Citations

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: B. Salama: None. O. Hamidi: None. T.S. Wang: None. A. Sada: None. M.A. Habra: None. P. Dogra: None. A.P. Dackiw: None. S.C. Oltmann: None. S. Mirfakhraee: None. I. Lingvay: None. T. Mckenzie: None. T. Foster: None. M. Lyden: None. B. Dy: None. V. Balderrama Brondani: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) are at risk for adrenal insufficiency (AI) after unilateral adrenalectomy. Guidelines recommend initiating glucocorticoid replacement post-adrenalectomy. However, identifying patients at risk and accurately diagnosing AI can enable individualized management. Objectives: Determine the prevalence, duration and predictors of postoperative AI after unilateral adrenalectomy for MACS and compare baseline and peak cortisol post cosyntropin stimulation test (CST) In diagnosing AI. Methods: We conducted a multicenter retrospective cohort study of patients with MACS who underwent unilateral adrenalectomy and post-operative CST evaluation between January 1, 2013, and August 31, 2024. MACS was defined as cortisol >1.8 mcg/dL following overnight administration of 1 mg dexamethasone (DST-cortisol). AI was diagnosed when post-operative day 1 early morning baseline cortisol was <10 μg/dL and/or CST peak cortisol was <18 μg/dL. Baseline and peak cortisol levels were considered concordant when both met cut-offs. Biochemical (BSS) and clinical (CSS) severity scores were calculated. Results: Among 281 adults with MACS (80% women, median age 57 years, interquartile range [IQR] (47-64), the median adenoma size was 3.0 cm (IQR, 2.3-3.9), and 62 (22%) had bilateral disease. The median BSS was 4 (IQR, 3-5), and the median CSS was 6 (IQR, 2-11). Postoperative AI was diagnosed in 153 (54.5%) patients. A multivariable analysis showed that a higher BSS (OR = 1.17, 95% CI 1.01-1.36) and younger age at diagnosis (OR = 0.64, 95% CI 0.50-0.81), but not sex, BMI, or laterality, were associated with AI. Diagnosis of AI was concordant based on the baseline and peak CST cortisol cutoffs in 78% of patients. Diagnosis of AI was discordant in 22%: in 35 patients (12%), baseline cortisol was <10 μg/dL, but CST peak cortisol was ≥18 μg/dL, and in 28 cases (10%), baseline cortisol was ≥10 μg/dL, but CST peak cortisol was <18 μg/dL. Patients with bilateral MACS were more likely to have discordant results (32% vs. 19%, P < 0.001). During a median postoperative follow-up period of 15.4 months, 108 patients (70.6%) recovered from AI. The median time to recovery was 3.9 months (IQR, 3-5.9), with 41% recovering by 3 months, 60% by 6 months, and 73% by 12 months. The median time to recovery was associated with baseline BSS: mild: 3 months, moderate: 4.7 months, and severe: 14.5 months. Conclusion: We found that more than half of patients with MACS develop postoperative AI, with 50% recovering by 4 months post-surgery. BSS was associated with both the development and duration of AI. Baseline and CST peak cortisol results were concordant only in 78% of patients, thus performing both should be considered for an accurate diagnosis of AI. Presentation: Sunday, July 13, 2025

Abstract Disclosure: A. Bancos: None. Y. Hleibiehova: None. R. Gregg garcia: None. N. Genere: None. S. Achenbach: None. E. Atkinson: None. S. Mahrokhian: None. A. Vaidya: None. I. Bancos: None. Background: Bilateral adrenalectomy (BLA) is a seldomly performed treatment for hypercortisolism, pheochromocytoma, or metastatic adrenal disease that leads to permanent primary adrenal insufficiency (PAI). PAI due to BLA is seldomly studied independently of PAI due to autoimmune adrenalitis (AA), despite differences in onset of disease, and neither group has large-scale data focusing on factors that impact quality of life (QOL) post-PAI. Furthermore, no study to date has compared patients’ burden of disease or number of adrenal crises