Assessing long-term safety and efficacy of osilodrostat in prior- and new-use patients with endogenous cushing

Frederic Castinetti; Eliza Geer; Beverly Biller; Richard Feelders; Maria Fleseriu; Rosario Pivonello; Martin Reincke; Antoine Tabarin; Mouhaer Jeannie Le; Julia Stermenska; Mario Maldonado; Irina Bancos

doi:10.1530/endoabs.99.P521

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Endocrine Abstracts (2024) 99 P521 | DOI: 10.1530/endoabs.99.P521

ECE2024 Poster Presentations Pituitary and Neuroendocrinology (120 abstracts)

Assessing long-term safety and efficacy of osilodrostat in prior- and new-use patients with endogenous cushing’s syndrome: a 1-year real-world interim analysis of the non-interventional, multinational LINC 6 study

Frederic Castinetti ¹ , Eliza Geer ² , Beverly Biller ³ , Richard Feelders ⁴ , Maria Fleseriu ⁵ , Rosario Pivonello ⁶ , Martin Reincke ⁷ , Antoine Tabarin ⁸ , Jeannie Le Mouhaër ⁹ , Julia Stermenska ¹⁰ , Mario Maldonado ¹⁰ & Irina Bancos ¹¹

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¹Aix Marseille University, INSERM, La Conception Hospital, Assistance Publique Hôpitaux de Marseille, Marseille Medical Genetics, Department of Endcrionology, Marseille, France; ²Memorial Sloan Kettering Cancer Center, Multidisciplinary Pituitary and Skull Base Tumor Center, New york, Ny, United States; ³Massachusetts General Hospital, Neuroendocrine and Pituitary Tumor Clinical Center, Boston, MA, United States; ⁴Erasmus Medical Center, Department of Internal Medicine, Endocrine Section, Rotterdam, Netherlands; ⁵Oregon Health & Science University, Pituitary Center, Departments of Medicine and Neurological Surgery, Portland, United States; ⁶Università Federico II di Napoli, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Naples, Italy; ⁷Ludwig-Maximilians-Universität München, Munich, Germany; ⁸CHU de Bordeaux, Bordeaux, France; ⁹Recordati Rare Diseases SpA, Paris, France; ¹⁰Recordati AG, Basel, Switzerland; ¹¹Mayo Clinic, Division of Endocrinology, Metabolism and Nutrition, Rochester, United States

Introduction: Potent 11β-hydroxylase inhibitor osilodrostat provides cortisol level control in patients with Cushing’s syndrome (CS), as demonstrated by the LINC clinical development programme in Cushing’s disease (CD) patients.¹ We report data from year 1 of the prospective observational LINC6 study (NCT05382156), evaluating long-term safety and efficacy of osilodrostat in CS patients during 3 years of routine clinical practice.

Methods: Irrespective of prior osilodrostat use, adult patients with endogenous CS are being enrolled in countries where osilodrostat is approved and available (USA and Europe). Incidence of osilodrostat-related adverse events (AE) and serious AEs (SAE) is the primary endpoint. Secondary endpoints include change in mean urinary free cortisol (mUFC), serum cortisol and late-night salivary cortisol (LNSC). AEs are recorded at baseline and each visit. Outcomes were separately analysed in patients with prior (any time before study entry) and new osilodrostat use. We report changes for patients with baseline and month (M) 3 assessments. All assessments are descriptive.

Results: The safety population (received ≥1 osilodrostat dose) comprises 94/106 enrolled patients: CD, n=78; non-CD CS, n=16 (adrenal adenoma, n=3; adrenal hyperplasia, n=3; ectopic, n=9; other, n=1). For prior and new users, mean (SD) age was 53.0 (12.8), n=71 and 54.0 years (12.7), n=23, respectively; 73.2% and 60.9% were female; median (min–max) on-study osilodrostat exposure and dose were 6.0M (0.1–13.9) and 5.0 mg/day (1.0–60.0), and 2.7M (0.7–9.2) and 5.7 mg/day (2.0–50.0), respectively. Seven prior and five new users reported 33 and 11 treatment-related AEs, most commonly (>1 occurrence) acute adrenocortical insufficiency, diarrhoea, dizziness (each 3/33, 9.1%) and vomiting (2/33, 6.1%) in prior users, and vomiting (2/11, 18.2%) in new users. In both groups, most AEs were mild or moderate. Two patients discontinued because of five treatment-related AEs (worsening hypertension, uncontrolled blood pressure and dizziness, n=1, prior user; nausea and vomiting, n=1, new user). SAEs occurred infrequently, in 2.8% of prior (n=2/71) and 17.4% of new (n=4/23) users. At M3, mUFC, serum cortisol and LNSC were normalised in 72.7% (n=8/11), 70.0% (n=14/20) and 54.5% (n=6/11) of prior users, and in 66.7% (n=2/3), 66.7% (n=4/6) and 33.3% (n=1/3) of new users.

Conclusion: Building on Phase III trial evidence (LINC3, NCT02180217; LINC4, NCT02697734), preliminary results from real-world clinical settings show that osilodrostat is generally well-tolerated in endogenous CS patients and provides control of cortisol production in most prior and new osilodrostat users.

ReferenceFleseriu M et al. Lancet Diabetes Endocrinol 2021;9:847–75