Dichtel, Laura E.

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: Nonresponse to selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment is common in patients with major depressive disorder (MDD), particularly in women, occurring in about 70% of patients despite adequate dosing. Well-tolerated augmentation strategies are needed, particularly ones that do not cause or exacerbate symptoms such as fatigue and sexual dysfunction. Low-dose testosterone has been shown to improve depression symptom severity, fatigue and sexual function in small studies of women not formally diagnosed with MDD. We sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with treatment-resistant MDD. A functional MRI (fMRI) substudy examined effects of testosterone on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. Methods: Randomized, double-blind, placebo-controlled, 8-week trial of adjunctive testosterone cream (AndroFeme® 1, Lawley Pharmaceuticals, Australia) in 101 women, ages 21–70, with treatment-resistant MDD. Testosterone was titrated to achieve blood levels near the upper normal reference limit. Primary outcome measure was depression severity by Montgomery-Asberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. fMRI substudy (n=20) primary outcome was change in ACC activity. Results: Mean age was 47±14 (SD) years and mean baseline MADRS score was 26.6±5.9. Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS depression scores decreased in both arms [testosterone: 26.8±6.3 to 15.3±9.6; placebo: 26.3±5.4 to 14.4±9.3 (baseline to 8 weeks, respectively)], with no difference between groups (p=0.91). Fatigue and sexual function improved without differences between groups. There were no group differences in side effects. fMRI results demonstrated a relationship between ACC activation and androgen levels pretreatment but no difference in ACC activation with treatment. Conclusions: This rigorously designed, double-blinded clinical trial did not find significant group differences between adjunctive low dose transdermal testosterone and placebo for antidepressant augmentation in women with treatment-resistant MDD and had a high placebo response rate. Low-dose testosterone was well tolerated but failed to differentially impact overall depressive symptom severity, fatigue, or sexual dysfunction. Testosterone did not result in greater activity in a brain region (ACC) implicated in MDD etiopathology compared to placebo. Thus, the addition of low-dose testosterone to ineffective antidepressant treatment should not be recommended for women with MDD. Further studies using strategies designed to reduce placebo effects may be warranted.