in patients with PAI due to BLA versus patients with PAI due to AA. Methods: We conducted a dual-center, cross-sectional study of adults with PAI due to AA or BLA, 2022-2025. All participants completed a questionnaire on symptoms, management, adrenal crises, and an adrenal insufficiency-specific QoL survey (AddiQoL). Outcomes included AddiQoL scores and self-reported adrenal crises. Pearson correlations were used to explore relationships with AddiQoL scores. Logistic regression models were used to examine associations with having an adrenal crisis in the past year. Results: Of the 343 participants, 203 had AA (median age of 54 years, IQR 42-67, 72% women) and 140 had BLA (median age of 57 years, IQR 44-67, 76% women). Median duration of PAI was similar for AA and BLA cohorts (13 vs 10 years, P=0.205). Patients with AA and BLA were treated with hydrocortisone (84% vs 78%), prednisone (19% vs 21%), or dexamethasone (1% vs 1%), with a similar median daily hydrocortisone equivalent dose (21 mg vs. 20 mg, P=0.259). No group differences in availability of glucocorticoid injections (85% vs 83%) and medical alert bracelet (81 vs 83%) were reported. AddiQoL scores were similar between patients with AA and BLA (median 84 vs 83, P=0.984). AddiQoL score was better in older patients (R=0.16, P=0.003), men (R=0.17, P=0.002), daily hydrocortisone ≤ 20 mg/day (R=0.11, P=0.04), and those with supportive health insurance (R=0.20, P<0.001). Patients with AA reported a higher number of adrenal crises since diagnosis (median of 0.1/person-years, IQR 0-0.4 vs 0/person-years, IQR 0-0.3, P=0.046), as well as in the last year (25% vs 13%, P=0.022), compared to patients with BLA. In a multivariable model of age, sex, glucocorticoid dose, availability of glucocorticoid injection/medical bracelet, type of PAI, and number of symptoms, patients with AA (OR 2.1, 95%CI 1.0-4.4) and those with more symptoms (OR 1.2, 95% CI 1.1-1.3) were more likely to have an adrenal crisis within the last year. Conclusion: We found no differences in the QoL scores, burden of disease, symptoms, or management of patients with AA and BLA. However, patients with AA reported more adrenal crises both overall and within the last year of assessment. Presentation: Sunday, July 13, 2025

Abstract Disclosure: A.J. Han: None. S.J. Achenbach: None. B.J. Atkinson: None. I. Bancos: None. Background: The prevalence of adrenal adenomas continues to rise with increased utilization of imaging. However, much remains unknown about what risk factors may predispose individuals to develop adrenal adenomas. In this study, we aimed to identify modifiable and non-modifiable risk factors associated with development of adrenal adenomas. Methods: Historical case-control population study was performed. Patients diagnosed with adrenal adenoma between 2005-2017 with no evidence of overt hormone excess were paired with age- and sex-matched individuals without a diagnosis of adrenal adenoma who had a CT/MRI scan performed within 5 years prior to index date. The prevalence of various social and metabolic risk factors present within 10 years prior to index date (date of adrenal adenoma diagnosis) was compared. Results: Total of 670 patients (median age 63, IQR 53-74 years, 56% women) with adrenal adenomas were identified. At 10 years prior to index date, patients with adrenal adenomas had a higher body mass index (BMI) (median 30.1 vs 28.2 kg/m2, p<0.001), lower socioeconomic status (SES) based on Area Deprivation Index (36.2% with national percentile score >50 vs 30.9%, p=0.037), and more tobacco use (70.2% vs 61.4%, p=0.001), compared to referent subjects. Patients also had a higher prevalence of diabetes (17.5% vs 11.7%, p=0.003) 5-10 years prior to index date, but no difference in prevalence of hypertension, myocardial infarction, chronic kidney disease, atrial fibrillation, stroke, or heart failure