ECE2020 Oral Communications Pituitary and Neuroendocrinology (7 abstracts)
Durability of response and gender-based analysis from the LINC3 trial of osilodrostat in the treatment in cushing’s disease
Rosario Pivonello 1 , Maria Fleseriu 2 , John Newell-Price 3 , Bertagna Xavier 4 , Findling James 5 , Shimatsu Akira 6 , Gu Feng 7 , Auchus Richard 8 , Leelawattana Rattana 9 , Eun Jig Lee 10 , Jung Hee Kim 11 , Lacroix Andre 12 & Beverly Biller 13
1Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy, Naples, Italy; 2Northwest Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, Portland, OR, United States, Portland, United States; 3The Medical School, University of Sheffield, Sheffield, United Kingdom; 4Department of Endocrinology, Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, Faculté de Médecine Paris Descartes, Université Paris 5, Paris, France, Paris, France; 5Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA, Milwaukee, United States; 6Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan and Advanced Medical Care Center, Kusatsu General Hospital, Kusatsu, Japan, Kusatsu, Japan; 7Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China, Bejing, China; 8Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA, Ann Arbor, United States; 9Prince of Songkla University, Kho Hong, Thailand; 10Pituitary Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea, Seoul, Korea, Democratic People’s Republic of Korea; 11Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea, Seoul, Korea, Democratic People’s Republic of Korea; 12CHUM, Montréal, Canada; 13Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston, MA, USA, Boston, United States
Introduction: In a Phase II study, osilodrostat, a potent oral 11β-hydroxylase inhibitor, normalized mean urinary free cortisol (mUFC) in most patients with CD. We report the efficacy and safety of osilodrostat in a large CD patient population (NCT02180217).
Methods: In this study, open-label osilodrostat was initiated at 2 mg bid in 137 adults with CD and mUFC > 1.5 × ULN, with dose adjustments every 2 weeks (range 1–30 mg bid) up to W12. At W26, patients achieving mUFC ≤ ULN at W24 without a dose increase after W12 (n = 71) were randomized to continue osilodrostat (n = 36) or matching placebo (n = 35) for 8 weeks, followed by open-label osilodrostat until W48. Patients ineligible for randomization continued open-label osilodrostat (n = 47). The primary endpoint was mUFC ≤ ULN at the end of the randomized withdrawal phase (W34) without a dose increase after W26.
Results: At baseline, median (range) mUFC was 3.5 × ULN (0.3–69.6). At W34, significantly more patients in the osilodrostat group maintained mUFC ≤ ULN (without a dose increase after W26) than in the placebo group (86% vs 29%; OR 13.7, P < 0.001). At W24, 53% of enrolled patients had mUFC ≤ ULN without a dose increase after W12. At W48, 66% of enrolled patients had mUFC ≤ ULN and 96% of enrolled patients had mUFC ≤ ULN at least once during the study, with a median time to first mUFC ≤ ULN of 41 days and no differences observed between males and females. In addition, 64/97 (66 × 0%) patients maintained normal mUFC for ≥6 months after the first mUFC normalization. By week 24, 72⋅2% were receiving an osilodrostat dose of ≤ 5 mg bid, irrespective of mUFC elevation at baseline. Median (range) duration of osilodrostat exposure was 75 weeks (1–165). By W48, 24 (18%) patients had discontinued the study, 15 (11%) because of adverse events (AEs). Overall, the most common AEs were nausea (42%), headache (34%), and fatigue (28%). AEs related to hypocortisolism and adrenal-hormone-precursor accumulation occurred in 51% and 42% of patients, respectively. No males experienced signs or symptoms related to increases in androgens or oestrogens. In females, AEs of hirsutism (8⋅8%), acne (8⋅8%), and hypertrichosis (0⋅7%) were reported, all grade 1–2, and none leading to study discontinuation.
Conclusion: Osilodrostat was significantly superior to placebo at maintaining mUFC ≤ ULN after randomized withdrawal, and normalized mUFC in two-thirds of enrolled patients at W48, with few patients discontinuing treatment because of AEs. This study demonstrates osilodrostat to be a highly effective treatment for CD, with good tolerability.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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