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Endocrine Abstracts (2022) 81 P404 | DOI: 10.1530/endoabs.81.P404

ECE2022 Poster Presentations Pituitary and Neuroendocrinology (127 abstracts)

Change in androgens and adrenal hormones during long-term osilodrostat treatment in patients with Cushing’s disease: Results from the Phase III, prospective LINC 3 study

Rosario Pivonello 1 , Beverly M.K. Biller 2 , Shimatsu Akira 3 , John Newell-Price 4 , Antoine Tabarin 5 , Greisa Vila 6 , Andrea Piacentini 7 , Alberto Pedroncelli 8 & Maria Fleseriu 9


1Università Federico II di Napoli, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Naples, Italy; 2Massachusetts General Hospital, Neuroendocrine and Pituitary Tumor Clinical Center, Boston, MA, United States; 3Omi Medical Center, Kusatsu, Japan; 4The Medical School, University of Sheffield, Department of Oncology and Metabolism, Sheffield, United Kingdom; 5CHU de Bordeaux, Bordeaux, France; 6Medical University of Vienna, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Vienna, Austria; 7Recordati SpA, Milan, Italy; 8Recordati AG, Basel, Switzerland; 9Oregon Health & Science University, Pituitary Center, Departments of Medicine and Neurological Surgery, Portland, OR, United States

Introduction: Osilodrostat decreases cortisol production by inhibiting 11β-hydroxylase, increasing adrenal hormones above the blockade. Here, we describe these effects of osilodrostat and associated adverse events (AEs). The efficacy and safety of osilodrostat in patients with Cushing’s disease (CD) were confirmed in the published Phase III, prospective LINC 3 study (NCT02180217).

Methods: 137 patients with CD (mUFC >1.5x upper limit of normal) were enrolled in a 48-week (W) core phase including an 8W double-blind, randomised-withdrawal period for eligible patients. 106/113 patients who completed W48 entered an optional extension, ending when all ongoing patients completed ≥72W of treatment or discontinued. Testosterone, 11-deoxycortisol, 11-deoxycorticosterone and aldosterone were assessed centrally at baseline and regular intervals by liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone sulfate (DHEAS) by chemiluminescence immunoassay. Hirsutism (females; rated on a semi-quantitative scale: 0=absent; 1=mild; 2=moderate; 3=severe), blood pressure, oedema and serum potassium were assessed regularly.

Results: Median osilodrostat exposure was 130W (range 1–245); median osilodrostat dose was 7.4 mg/day (range 0.8–46.6). Following an increase during the core phase, mean testosterone levels stabilised in males and decreased towards baseline levels in females during long-term treatment. Of females with baseline, W48 (n=76) and W72 (n=64) assessments, hirsutism score improved from baseline in 26 and 22 patients at W48 and W72, respectively, and remained unchanged in 37 and 33 patients. Mean (SD) DHEAS levels decreased during the core phase to within the normal range, then stabilised during the extension (W48 and W72; females: 1.6 [1.6] and 1.0 [0.9] μmol/l; males: 3.4 [3.3] and 3.0 [3.1] μmol/l). Aldosterone levels also decreased and then stabilised during long-term treatment. Overall, mean potassium levels remained stable throughout the study. AEs related to accumulation of adrenal hormone precursors were reported in 58.4% (n=80/137) of patients, regardless of study drug relationship, and managed with additional therapy in 36.5% (n=50/137) of patients. The most common AEs were hypertension (n=24), peripheral oedema (n=22) and hypokalaemia (n=18), managed with concomitant medication in 17, 6 and 4 patients, respectively. They mostly occurred during the first 26W of treatment (females: 35.5%; males: 49.1%) at different osilodrostat doses (1–60 mg), with no discernable dose-related effect. Few patients discontinued treatment because of these AEs (1.5%; n=2/137).

Conclusions: Adrenal hormone levels frequently change when initiating osilodrostat but stabilise during long-term treatment. AEs associated with these changes are manageable without osilodrostat discontinuation; they should be closely monitored and treatment initiated as needed to achieve optimal patient outcomes.

Volume 81

European Congress of Endocrinology 2022

Milan, Italy
21 May 2022 - 24 May 2022

European Society of Endocrinology 

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