was observed between groups. Based on multivariable analysis, increased BMI and tobacco use 10 years prior to index date was associated with increased odds of adrenal adenoma diagnosis with odds ratio (OR) of 1.18 (95% Confidence Interval 1.06-1.32) and 1.41 (1.06-1.87), respectively. Conclusions: Compared to controls, patients with adrenal adenoma were more likely to be obese, have lower SES, endorse tobacco use, and demonstrate evidence of impaired glucose metabolism at least 5-10 years prior to diagnosis. In particular, increased BMI and prior tobacco use was associated with increased odds of adrenal adenoma diagnosis. Further exploration of these intricate relationships may help identify modifiable risk factors for development of adrenal adenomas. Presentation: Saturday, July 12, 2025

Abstract Disclosure: S. Ahmadian: None. C.A. Villavicencio Torres: None. V.M. Fell: None. K.L. Moehnke: None. Y. Chai: None. R.L. Taylor: None. S.K. Grebe: None. A.D. Maus: None. I. Bancos: None. Background: Salivary cortisol (SalF), and cortisone (SalE) interpretation can be influenced by intra-individual variability arising from cortisol secretion cyclicity, assay performance, and sampling techniques. No studies to date have examined the impact of sampling on intra-individual variability. Methods: We conducted a single-center cross-sectional study of adults evaluated with total serum cortisol measurements as a part of the overnight dexamethasone suppression test (DST) or cosyntropin stimulation test (CST), November 2024- January 2025. Participants were provided with two cotton swabs (salivettes) and asked to collect two consecutive saliva samples immediately after the venipuncture for total cortisol. Each cotton swab was kept in the mouth for 2-2.5 minutes. Saliva was tested for SalF and SalE by mass spectrometry. Variability was examined based on cortisol tertiles. Results: A total of 78 paired saliva samples were obtained from 60 participants (45 [75%] women; median age 55 years [IQR 39-66]), who were undergoing either DST (42 [70%]) or CST (18 [30%]). A total of 10 (17%) saliva samples did not contain a sufficient sample for analysis during the first or second saliva collection (7 [12%] from DST group, and 3 [5%] from CST group).Among 53 patients undergoing DST, the median serum total cortisol was 1.3 mcg/dL [IQR 0.9-3], the median first SalF was 20 ng/dL [IQR 7-28], the median second SalF was 12 ng/dL [IQR 6-23], and the median variability was 11% [IQR 3-22%]. The median first SalE was 69 ng/dL [IQR 54-185], while the median second SalE was 63 ng/dL [IQR 56-178], with a median variability of 6% [IQR 4-10].In patients undergoing CST, peak median serum total cortisol was 20 mcg/dL [IQR 18-24], median first SalF was 809 ng/dL [IQR 536-1227], and median second SalF was 1063 ng/dL [IQR 667-1503], with the median variability of 14% [IQR 8-22]. The median first SalE was 2507 ng/dL [IQR1697-2966], while the median second SalE was 2485 ng/dL [IQR 1530-2976], with a median variability of 9% [IQR 3-12].When examining intra-individual variability of SalF, the variability was lowest in the middle tertile, corresponding to serum cortisol of 1.8-8.9 mcg/dL, at 9% [IQR 5-16]. Variability was higher in the lowest tertile (14% [IQR 0-52]) and the highest tertile (12% [IQR 6-16]). Overall, the variability of SalE was lower than that of SalF: 7% [IQR 4-13] in the lowest tertile, 5% [IQR 2-9] in the middle tertile, and 10% [IQR 4-12] in the highest tertile. Conclusion: We show that saliva sampling may impact the results, with 17% patients providing insufficient sample for analysis, and variability of 9-14% for SalF and 5-10% for SalE. Same time-point sampling-related variability should be considered in interpretation of SalF and SalE measurements. Presentation: Sunday, July 13, 2025

