Nowak, Elisabeth

Abstract Context Biochemical test results are central to clinical decision-making for the diagnosis and management of Cushing syndrome (CS). With emerging research and increasing availability of different tests, updated consensus on the utility of these biomarkers is warranted. Objective To establish an updated consensus on the role of biomarkers in the diagnosis and monitoring of adrenocorticotropic hormone-dependent CS, address novel therapeutic approaches, and identify areas for future research. Design A modified 2-round Delphi panel was conducted. Consensus was defined as ≥70% agreement/disagreement for Likert-scale statements or ≥70% selection of the same option for single-choice questions. Setting Participants represented a range of international expertise. Participants Forty-one participants took part in the Delphi panel, with no attrition between rounds (one nonclinician was not required to complete the second round). An 8-member Steering Committee guided statement development. Results Of statements designed to reach consensus, 45% (14/31) and 44% (11/25) statements reached consensus in Rounds 1 and 2, respectively. Notably, most panelists reported the use of late-night salivary cortisol for diagnosis of mild CS and for monitoring following pituitary surgery or medical or radiation therapy. Most panelists responded that block-and-replace therapies can be considered in patients with cyclical or severe CS, and consensus was reached that restoration of circadian rhythm is a treatment goal for patients with CS. Conclusion Areas of alignment among experts on the diagnosis and monitoring of CS are presented. The findings from this study are intended to support clinicians in their clinical decision-making and highlight priority areas for future research.

Abstract Disclosure: I. Bancos: Adrenas, consulting, advisory board, or data safety monitoring board fees (paid to institution outside this work), AstraZeneca, consulting, advisory board, or data safety monitoring board fees (paid to institution outside this work), Corcept Therapeutics, consulting, advisory board, or data safety monitoring board fees (paid to institution outside this work), Diurnal, consulting, advisory board, or data safety monitoring board fees (paid to institution outside this work), HRA Pharma, consulting, advisory board, data safety monitoring board fees (paid to institution outside this work), or funding for investigator-initiated research, Neurocrine, consulting, advisory board, or data safety monitoring board fees (paid to institution outside this work), NovoNordisk, consulting, advisory board, or data safety monitoring board fees (paid to institution outside this work), Recordati Rare Diseases, consulting, advisory board, data safety monitoring board fees (paid to institution outside this work), or funding for investigator-initiated research, Sparrow, consulting, advisory board, or data safety monitoring board fees (paid to institution outside this work), Spruce, consulting, advisory board, or data safety monitoring board fees (paid to institution outside this work), Xeris, consulting, advisory board, or data safety monitoring board fees (paid to institution outside this work). F. Castinetti: HRA Pharma, consultancy for and research grants, Lundbeck, consultancy for and research grants, Recordati Rare Diseases, consultancy for and research grants. E.B. Geer: Corcept Therapeutics, research grants to her hospital, Recordati Rare Diseases, research grants to her hospital and occasional consulting honoraria, Sparrow, research grants to her hospital and occasional consulting honoraria, Xeris Pharmaceuticals (Strongbridge), research grants to her hospital and occasional consulting honoraria, Crinetics Pharmaceuticals, occasional consulting honoraria, HRA Pharma, occasional consulting honoraria, Lundbeck, occasional consulting honoraria, Member of the LINC 6 steering committee. S. Espiard: Recordati Rare Diseases, reports invitations to training courses and medical congresses. C. Mouly: Pfizer, consulting