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.
Duchenne muscular dystrophy, idebenone, respiratory function, peak expiratory flow, glucocorticoid steroid
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.
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.
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.
May 25, 2015 Accepted
June 29, 2015
Gunnar M Buyse, Child Neurology, University Hospitals Leuven, Herestraat 49, B – 3000 Leuven, Belgium. E: firstname.lastname@example.org
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 lifechanging 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 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
In the absence of obstructive pulmonary disease, FVC (measured in litres), peak expiratory flow (PEF, measured in l/minute), and forced expiratory volume in 1 second (FEV1, measured in litres) are major interrelated spirometry measures reflecting both inspiratory and expiratory muscle force impairment and restrictive lung volume changes due to neuromuscular weakness. In DMD both inspiratory and expiratory respiratory weakness is indicated by abnormal flow-volume curves (see Figure 1).
FVC is used to assess respiratory muscle involvement in many neuromuscular diseases, such as DMD. One may infer the presence of a restrictive ventilatory defect due to neuromuscular weakness when the FVC is reduced and the FEV1/FVC ratio is normal or increased. Previous studies have shown excellent test–retest reliability of FVC among DMD subjects. However, a limitation of FVC as a respiratory endpoint in DMD is that it is potentially affected by thoracic wall compliance/ fibrosis and thoracic deformities resulting from progressive scoliosis. FEV1 typically follows the decline measured in FVC. In the absence of obstructive pulmonary disease such as asthma, FEV1 is also an indicator of respiratory impairment due to neuromuscular weakness of combined inspiratory and expiratory weakness.
In DMD patients who do not exhibit bronchial obstruction, PEF reflects expiratory muscle force.5 Abnormal respiratory mechanics in DMD are not limited to the lung and chest wall and may also involve the upper airways.6 Therefore, respiratory strength in DMD (assessed by PEF) is a measure not only of expiratory strength but also inspiratory effort and upper airway resistance, which are both abnormal in DMD.11,12 There is a theoretical possibility that PEF may be more sensitive to a treatment intervention than FVC due to the impact of fibrosis and chest wall deformities on FVC. All three of these measures – PEF, FVC and FEV1 – can be obtained with high reliability in DMD patients older than ~8 years.
As respiratory function tests are influenced by body growth and age, these measures are typically normalised to height-matched (PEF)13 or height- and age-matched (FVC and FEV1)14 normative populations and expressed as ‘per cent predicted’ values (PEF%p, FVC%p, FEV1%p).
Recent care guidelines recommend changes in DMD disease management as soon as patients fall below certain thresholds in FVC.2,15–17 For example, preoperative training prior to surgical procedures and post-operative use of non-invasive ventilation should be strongly considered for patients with FVC <50 %p, and is necessary for patients with FVC <30 %p. Various levels of impairment of FVC have been reported to be prognostically associated with an increased risk of respiratory complications and death in DMD.15,18
1. Bushby K, Finkel R, Birnkrant DJ, et al., Diagnosis and
management of Duchenne muscular dystrophy, part
1: diagnosis, and pharmacological and psychosocial
management, Lancet Neurol, 2010;9:77–93.
2. Bushby K, Finkel R, Birnkrant DJ, et al., Diagnosis and
management of Duchenne muscular dystrophy, part 2:
implementation of multidisciplinary care, Lancet Neurol,
3. McDonald CM, Abresch RT, Carter GT, Profiles of neuromuscular
diseases, Am J Phys Med Rehabil, 1995;74: S70–S94.
4. Hahn A, Bach JR, Delaubier A, et al., Clinical implications of
maximal respiratory pressure determinations for individuals
with Duchenne muscular dystrophy, Arch Phys Med Rehabil,
5. Suárez AA, Pessolano FA, Monteiro SG, et al., Peak flow
and peak cough flow in the evaluation of expiratory
muscle weakness and bulbar impairment in patients
with neuromuscular disease, Am J Phys Med Rehabil,
6. Vincken WG, Elleker MG, Cosio MG, Flow-volume loop
changes reflecting respiratory muscle weakness in chronic
neuromuscular disorders, Am J Med, 1987;83:673–80.
