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Endocrine Abstracts (2019) 63 OC3.1 | DOI: 10.1530/endoabs.63.OC3.1

1Università Federico II di Napoli, Naples, Italy; 2Northwest Pituitary Center, Oregon Health & Science University, Portland, OR, USA; 3The Medical School, University of Sheffield, Sheffield, UK; 4Department of Endocrinology, Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, Faculté de Médecine Paris Descartes, Université Paris V, Paris, France; 5Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA; 6Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan; 7Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China; 8Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA; 9Prince of Songkla University, Songkhla, Thailand; 10Pituitary Tumor Center, Yonsei University College of Medicine, Seoul, Republic of Korea; 11Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 12Centre hospitalier de l’Université de Montréal, Montreal, Canada; 13Novartis Pharma AG, Basel, Switzerland; 14Neuroendocrine & Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston, MA, USA.

Introduction: Osilodrosat is a potent oral 11β-hydroxylase inhibitor. During the 24-week, single-arm, open-label period of the Phase III LINC 3 study (NCT02180217), osilodrostat treatment demonstrated rapid, sustained reduction in mean urinary free cortisol (mUFC) in most Cushing disease (CD) patients. In the subsequent 8-week, double-blind, randomized-withdrawal phase, a significantly higher proportion of patients receiving osilodrostat maintained normal mUFC at week (W)34 without a dose increase versus placebo (86.1% vs 29.4%; OR: 13.7, P<0.001 [primary efficacy endpoint]; Pivonello R et al. ICE 2018;abstract 1025). The effects of osilodrostat on CD signs/symptoms/biochemistry parameters are reported here for the first time.

Methods: 137 adults with CD and mUFC>1.5xULN (ULN=138 nmol/24h; baseline median mUFC=3.5×ULN) initiated open-label osilodrostat 2mg bid with dose adjustments every 2 weeks (maximum 30 mg bid) until W12 based on mUFC and safety. At W26, 71 eligible patients (mUFC≤ULN at W24 without up-titration after W12) were randomized to continue osilodrostat (n=36) or matching placebo (n=35) in an 8-week double-blind phase (ineligible patients continued open-label osilodrostat; n=47), followed by open-label osilodrostat until W48. Cardiovascular-related metabolic parameters and CushingQoL and Beck Depression Inventory (BDI) scores were evaluated at baseline, every 2, 4 or 12 weeks (depending on study phase), and at end of treatment (W48).

Results: By W48, in all patients (N=137), mean absolute change±SD from baseline in signs/symptoms/biochemistry parameters were: weight, −3.8±5.7 kg; BMI, –1.4±2.2 kg/m2; waist circumference, –4.6±7.8 cm; fasting plasma glucose, –0.5±1.3 mmol/L; HbA1c, –0.4±0.7%; total cholesterol, –0.5±0.9 mmol/L; LDL cholesterol, –0.2±0.8 mmol/L; HDL cholesterol, –0.3±0.3 mmol/L; triglycerides, –0.1±0.9 mmol/L; systolic blood pressure (BP), –9.8±15.5 mmHg; diastolic BP, –6.3±11.1 mmHg. Mean±SD CushingQoL score (including physical problems and psychological issues subscores) improved by 52.4±107.4% and BDI score by –31.8±65.0%. Osilodrostat was generally well tolerated; most common AEs were nausea (42%), headache (34%), fatigue (29%). Hypocortisolism-related AEs were experienced by 51% of patients, occurring mainly during dose titration (W0–12) as a single episode. Anticipated AEs of interest (based on osilodrostat mechanism of action) were manageable; those leading to discontinuation were adrenal insufficiency (n=4 [2.9%]), hypokalaemia, increased diastolic or systolic BP, and electrocardiogram QT prolonged (n=1 [0.7%] each).

Conclusion: Reductions in mUFC during 48 weeks of osilodrostat treatment were accompanied by weight, waist circumference, glucose, and systolic/diastolic BP improvements, as well as improved CushingQoL and BDI scores. Osilodrostat was effective and generally well tolerated, showing promise for the treatment of patients with CD.

Volume 63

21st European Congress of Endocrinology

Lyon, France
18 May 2019 - 21 May 2019

European Society of Endocrinology 

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