and advisory board fees, Recordati Rare Diseases, consulting and advisory board fees. L. Dichtel: Lumos Pharma, consultant and received research support to her hospital, Novo Nordisk, consultant and received research support to her hospital, Perspectum, received research support to her hospital, Recordati Rare Diseases, research support to her hospital, Flare Therapeutics, consultant, Marea Therapeutics, consultant and has equity in company, Third Rock Ventures, consultant, Merida Biosciences, consultant and has equity in company. E.V. Varlamov: Lumiio, research support to her university, Novo Nordisk, research support to her university, Pfizer, research support to her university, Recordati Rare Diseases, research support to her university. A. Ferriere: Novo Nordisk, Recordati Rare Diseases. E. Nowak: Supported by the Else Kröner-Fresenius–Stiftung and the Eva Luise und Horst Köhler–Stiftung within the Clinician Scientist program RISE (2022_EKFKSE.03). C. Simeoli: Neurocrine UK Ltd, consultancy, Recordati Rare Diseases, consultancy. R.A. Feelders: HRA Pharma, consultancy, Recordati Rare Diseases, consultancy, Corcept Therapeutics, research grant, Member of the LINC 6 steering committee. J. Le Mouhaër: Recordati Rare Diseases, employee. P. Raunioniemi: Recordati Rare Diseases, employee. A. Mueller: Recordati Rare Diseases, employee. N. Scheyer: HRA Pharma, invitations to training courses and medical congresses, Pfizer, invitations to training courses and medical congresses, Recordati Rare Diseases, invitations to training courses and medical congresses. Introduction: LINC 6 (NCT05382156) is an ongoing prospective, observational study evaluating the long-term safety and effectiveness of osilodrostat, a potent 11β-hydroxylase inhibitor, over 3 years in patients (pts) with Cushing’s syndrome (CS). We report results from a prespecified 2-year interim analysis. Methods: Adult pts with endogenous CS were enrolled in 5 countries (USA and Europe) where osilodrostat is approved and available. The primary objective is long-term safety and tolerability, assessed by incidence of osilodrostat-related adverse events (AEs) and serious AEs (SAEs), with a focus on hypocortisolism-, adrenal hormone precursor accumulation-, arrhythmia/QT prolongation-, and pituitary tumor enlargement-related AEs. Secondary effectiveness endpoints include change in mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC). Here, we report AEs in the safety population (≥1 osilodrostat dose; n=206) among pts with Cushing’s disease (CD) and non-pituitary CS (non-PCS, adrenal or ectopic CS; data cutoff July 2024). Results: Data were available for 205 pts: 75.6% were female, mean (standard deviation) age was 53.0 (14.4) years. 161 pts had CD and 44 had non-PCS (adrenal adenoma, n=12; adrenal carcinoma, n=2; bilateral adrenal nodular disease, n=10; ectopic adrenocorticotropic hormone secretion, n=17; other, n=3). Median (min-max) on-study osilodrostat exposure and dose were 8.3 months (0.0-20.8) and 5.0 mg/day (0.5-80.0). 34 (21.1%) CD and 9 (20.5%) non-PCS pts reported 91 and 14 AEs considered treatment related, respectively; most were mild or moderate (95.6% CD and 85.7% non-PCS). Most common (>5% of events) treatment-related AEs: CD, adrenal insufficiency (9.9%, n=9/91 events), diarrhea, dizziness, fatigue (6.6% [n=6/91] each) and nausea (5.5%, n=5/91); non-PCS, adrenal insufficiency (42.9%, n=6/14 events), hypokalemia (14.3%, n=2/14), abnormal hormone (cortisol) level, dizziness, hirsutism, joint stiffness, musculoskeletal stiffness, and nervous system disorder (7.1% [n=1/14] each). 17 (10.6%) CD and 10 (22.7%) non-PCS pts reported 29 and 16 SAEs (7 and 4 were considered treatment related), respectively. 5 (3.1%) CD and 2 (4.5%) non-PCS pts discontinued because of 8 and 3 treatment-related AEs. CD and non-PCS pts reported 21 and 9 hypocortisolism-related AEs, 16 and 6 adrenal hormone precursor accumulation-related AEs, and 3 and 0 arrhythmogenic potential/QT interval prolongation-related AEs, respectively. CD pts had 3 pituitary tumor enlargement-related AEs. At month 3, mUFC and LNSC were normal in 73.9% (n=34/46) and 56.3% (n=18/32) of pts. By month 6, mUFC and LNSC were normal in 63.0% (n=29/46) and 30.4% (n=7/23) of pts. Conclusions: These LINC 6 2-year interim data show that osilodrostat is effective for the management of different etiologies of CS. AEs were mostly mild or moderate, with few leading to treatment discontinuation. Presentation: Sunday, July 13, 2025