7. Griggs RC, The use of pulmonary function testing as a
quantitative measurement for therapeutic trials, Muscle &
8. Inkley SR, Oldenburg FC, Vignos PJ, Pulmonary function in
Duchenne muscular dystrophy related to stage of disease,
Am J Med, 1974;56:297–306.
9. Rideau Y, Jankowski LW, Grellet J, Respiratory function in the
muscular dystrophies. Muscle & Nerve, 1981;4:155–64.
10. Khan Y, Heckmatt JZ, Obstructive apnoeas in Duchenne
muscular dystrophy, Thorax, 1994;49:157–61.
11. Tzelepis GE, Zakynthinos S, Vassilakopoulos T, et al.,
Inspiratory maneuver effects on peak expiratory flow: Role of
lung elastic recoil and expiratory pressure, Am J Respir Crit
Care Med, 1997;156:1399–404.
12. Humbertclaude V, Hamroun D, Bezzou K, et al., Motor and
respiratory heterogeneity in Duchenne patients: Implication
for clinical trials, Eur J Paediatr Neurol, 2012;16:149–60
13. Quanjer PH, Stocks J, Polgar G, et al., Compilation of reference
values for lung function measurements in children, Eur Respir
J Suppl, 1989;Suppl. 4:184S–261S.
14. Hankinson IL, Odencrantz JR, Fedan KB, Spirometric reference
values from a sample of the general U.S. population, Am J
Respir Crit Care Med, 1999;159:179–87.
15. Finder JD, Birnkrant D, Carl J, et al., Respiratory care of the
patient with Duchenne muscular dystrophy: ATS consensus
statement, Am J Respir Crit Care Med, 2004;170:456–65.
16. Birnkrant DJ, Panitch HB, Benditt JO, et al., American College
of Chest Physicians consensus statement on the respiratory
and related management of patients with Duchenne
muscular dystrophy undergoing anesthesia or sedation,
17. Birnkrant DJ, Bushby KMD, Amin RS, et al., The respiratory
management of patients with Duchenne muscular dystrophy:
A DMD care considerations working group specialty article,
Pediatr Pulmonol, 2010;45:739–48.
18. Phillips MF, Quinlivan RCM, Edwards RHT, Calverley PM,
Changes in spirometry over time as a prognostic marker in
patients with Duchenne muscular dystrophy, Am J Respir Crit
Care Med, 2001;164:2191–4.
19. Pelligrino R, Viegi G, Bruscasco RO, et al., Interpretative
strategies for lung function tests, Eur Respir J, 2005;26:948–68
20. Becklake MR, Helms R, Lebowitz MD, et al., NHLBI workshop
summary. Longitudinal analysis in pulmonary disease
epidemiology, Am Rev Respir Dis, 1988;137:1241–3.
21. Kanner RE, Renzetti AD, Stanish WM, et al., Predictors of
survival in subjects with chronic airflow limitation, Am J Med,
22. Traver GA, Cline MG, Burrows B, Predictors of mortality in
chronic obstructive pulmonary disease. A 15-year follow-up
study, Am Rev Respir Dis, 1979;119:895–902.
23. Anthonisen NR, Wright EC, Hodgkin JE, Prognosis in
chronic obstructive pulmonary disease, Am Rev Respir Dis,
24. Hukins CA, Hillmann DR, Daytime predictors of sleep
hypoventilation in Duchenne Muscular Dystrophy, Am J Respir
Crit Care Med, 2000;161:166–70.
25. Gauld LM, Boynton A, Relationship between peak cough flow
and spirometry in Duchenne muscular dystrophy, Pediatr
26. Bach JR, Ishikawa Y, Kim H, Prevention of pulmonary
morbidity for patients with Duchenne muscular dystrophy,
27. Tzeng AC, Bach JR, Prevention of pulmonary morbidity for
patients with neuromuscular disease, Chest, 2000;118:1390–6.
28. Abresch RT, McDonald CM, Henricson EK, et al., Pulmonary
function characteristics of boys with Duchenne Muscular
Dystrophy : Data from the CINRG longitudinal study project,
Neuromuscul Disord, 2013;23:802.
29. Mayer OH, Finkel RS, Rummey C, et al., Characterization of
pulmonary function in Duchenne Muscular Dystrophy,
Pediatr Pulmonol, 2015;50:487–94.