Abstract Disclosure: M. Salehi: None. K. Yu: None. C.A. Villavicencio Torres: None. V. Fell: None. I. Bancos: None. Context: The use of the 1 mg overnight dexamethasone suppression test (1 mg-DST) is considered the standard-of-care test for the assessment of hypercortisolism. Scarce data are available on the utility of 8 mg-DST in distinguishing adrenal from pituitary hypercortisolism. Objective: To determine the value of 8 mg-DST in diagnosing hypercortisolism subtype. Methods: We conducted a single-center retrospective cohort study (2005-2024) of consecutive adults who underwent both the 1 mg-DST and the 8 mg-DST within a 6-month period. Only patients with optimal reference standard confirming the type of hypercortisolism were included. Patients were excluded if they had an abnormal DST and dexamethasone concentration <100 ng/dL or were receiving oral estrogen therapy. Delta cortisol [(post 1 mg-DST cortisol- post 8 mg-DST cortisol) x100/post 1 mg-DST cortisol)] was calculated for each patient. Results: A total of 61 patients (50, 82% women, median age 60 years, interquartile range, IQR 47-67) underwent both 1- and 8 mg-DST at least once, with 8 (13%) patients undergoing the 1 mg-DST and 8 mg-DST twice, and 1 (1.6%) patient undergoing both tests thrice. Adrenal hypercortisolism was diagnosed in 44 (72%) patients and pituitary hypercortisolism in 17 (28%) patients. Median post 1 mg-DST cortisol was 4.6 mcg/dL (IQR 2.8-7.2) in adrenal and 13.7 mcg/dL (IQR 7.3-21.7) in pituitary hypercortisolism. Median post 8 mg-DST cortisol was 3.2 mcg/dL (IQR 2.5-6.3) in adrenal and 3.6 mcg/dL (IQR 2.2-7.5) in pituitary hypercortisolism. Median delta cortisol was higher in pituitary hypercortisolism when compared to adrenal hypercortisolism (69%, IQR 25-83 vs 5 %, IQR -20-16, P<0.001). Delta cortisol demonstrated a good discrimination in distinguishing adrenal from pituitary hypercortisolism with a median area under receiver operator of 82% (95%CI 69-92). A cut-off of 25% provided a specificity of > 85%, while a cut-off of -1% yielded a sensitivity of > 85% in diagnosing adrenal hypercortisolism. Conclusion: In this study, we show that performing 8 mg-DST in addition to 1 mg-DST in selected patients with hypercortisolism and calculating delta cortisol is a valuable in distinguishing hypercortisolism subtype. Presentation: Sunday, July 13, 2025

Abstract Disclosure: J. Herndon: None. Y. Hleibiehova: None. A. Bancos: None. S. Achenbach: None. E. Atkinson: None. D. Donegan: Camarus, Recordati. I. Bancos: None. Introduction: Studies show that quality of life (QOL) among patients with adrenal insufficiency (AI) (primary (PAI) or secondary (SAI)) improves following adequate glucocorticoid replacement, however decreased QOL persists. SAI due to hypophysitis or infrequently PAI due to adrenalitis are recognized complications of immune-checkpoint-inhibitors (ICI). It is unknown if patients with ICI induced AI (ICI-AI) would report similar findings in QOL. Aim: To assess the impact of ICI-AI on specific determinants of health-related QOL (HRQOL) and compare management and outcomes to SAI due to other etiologies (oSAI). Methods: A cross-sectional survey study of adult patients who completed at least 1 AddiQOL survey with a diagnosis of ICI- AI or oSAI evaluated between 2015 and 2024 were included. Patients with opioid- or glucocorticoid-induced-AI were excluded. A study survey obtained information regarding diagnosis and treatment. Results: 112 patients with ICI-AI were included (SAI n=109, PAI n=3). Among those with ICI-AI, 59% were female, median age at diagnosis was 59.7 ±12.8 years and melanoma was the most common indication for ICI use (51%). The median time to ICI-AI diagnosis was 5.5 (range 0.3-80.8) months and 46% used combination ICI therapy. When compared to those with oSAI (n=139), patients with central ICI-AI were older at diagnosis (59 ±12.7 vs 46 ±18.1 years, p <0.01), more were female (59 vs 