Abstract
Disclosure: R.J. Auchus: Corcept Therapeutics, received grants and personal fees, Crinetics Pharmaceuticals, received grants and personal fees, Diurnal Ltd, received grants and personal fees, Neurocrine Biosciences, received grants and personal fees, Sparrow Pharmaceuticals, received grants and personal fees, Spruce Biosciences, received grants and personal fees, Recordati Rare Diseases, received grants and personal fees, Xeris Pharmaceuticals, received grants and personal fees, Adrenas Therapeutics, received personal fees, Besins Pharmaceuticals, received personal fees, H Lundbeck A/S, received personal fees, Novo Nordisk, received personal fees, Quest Diagnostics, received personal fees. P. Witek: Berlin Chemie, received travel grants and speaker fees, Ipsen, received travel grants and speaker fees, Merck-Serono, received travel grants and speaker fees, Novartis, received travel grants and speaker fees, Novo Nordisk, received travel grants and speaker fees, Recordati Rare Diseases, received travel grants and speaker fees, Strongbridge Biopharma, received travel grants and speaker fees. M.A. Bex: Recordati Rare Diseases, consultancy and received travel grants. Y. Yu: None. Z. Belaya: None. A. Lacroix: Corcept Therapeutics, received grants and personal consulting fees, Novartis, received grants and personal consulting fees, Pfizer, received grants and personal consulting fees, Recordati Rare Diseases, received grants and personal consulting fees. C.M. Scaroni: HRA, received occasional consulting honoraria, Novartis, received occasional consulting honoraria, Pfizer, received occasional consulting honoraria, Recordati Rare Diseases, received occasional consulting honoraria, Sandoz, received occasional consulting honoraria. Y. Hwang: None. P. Kadioglu: None. A. Piacentini: Recordati, employee. A. Mueller: Recordati, employee. R. Pivonello: Corcept Therapeutics, received research funding and served as a consultant, Neurocrine Biosciences, received research funding, Recordati Rare Diseases, received research funding and served as a consultant, Spruce Bioscience, received research funding, Xeris Pharmaceuticals (Strongbridge Biopharma), received research funding, Crinetics Pharmaceuticals, served as a consultant, H Lundbeck A/S, served as a consultant. Introduction: The LINC clinical trial program demonstrated that osilodrostat is effective and well tolerated in patients with Cushing’s disease (CD); however, lifelong treatment is often required. The open-label, multicenter LINC rollover (NCT03606408) study evaluated long-term osilodrostat safety and effectiveness in patients with CD. Methods: The study was planned to be open for ∼5 years (or until December 31, 2023 in the UK). Participants benefiting from osilodrostat treatment after completing either the LINC 2, LINC 3 or LINC 4 trial extension phases were eligible for inclusion. Participants continued in the rollover until osilodrostat no longer provided (investigator-judged) clinical benefit, became commercially available in their country, or one of the protocol-defined discontinuation criteria was met. Participants attended quarterly visits for safety/clinical benefit assessments. The primary objective was to evaluate long-term safety of osilodrostat treatment, assessed by frequency of adverse events (AEs)/serious AEs (SAEs). Cumulative data are reported from parent study baseline (BL) to rollover end, unless otherwise stated. Results: 127 participants entered the rollover (mean [SD] age: 41.3 years [12.4]; female: 74.8%). Median (min–max) osilodrostat exposure and dose was 5.0 (1.7–8.6) years and 4.9 (1.0–46.0) mg/day. All patients experienced ≥1 AE; 86.6% (n=110) were considered treatment related, most commonly (≥25% of patients) nausea (30.7%, n=39), adrenal insufficiency (AI; 28.3%, n=36) and fatigue (28.3%, n=36). SAEs were reported in 44.9% (n=57) of participants; 8.7% (n=11) were considered treatment related, most commonly AI (4.7%, n=6). AEs related to accumulation of adrenal hormone precursors were reported in 65.4% (n=83), hypocortisolism in 55.9% (n=71), pituitary tumor enlargement in 8.7% (n=11), and arrhythmogenic potential and QT prolongation in 5.5% (n=7). During the rollover, 22.0% (n=28) discontinued osilodrostat; 3.9% (n=5) discontinued because of treatment-related AEs, most commonly AI (n=3). At the end of osilodrostat treatment, 78.0% (n=99) continued to receive clinical benefit. From BL to week (W) 12 of the parent studies, mean urinary free cortisol levels decreased from 561.5 nmol/24 h (4.1 x upper limit of normal [ULN]) to 85.0 nmol/24 h (0.6 x ULN), mean glycated hemoglobin levels decreased from 5.8% to 5.6%, and mean systolic blood pressure decreased from 130.7 mmHg to 123.2 mmHg. These parameters then generally remained within normal range during the study. Body weight generally decreased over time. Potassium and sodium levels remained stable and normal throughout the study. Conclusion: The LINC rollover study complements existing evidence demonstrating that osilodrostat is well tolerated and provides sustained effects in patients with CD during long-term treatment (for up to 8.6 years); no new safety signals were identified. Presentation: Sunday, July 13, 2025