Simeoli, Chiara

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 Objective To study pregnancy outcomes and complications in women with congenital adrenal hyperplasia (CAH). Methods A retrospective multicenter study was conducted at tertiary reference centers in 5 countries (Austria, Germany, Italy, Sweden, USA), including 72 adult women with CAH (nonclassic [NC] n = 34, simple virilizing [SV] n = 21, salt wasting [SW] n = 17). Results A total of 133 pregnancies, 112 live births, and 25 abortions were documented. Prolonged latency to pregnancy was observed (median 11 months in SW, 24 months in SV, 8 months in NC), with a notable use of fertility-enhancing medication (25.6%) and assisted reproductive techniques (30.8%). Over half of the women in each group took more than 12 months to conceive. The average number of live births (1.4-1.6 children per woman) was similar across CAH phenotypes and comparable to the general population. Spontaneous abortion rates (18.0%) were also similar across phenotypes. Primary cesarean section rates (60.9%) were higher than in the general population, though 23.8% of women with SV and 29.4% of women with SW gave birth naturally, despite most having undergone genital surgery. Children categorized as small for gestational age were 20.5%. Pregnancy, delivery, and postpartum complications were rare for mothers and neonates. Conclusion The study indicates a prolonged latency to pregnancy and high use of fertility treatments in CAH patients, regardless of phenotype. Abortion rates were not increased, and overall pregnancy and perinatal outcomes were favorable.

Abstract Context Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. Objective Multicenter survey on current clinical approaches in managing AI during pregnancy. Design Retrospective anonymized data collection from 19 international centers from 2013 to 2019. Setting and Patients 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). Results Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. Conclusions This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.