43%, p=0.015) and most were diagnosed in the last year (88% vs 42%, p<0.01). Those with ICI-AI received higher hydrocortisone (HC) equivalent daily doses than those with oSAI (25.1± 18.3 vs 22.1 ±16.9 mg/day, p<0.01), however there was no difference in the number of adrenal crises (AC) reported within the last year (14 vs 16, p=0.78). Patients with ICI-AI felt that emergency personnel understood their diagnosis and treated them promptly (75% vs 0% p=0.012). Logistic regression analysis of the entire group (ICI-AI + oSAI) did not identify an association between the occurrence of AC in the last year and HC dose >20 mg/day or type of glucocorticoid. Furthermore, there was no difference in number of AC per person year assessed between the ICI-AI and oSAI (0.23 ±0.5 vs 0.21 ±0.5, p= 0.4). The mean total AddiQOL score was higher in those with ICI-AI (87.2 ±13.9 vs 81.8 ±15.8, p=0.02). When adjusted for age and sex, total AddiQOL score was inversely related to number of symptoms present (r: -0.49, p<0.01; r: -0.58, p<0.01), occurrence of AC in the last year (r: -0.27, p=0.01; r: -0.33, p<0.01) and positively related to current employment (r:0.33 p<0.01 0.2,p=0.02) in ICI-AI and oSAI respectively. Conclusion: This is the first study to compare management and HRQOL in patients with ICI-AI compared to oSAI and although there were no significant differences in total number of AC events between the 2 groups, differences exist in terms of AI presentation, management and reported QOL. Presentation: Sunday, July 13, 2025

Abstract Disclosure: I. Bancos: None. H. Falhammar: None. J. Young: None. R. Pivonello: Received research funding from Corcept Therapeutics, Neurocrine Biosciences, Recordati AG, Spruce Bioscience and Xeris Pharmaceuticals (Strongbridge Biopharma), Consultant for Corcept Therapeutics, Crinetics Pharmaceuticals, HLundbeck A/S and Recordati Rare Diseases.. G. Russo: None. M.R. Stancampiano: None. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. Background: In patients with classic congenital adrenal hyperplasia (CAH), chronic glucocorticoid (GC) treatment, especially at supraphysiologic doses, can lead to weight gain or obesity. Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to GC replacement to control androgens in patients with CAH. In CAHtalyst™ Adult (NCT04490915), least-squares mean (LSM) percent changes in GC dose at Week 24 (end of double-blind placebo-controlled [DBPC] period) indicated a significant reduction with crinecerfont (-27.3% vs 10.3% for placebo; LSM difference [LSMD] -17.0%; P<0.0001) while androstenedione was maintained or improved relative to Day 1 baseline (BL). At Month 12 (end of open-label [OL] period), mean percent decreases from BL were -24.6% in participants continuing crinecerfont (CFT/CFT) and -29.7% in those switched from placebo (PBO/CFT). Objective: To evaluate weight-related outcomes in adults with CAH who received up to 1 year of crinecerfont. Methods: Mean change from Day 1 BL in body mass index (BMI) and mean percentage change from BL in weight were analyzed at Week 24 and Month 12. Achievement of >5% reduction in weight was also analyzed, with results presented as % (n/N: n=number meeting response threshold, N=number who were overweight/obese [BMI ≥25 kg/m2]) at BL and had available data at assessment [Week 24 and Month 12]). For predefined endpoints in the DBPC period, results are presented as LSM changes with LSMD and P-value. Results: Mean BMI at BL was 30.1 kg/m2 (crinecerfont) and 29.0 kg/m2 (placebo), and >70% of participants were overweight or obese (74.6% [91/122] crinecerfont; 63.3% [38/60] placebo). At Week 24, LSM changes from BL for crinecerfont vs placebo were as follows: BMI (-0.42 vs -0.02; LSMD: 0.40, P=0.1068); percent change in weight (1.45% vs -0.07%; LSMD: 1.38%, P=0.0856). At Month 12, further mean reductions from BL were observed with crinecerfont in BMI (-0.81 kg/m2 CFT/CFT, -0.44 kg/m2 PBO/CFT) and weight (-2.72% CFT/CFT, -1.37% PBO/CFT). Among participants who were overweight or obese at BL, a higher percentage achieved >5% reduction in weight at Week 24 with crinecerfont 18.4% (16/87) versus placebo 13.5% (5/37). At Month 12, 27.4% (23/84) and 38.9% (14/36) achieved this threshold in the CFT/CFT and PBO/CFT groups, respectively. Conclusion: Adults with CAH who received up to 1 year of crinecerfont showed reductions in BMI and weight. Among participants who were overweight or obese at BL, 30.8% achieved a >5% reduction in weight at Month 12. These analyses indicate that the substantial GC dose reductions enabled by crinecerfont can allow for improvements in the weight-related effects associated with chronic supraphysiologic GC exposure. Presentation: Sunday, July 13, 2025

Abstract Disclosure: S. Sharma Sharma: None. J. Saini: None. S.R. Chacko: None. S. Ahmadian: None. V. Fell: None. S.J. Achenbach: None. E.J. Atkinson: None. W.F. Young: None. I. Bancos: None. Context: The impact of active hypercortisolism on sleep is incompletely characterized. Several studies report impaired sleep in patients with Cushing syndrome (CS). Patients with mild autonomous cortisol secretion (MACS) demonstrate an abnormal circadian cortisol secretion with mild nocturnal hypercortisolism that could also impact sleep. Objectives: To characterize sleep abnormalities and to identify factors associated with impaired sleep in patients with CS and MACS. Methods: We conducted a single-center cross-sectional study of prospectively enrolled adults with active CS and MACS evaluated between August 31, 2020, and December 2, 2024. Clinical and biochemical severity scores for hypercortisolism were calculated. Quality of life (QoL) was assessed using 1) Short Form-36 (SF-36), physical (PCS) and mental (MCS) component summaries, and 2) Cushing QOL survey, with psychosocial and physical domains. Sleep quality was assessed using Pittsburgh Sleep Quality Index (PSQI), a global score of ≥5 was considered abnormal. Pearson correlations and linear regression models were used to explore associations with PSQI scores. Results: In 285 patients (226 [79%] women, 259 [91%] White, median age of 54 [IQR 44-64] years), MACS was diagnosed in 147 (52%) and CS in 138 (48%). Patients reported abnormal sleep (median PSQI of 12 (IQR 8-16) in CS vs 10 (IQR 7-15) in MACS (P=0.086). Most prevalent sleep abnormalities included report of “fairly bad” or “very bad” overall sleep quality (73% in CS and 54% in MACS) and report of severe day dysfunction due to sleepiness (70% in CS and 56% in MACS). In an age-, sex- and BMI- adjusted univariable analysis of patients with hypercortisolism, higher clinical hypercortisolism severity score (r=0.13, P=0.024) and worse QoL, as measured by SF-36 and Cushing QoL (P=<0.001 for all), were associated with higher PSQI scores, a reflection of poor sleep. In a multivariable analysis of patients with hypercortisolism, we found that younger age (est -0.08, P=<0.001), female sex (est 1.95, P=0.004), lower BMI (est -0.07, P=0.041), and higher clinical severity score (est 0.12, P=0.024) were associated with higher PSQI scores, indicating impaired sleep. In a multivariable analysis of only patients with MACS, female sex (est 2.17, P=0.012), lower BMI (est -0.12, P=0.017), and higher clinical severity score (est 0.24, P=0.003), but not age were associated with higher PSQI scores, indicating impaired sleep. In patients with CS, only younger age (est -0.12, P=<0.001), but not other variables were associated with higher PSQI scores. Conclusion: We found that patients with MACS have impaired sleep, possibly due to nocturnal hypercortisolism. In patients with MACS, but not CS, clinical hypercortisolism severity score was associated with more impaired sleep. 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