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Neuromuscular Disorders Idebenone as a Novel Therapeutic Approach for Duchenne Muscular Dystrophy Gunnar M Buyse, 1 Nuri Gueven 2 and Craig M McDonald 3 1. University Hospitals Leuven, Leuven, Belgium; 2. Pharmacy, School of Medicine, University of Tasmania, Hobart, Australia; 3. University of California Davis Medical Center, Sacramento, US Abstract Progressive loss of pulmonary function leads to early morbidity and mortality in Duchenne muscular dystrophy (DMD) due to both expiratory impairment with ineffective airway clearance, and inspiratory impairment leading to nocturnal and daytime hypoventilation and respiratory failure. Glucocorticoid steroids have become a mainstay of DMD therapy with well-documented efficacy on muscle strength and respiratory function. However, the side-effect profile restricts their long-term use, particularly in non-ambulant patients. Idebenone improves secondary mitochondrial dysfunction caused by dystrophin deficiency, intracellular calcium accumulation and increased reactive oxygen species (ROS). Idebenone-mediated improved bioenergetics leads to enhanced adenosine triphosphate (ATP) production and reduced ROS. Based on this rationale, idebenone has been investigated clinically for efficacy on reducing respiratory function decline in exploratory phase II (DELPHI) and confirmatory phase III (DELOS) trials. Idebenone significantly reduced the loss of respiratory function in 8–18-year-old DMD patients who were not using concomitant glucocorticoids. These results indicate that idebenone can modify the natural course of respiratory disease progression in DMD, which is relevant in clinical practice where loss of respiratory function continues to be a predominant cause of early morbidity and mortality in DMD. Keywords Duchenne muscular dystrophy, idebenone, respiratory function, peak expiratory flow, glucocorticoid steroid Disclosure: Gunnar M Buyse, Nuri Gueven and Craig M McDonald act as scientific consultants to Santhera Pharmaceuticals (Switzerland). Gunnar M Buyse was an investigator for clinical trials in Duchenne muscular dystrophy sponsored by GlaxoSmithKline, Prosensa and Santhera Pharmaceuticals and is Senior Clinical Investigator of the Research Foundation Flanders (FWO Vlaanderen, Belgium). He also is inventor of relevant patent applications. Craig M McDonald consulted on Duchenne muscular dystrophy clinical trials for Akashi Therapeutics, Biomarin, Bristol Myers Squibb, Cardero Therapeutics, Eli Lilly, Gilead, Italfarmaco, Mitobridge, Novartis, Pfizer, Prosensa, PTC Therapeutics, Santhera Pharmaceuticals and Sarepta Therapeutics. Compliance with Ethics: The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors. Acknowledgements: The authors thank the DELOS Study Group and all Duchenne muscular dystrophy patients and families who participated in the DELPHI and DELOS trials, Christian Rummey and Mika Leinonen (4Pharma, Switzerland and Sweden) for statistical analyses, Thomas Meier (Santhera Pharmaceuticals, Switzerland) for contributing to the manuscript and support in the preparation of figures and tables and Anna Carratu for editorial support. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 23 May 2015 Accepted: 29 June 2015 Citation: European Neurological Review, 2015;10(2):189–94 Correspondence: Gunnar M Buyse, Child Neurology, University Hospitals Leuven, Herestraat 49, B – 3000 Leuven, Belgium. E: Support: Santhera Pharmaceuticals was the sponsor of the DELPHI and DELOS trials and supported this publication. Respiratory Function Loss and Respiratory Endpoints in DMD Duchenne muscular dystrophy (DMD) is the most common and devastating type of muscular dystrophy. Lack of the protein dystrophin causes severe and progressive myofibre degeneration, general muscle weakness and wasting. With increasing age, DMD patients are confronted with loss of ambulation, loss of upper limb function, cardiac dysfunction and dependence on mechanical airway clearance and mechanical assisted ventilation representing irreversible and life- changing events of disease progression. Although early diagnosis and multi-stage disease management regimes (e.g. Bushby et al.) 1,2 increase quality of life and life expectancy, the disease is still associated with early morbidity and mortality. In DMD, progressive weakness of the chest wall muscles precedes weakness of the diaphragm (used predominantly for inspiratory function) and leads to restrictive lung volume changes TOU CH MED ICA L MEDIA measured as reduced total lung capacity and forced vital capacity (FVC). 3–7 Initially, this loss of lung volume results from the inability to pull up the respiratory system to total lung capacity and to push it down to residual volume. In later disease stages, additional restrictions occur as a result of progressing muscle fibrosis and changes in lung and chest wall recoil, thoracic wall compliance and spinal deformities (i.e. scoliosis). In the late first decade the earliest signs of respiratory impairment manifest by reduced static airway pressures (maximal expiratory and inspiratory pressures). The gradual loss of respiratory function in DMD measured by spirometry usually begins early in the second decade and progresses to restrictive pulmonary syndrome, impaired respiratory secretion clearance, life-threatening pulmonary infections due to ineffective cough, nocturnal and daytime hypoventilation, obstructive apnoeas and eventually respiratory failure during the late second or third decade of life. 3,8–10 189