Abstract Disclosure: A. Prete: HRA Pharmaceuticals, Lundbeck, Diurnal. L. Adbi: None. J.T. Bain: None. F. Shaheen: None. O. Suntornlohanakul: None. E. Deflorenne: None. A. Blanchard: None. M. Nestola: None. C. Pamporaki: None. I. Tizianel: None. E. Nowak: None. J. Bertherat: None. D.A. Vassiliadi: None. I. Bancos: None. C.M. Dennedy: None. D. Kastelan: None. M. Fassnacht: None. P. Mulatero: None. U. Ambroziak: None. A. Tabarin: None. M. Quinkler: None. S. Puglisi: None. J. Deinum: None. G.Å. Ueland: None. L. Lenzini: None. F. Beuschlein: None. M. Reincke: None. F. Ceccato: None. G. Eisenhofer: None. S.M. Corsello: None. L. Amar: None. M. Zennaro: None. N. Karavitaki: None. A.E. Taylor: None. W. Arlt: None. Introduction: Twenty-four-hour urinary free cortisol is used to diagnose Cushing’s syndrome (CS); amongst its limitations is failure to differentiate ACTH-dependent CS (AD-CS) from ACTH-independent CS (AI-CS). We tested the performance of urine steroid metabolomics (USM), the computational analysis of 24-hour urine steroid metabolome data by machine learning, for the diagnosis and differential diagnosis of CS. Given the physiological diurnal rhythm of cortisol secretion and its loss in CS, we also hypothesised that the difference in glucocorticoid excretion between CS and controls should be higher during nighttime, thereby facilitating more sensitive detection of CS. Methods: 264 subjects completed a 24-hour urine collection (40 AD-CS, 103 AI-CS due to adrenocortical adenoma or hyperplasia, 121 healthy subjects). A subset of 52 individuals (13 CS, 39 healthy) provided a nighttime urine collection and a daytime urine collection. Mass spectrometry-based multi-steroid profiling was used to quantify the urinary excretion of 27 steroid metabolites. Data were analysed by generalised matrix learning vector quantisation (a prototype-based supervised machine learning approach), multiple linear regression adjusted for age, sex, and BMI, and multiple logistic regression adjusted for age, sex, and BMI. Results: Twenty-four-hour USM demonstrated very high accuracy in differentiating CS from healthy individuals (AUC-ROC 0.99, 95%CI 0.99-0.99), reflected by higher urinary excretion of glucocorticoid and glucocorticoid precursor metabolites in CS. USM yielded high accuracy in differentiating AD-CS from AI-CS (AUC-ROC 0.91, 95%CI 0.89-0.94), with androgen metabolites being the most discriminatory. We observed significant sex differences in steroid excretion in both healthy individuals and those with CS. Women exhibited markedly lower excretion of both glucocorticoids and mineralocorticoids compared to men: average glucocorticoid excretion was reduced by 43% in healthy women and 30% in CS women, while average mineralocorticoid excretion was 29% lower in healthy women and 51% lower in CS women (results adjusted for age and BMI). Timed steroid excretion in healthy individuals reflected the diurnal pattern of adrenal steroid secretion, with lower nighttime than daytime excretion of glucocorticoid metabolites. Nighttime glucocorticoid metabolite excretion (AUC-ROC 1.00, 95%CI 0.99-1.00) performed better than daytime (AUC-ROC 0.91, 95%CI 0.77-1.00) and 24-hour excretion (AUC-ROC 0.94, 95%CI 0.86-1.00) in separating CS cases from healthy individuals. Conclusions: USM is a non-invasive, one-step candidate test for the accurate diagnosis and differential diagnosis of CS. Timed nighttime urine collection leverages cortisol circadian rhythmicity and improves the diagnostic accuracy of the current reference standard 24-hour collection. Presentation: Sunday, July 13, 2025