30. Moxley RT, Ashwal S, Pandya S, et al., Practice parameter:
corticosteroid treatment of Duchenne dystrophy: report
of the Quality Standards Subcommittee of the American
Academy of Neurology and the Practice Committee of the
Child Neurology Society, Neurology, 2005;64:13–20.
31. Biggar WD, Gingras M, Fehlings DL, Deflazacort treatment of
Duchenne muscular dystrophy, J Pediatr, 2001;138:45–50.
32. Henricson EK, Abresch RT, Cnaan A, et al., The cooperative
international neuromuscular research group Duchenne
natural history study: Glucocorticoid treatment preserves
clinically meaningful functional milestones and reduces
rate of disease progression as measured by manual muscle
testing and other commonly used clinical trial outcome
measures, Muscle & Nerve, 2013:48:55–67.
33. Biggar W D, Harris V, Eliasoph L, Long-term benefits of
deflazacort treatment for boys with Duchenne muscular
dystrophy in their second decade. Neuromuscul Disord,
34. King WM, Ruttencutter R, Nagaraja HN, et al., Orthopedic
outcomes of long-term daily corticosteroid treatment in
Duchenne muscular dystrophy, Neurology, 2007;68:1607–13.
35. Manzur A, Kuntzer T, Pike M, Swan A, Glucocorticoid
corticosteroids for Duchenne muscular dystrophy, Cochrane
Database Syst Rev, 2008;1:1–72.
36. Connolly AM, Schierbecker J, Renna R, Florence J, High
dose weekly oral prednisone improves strength in boys
with Duchenne muscular dystrophy, Neuromuscul Disord,
37. Abresch RT, McDonald CM, Henricson EK, et al., Pulmonary
function characteristics of boys with Duchenne Muscular
Dystrophy by age groups, ambulatory status and steroid use,
Neuromuscul Disord, 2013;23:801–2.
38. Cardoso SM, Pereira C, Oliveira R, Mitochondrial function is
differentially affected upon oxidative stress, Free Radic Biol
Med, 1999;26 3–13.
39. Brookes PS, Yoon Y, Robotham JL, et al., Calcium, ATP, and
ROS: a mitochondrial love-hate triangle, Am J Physiol Cell
40. Peng TI, Jou MJ, Oxidative stress caused by mitochondrial
calcium overload, Ann N Y Acad Sci, 2010;1201: 183–188.
41. Dunn JF, Radda GK, Total ion content of skeletal and cardiac
muscle in the mdx mouse dystrophy: Ca2+ is elevated at all
ages, J Neurol Sciences, 1991;103:226–31.
42. Culligan K, Ohlendieck K, Abnormal calcium handling in
muscular dystrophy, Basic Appl Myol, 2002;12: 147–157.
43. Scholte HR, Luyt-Houwen I, Bush H, Jennekens F, Muscle
mitochondria from patients with Duchenne muscular
dystrophy have a normal beta oxidation, but an impaired
oxidative phosphorylation, Neurology, 1985;35:1396–7.
44. Lucas-Heron B, Schmitt N, Ollivier B, Muscular dystrophy:
possible role of mitochondrial deficiency in muscle
degeneration processes, J Neurol Sci, 1990;95:327–34.
45. Even PC, Decrouy A, Chinet A. Defective regulation of energy
metabolism in mdx-mouse skeletal muscles, Biochem J,
46. Sperl W, Skladal D, Gnaiger E, et al., High resolution
respirometry of permeabilized skeletal muscle fibers in the
diagnosis of neuromuscular disorders, Mol Cell Biochem,
47. Kuznetsov AV, Winkler K, Wiedemann FR, Impaired
mitochondrial oxidative phosphorylation in skeletal muscle
of the dystrophin-deficient mdx mouse, Mol Cell Biochem,
48. Passaquin AC, Renard M, Kay L, Creatine supplementation
reduces skeletal muscle degeneration and enhances
mitochondrial function in mdx mice, Neuromuscul Disord,
49. Onopiuk M, Brutkowski W, Wierzbicka K, et al., Mutation
in dystrophin-encoding gene affects energy metabolism
in mouse myoblasts, Biochem Biophys Res Commun,
50. Godin R, Daussin F, Matecki S, et al., Peroxisome proliferatoractivated
receptor γ coactivator1- gene α transfer restores
mitochondrial biomass and improves mitochondrial calcium
handling in post-necrotic mdx mouse skeletal muscle,
J Physiol, 2012;590:5487–502.
