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Efficacy and Safety of Osilodrostat in Patients with Cushing's Disease (LINC 3) : a Multicentre Phase III Study with a Doubleblind, Randomised Withdrawal Phase

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Efficacy and Safety of Osilodrostat in Patients with Cushing's Disease (LINC 3) : a Multicentre Phase III Study with a Doubleblind, Randomised Withdrawal Phase This is a repository copy of Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3) : a multicentre phase III study with a doubleblind, randomised withdrawal phase. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/163983/ Version: Accepted Version Article: Pivonello, R., Fleseriu, M., Newell-Price, J. et al. (14 more authors) (2020) Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3) : a multicentre phase III study with a doubleblind, randomised withdrawal phase. The Lancet Diabetes & Endocrinology. ISSN 2213-8587 https://doi.org/10.1016/s2213-8587(20)30240-0 Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can’t change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Pivonello R et al. Lancet Diabetes Endocrinol 2020; doi: S2213‒8587(20)30240-0 https://www.thelancet.com/journals/landia/home Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a Phase III multicentre study with a double­blind, randomised withdrawal phase Rosario Pivonello (MD) ,1 Maria Fleseriu (MD),2 John Newell-Price (MD),3 Xavier Bertagna (MD),4 James Findling (MD),5 Akira Shimatsu (MD),6 Feng Gu (MD),7 Richard Auchus (PhD),8 Rattana Leelawattana (MD),9 Eun Jig Lee (MD),10 Jung Hee Kim (MD),11 André Lacroix (MD),12 Audrey Laplanche (MSc),13 Paul O’Connell (MSc),13 Libuse Tauchmanova (MD),13 Alberto M Pedroncelli (MD)13 and Beverly MK Biller (MD)14 on behalf of the LINC3 investigators* 1Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy; 2Northwest Pituitary Center, Departments of Medicine and Neurological Surgery, 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 5, Paris, France; 5Division of Endocrinology and Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; 6Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan and Advanced Medical Care Center, Kusatsu General Hospital, Kusatsu, 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, Severance Hospital, 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, 1 Basel, Switzerland; 14Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston, MA, USA Corresponding author: Rosario Pivonello, Università Federico II di Napoli, Via Sergio Pansini 5, 80131 Naples, Italy; Tel: +39 3317328474; Fax: +39 081 746 3668; Email: [email protected] *All principal investigators are listed in the supplementary appendix Target journal: Lancet Diabetes Endocrinol Figures/tables: 3/3 References: 28 (max 30) Running title: Randomised withdrawal study of osilodrostat in patients with Cushing’s disease Keywords: LCI699, osilodrostat, 11β-hydroxylase, Cushing’s, cortisol Word count: 6085 Supplementary figures/tables: 7/6 2 Author postal addresses Rosario Pivonello: Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131 Naples, Italy Maria Fleseriu: Northwest Pituitary Center, Oregon Health & Science University, 3303 SW Bond Avenue, CHN8,Portland, OR 97239, USA John Newell­Price: Department of Oncology and Metabolism, The Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK Xavier Bertagna: Department of Endocrinology, Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, Faculté de Médecine Paris Descartes, Université Paris 5, rue de l’école de médecine 75006 Paris, France James Findling: Endocrinology Center and Clinics, W129 N7055 Northfield Drive, A-203, Menomonee Falls, WI 53051, USA Akira Shimatsu: Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan and Advanced Medical Care Center, Kusatsu General Hospital, 525-8585 Shiga, Kusatsu, Japan Feng Gu: Department of Endocrinology, Peking Union Medical College Hospital, No. 1 Shuaifuyuan Wangfujing, Beijing 100730, China Richard Auchus: Division of Metabolism, Endocrinology and Diabetes, Departments of Internal Medicine and Pharmacology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, USA Rattana Leelawattana: Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, 15 Karnjanavanit Road, Hat Yai, Songkhla 90110, Thailand Eun Jig Lee: Pituitary Tumor Center, Severance Hospital, Yonsei University College of Medicine, 107-11 Sinchon-dong, Seodaemun-gu, Seoul 03722, Republic of Korea Jung Hee Kim: Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea André Lacroix: Département de Médecine, Service d’Endocrinologie et Centre de Recherche du CHUM (CRCHUM), Centre hospitalier de ’Universitél de Montréal (CHUM), 3840 Saint-Urbain, Montreal, H2W 1T8, Canada 3 Audrey Laplanche: Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland Paul O’Connell: Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland Libuse Tauchmanova: Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland Alberto M Pedroncelli: Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland Beverly MK Biller: Neuroendocrine Unit – BULF 457B, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA 4 Abstract Background: Cushing’s disease is a rare endocrine disorder characterised by cortisol overproduction, with severe complications. Therapies for cortisol reduction are often necessary. Outcomes from the pivotal Phase III study of osilodrostat (new, potent oral 11β-hydroxylase inhibitor) in Cushing’s disease patients (LINC 3; NCT02180217) are reported. Methods: LINC 3 (prospective, multicentre study) comprised four periods. Cushing’s disease patients with mean urinary free cortisol (mUFC)>1·5xULN were enrolled. Period 1: open-label osilodrostat was initiated and adjusted every 2 weeks (1–30mg twice daily) based on mUFC and safety until week (W)12. Period 2 (W13–24): osilodrostat was continued at the therapeutic dose determined during period 1. Period 3 (W26): 71 eligible participants (mUFC≤ULN at W24 without up-titration after W12) were randomised (1:1 via interactive-response technology; double blind, stratified by osilodrostat dose at W24 and history of pituitary irradiation) to continue osilodrostat (n=36) or switch to placebo (n=35) for 8 weeks. Ineligible participants continued open-label osilodrostat. Period 4: all participants then received open-label osilodrostat until core-study end (W48). Primary objective: compare osilodrostat efficacy versus placebo at end of period 3. Primary endpoint: proportion of randomised participants with mUFC≤ULN at end of randomised withdrawal (W34), without up-titration during this period. Findings: 137 patients were enrolled. The primary objective was met: more patients maintained mUFC≤ULN with osilodrostat versus placebo at W34 (86·1% vs 29·4%; OR 13·7 [95%CI 3·7,53·4], P<0·001). At W24, 72/137 (52·6%; 95%CI 43·9,61·1) patients maintained mUFC≤ULN without up-titration after W12. At W48, 66·4% of enrolled patients had mUFC≤ULN. Most common adverse events (>25% of all patients): nausea (n=57, 41·6%), headache (n=46, 33·6%), fatigue (n=39, 28·5%), and adrenal insufficiency (n=38, 27·7%). Hypocortisolism and adverse events related to adrenal hormone precursors occurred in 70 (51·1%) and 58 (42·3%) patients, respectively. 5 Interpretation: Osilodrostat is an effective new treatment option for Cushing’s disease patients. Funding: Novartis Pharma AG. Word count: 300 (max 300) 6 Introduction Cushing’s disease is a rare, serious disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumour, which stimulates the adrenal glands to overproduce cortisol.1 Excess cortisol leads to an increased mortality risk largely driven by cardiovascular disease and infections.2,3 First-line treatment for most patients is transsphenoidal surgery.4 However, additional second-line treatments are often needed as persistent or recurrent Cushing’s disease after surgery has been documented in approximately one-third of patients.2 For these patients or in cases where surgery or radiotherapy are not possible, medical therapies
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