, and arrhythmogenic potential and QT prolongation in 5.5%.
At the end of treatment, 78% continued to receive clinical benefit. From baseline to week 12 of the parent studies, mean urinary free cortisol levels decreased from 561.5 nmol/24 h to 85.0 nmol/24 h, mean glycated hemoglobin levels decreased from 5.8% to 5.6%, mean systolic blood pressure decreased from 130.7 mmHg to 123.2 mmHg, body weight generally decreased over time, and potassium and sodium levels remained stable and normal.
Pasireotide Rollover Study
This open-label, multicenter, phase 4 rollover study evaluated the long-term safety of pasireotide in patients with CD, acromegaly, and other rare endocrine disorders. Pasireotide is a second-generation, multireceptor-targeted somatostatin receptor ligand. Final data was presented on 62 patients with CD who received pasireotide for up to 10 years during the rollover.
Adverse events were reported in 77.4% of patients with the most common events being nasopharyngitis, pharyngitis, diarrhea, hypoglycemia, urinary tract infection, and back pain. Hyperglycemia and diabetes mellitus were reported in 6 patients total. 62.9% of patients required additional therapy to manage adverse events, most commonly for nasopharyngitis. 9.7% of patients required dose interruption/adjustment to manage adverse events, most commonly for endocrine disorders. A total of 4 patients discontinued treatment due to adverse events.
Serious adverse events were reported in 33.9% of patients with the most common being cholelithiasis. A total of 4 patients died during the rollover study from colon cancer, COVID-19, pneumonia, and septic shock. No new safety signals were identified.
Pasireotide for Post-Bariatric Hypoglycemia
Post-bariatric hypoglycemia (PBH) is caused by rapid gastric emptying and excessive glucagon-like peptide 1 (GLP-1) and insulin secretion. It is characterized by frequent postprandial hyperinsulinemic hypoglycemic episodes and neuroglycopenic symptoms. The condition complicates up to 38% of gastric bypass surgeries and up to 12% of vertical sleeve gastrectomy surgeries.
The phase 2, dose-fiding PASIPHY study plans to evaluate the safety and efficacy of pasireotide in about 72 patients with PBH. Pasireotide has the ability to bind with high affinity to four of the five human somatostatin receptor subtypes, resulting in the inhibition of GLP-1 and insulin secretion, thereby slowing gastric emptying. The study will comprise of a 3 week screening, 4 week run-in, and 12 week randomized, double-blind, placebo-controlled treatment period. Those who complete the 12 week core phase will be eligible for a 36 week open-label extension.
The primary endpoint of the study is change in blood glucose levels from baseline to week 12 of treatment. Key secondary endpoints will include change from baseline in rate of level 2 hypoglycemic events; proportion of patients with no level 2 hypoglycemic events during a 3-hour MMTT at week 12; change from baseline in rate of level 3 hypoglycemic events; change from baseline in frequency of rescue therapy use for level ⅔ hypoglycemic events; change from baseline to week 12 in insulin, glucagon, and GLP-1 secretion during MMTT; change from baseline to week 12 in health-related quality of life; and incidence of adverse events throughout the study.
For more information on rare endocrine disorders, visit https://checkrare.com/diseases/endocrine-disorders/
