Safety and effectiveness of >8 years of osilodrostat treatment in patients with cushing

Rosario Pivonello; Przemyslaw Witek; Marie Bex; Yerong Yu; Zhanna Belaya; Andre Lacroix; Carla Scaroni; Yoon-a Hwang; Pinar Kadioglu; Andrea Piacentini; Arnd Mueller; Richard Auchus

doi:10.1530/endoabs.110.P851

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Endocrine Abstracts (2025) 110 P851 | DOI: 10.1530/endoabs.110.P851

ECEESPE2025 Poster Presentations Pituitary, Neuroendocrinology and Puberty (162 abstracts)

Safety and effectiveness of >8 years of osilodrostat treatment in patients with cushing’s disease: findings from the LINC rollover open-label, multicentre study

Rosario Pivonello ¹ , Przemyslaw Witek ² , Marie Bex ³ , Yerong Yu ⁴ , Zhanna Belaya ⁵ , Andre Lacroix ⁶ , Carla Scaroni ⁷ , Yoon-a Hwang ⁸ , Pinar Kadioglu ⁹ , Andrea Piacentini ¹⁰ , Arnd Mueller ¹¹ & Richard Auchus ¹²

Author affiliations

¹Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy; ²Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw, Warsaw, Poland; ³Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium; ⁴West China Hospital of Sichuan University, Chengdu, China; ⁵Department of Neuroendocrinology and Bone Disease, Endocrinology Research Centre, Moscow, Russian Federation; ⁶Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada; ⁷Endocrinology Unit, Department of Medicine, University Hospital, Padova, Italy; ⁸Pituitary Tumor Center, Severance Hospital, Yonsei University Health System, Seoul, South Korea; ⁹Division of Endocrinology, Metabolism and Diabetes, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Türkiye; ¹⁰Recordati SpA, Milan, Italy; ¹¹Recordati AG, Basel, Switzerland; ¹²Department of Pharmacology and Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, United States

JOINT884

Introduction: The LINC clinical trial programme demonstrated that osilodrostat is effective and well tolerated in patients with Cushing’s disease (CD); however, lifelong treatment is often required. The open-label, multicentre LINC rollover (NCT03606408) study evaluated the long-term safety and effectiveness of osilodrostat in patients with CD.

Methods: The study was planned to be open for ~5 years (or until 31/12/2023 in the UK). Participants benefitting from osilodrostat (investigator judged) after completing either the LINC 2, 3 or 4 trial extension phases were eligible for inclusion. Participants continued in the rollover until osilodrostat no longer provided 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 the long-term safety of osilodrostat, assessed by frequency of adverse events (AEs)/serious AEs (SAEs). Cumulative data are reported from parent study baseline to rollover end, unless otherwise stated.

Results: 127 participants entered the rollover study (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 tumour 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). Adrenocorticotropic hormone, testosterone, 11-deoxycortisol and 11-deoxycorticosterone levels initially increased from baseline but generally stabilised during long-term treatment. Tumour volume generally decreased during the study, although inter-individual variability was high. At the end of osilodrostat treatment, 78.0% (n = 99) continued to receive clinical benefit. Mean urinary free cortisol levels decreased from 561.5 (4.1 x upper limit of normal [ULN]) at baseline to 85.0 nmol/24 h (0.6 x ULN) at week 12 of the parent studies and generally remained ≤ULN throughout treatment.

Conclusions: 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 ≤8.6 years); no new safety signals were identified.