51. Schuh RA, Jackson KC, Khairallah RJ, et al., Measuring
mitochondrial respiration in intact single muscle fibers, Am J
Physiol Regul Integr Comp Physiol, 2012;302:R712–R719.
52. Percival JM, Siegel MP, Knowels G, Marcinek DJ, Defects in
mitochondrial localization and ATP synthesis in the mdx mouse
model of Duchenne muscular dystrophy are not alleviated
by PDE5 inhibition, Hum Mol Genet, 2013;22:153–67.
53. Cole M., Rafael J, Taylor DJ, et al., A quantitative study of
bioenergetics in skeletal muscle lacking utrophin and
dystrophin, Neuromuscul Disord, 2002;12:247–57.
54. Rybalka E, Timpani CA, Cooke MB, et al., Defects in
mitochondrial ATP synthesis in dystrophin-deficient mdx
skeletal muscles may be caused by Complex I insufficiency,
PLoS ONE, 2014;9:e115763.
55. Millay DP, Sargent MA, Osinska H, et al., Genetic and
pharmacologic inhibition of mitochondrial-dependent
necrosis attenuates muscular dystrophy, Nature Medicine,
56. Selsby JT, Morine KJ, Pendrak K, et al., Rescue of dystrophic
skeletal muscle by PGC-1alpha involves a fast to slow fiber
type shift in the mdx mouse, PLoS ONE, 2012;7:e30063.
57. Chen YW, Zhao P, Borup R, Hoffman EP, Expression profiling in
the Muscular Dystrophies: Identification of novel aspects of
molecular pathophysiology, J Cell Biol, 2000;151:1321–36.
58. Timmons JA, Larsson O, Jansson E, et al., Human muscle gene
expression responses to endurance training provide a novel
perspective on Duchenne Muscular Dystrophy.
FASEB J, 2005;19:750–60.
59. Gueven N, Woolley K, Smith J, Border between natural
product and drug: Comparison of the related benzoquinones
idebenone and coenzyme Q10, Redox Biology, 2015;4:289–95.
60. Jaber S, Polster BM, Idebenone and neuroprotection:
antioxidant, pro-oxidant, or electron carrier?, J Bioenerg
61. Rauchová H, Vrbacký M, Bergamini C, et al., Inhibition of
glycerophosphate-dependent H2O2 generation in brown fat
mitochondria by idebenone, Biochem Biophys Res Commun,
62. Haefeli R H, Erb M, Gemperli AC, et al., NQo1-dependent
redox cycling of idebenone: Effects on cellular redox potential
and energy levels, PLoS ONE, 2011;6.
63. Giorgio V, Petronilli V, Ghelli A, et al., The effects of idebenone
on mitochondrial bioenergetics, Biochim Biophys Acta,
64. Erb M, Hoffmann-Enger B, Deppe H, et al., Features of
idebenone and related short-chain quinones that rescue ATP
levels under conditions of impaired mitochondrial complex I,
PLoS ONE 2012;7.
65. Mordente A, Martorana GE, Minotti G, Giardina B, Antioxidant
Properties of 2 , 3-Dimethoxy-5-methyl- 6- (10-hydroxydecyl)
-1 , 4-benzoquinone (Idebenone), Chem Res Toxicol,
66. Gil J, Almeida S, Oliveira CR, Rego AC, Cytosolic and
mitochondrial ROS in staurosporine-induced retinal cell
apoptosis, Free Radic Biol Med, 2003;35:1500–14.
67. Buyse GM, Van Der Mieren G, Erb M, et al., Long-term
blinded placebo-controlled study of SNT-MC17/idebenone
in the dystrophin deficient mdx mouse: Cardiac protection
and improved exercise performance, Eur Heart J,
68. Buyse GM, Goemans N, van den Hauwe M, et al., Idebenone
as a novel, therapeutic approach for Duchenne muscular
dystrophy: Results from a 12 month, double-blind,
randomized placebo-controlled trial, Neuromuscul Disord,
69. Buyse GM, Voit T, Schara U, et al., Efficacy of idebenone on
respiratory function in patients with Duchenne muscular
dystrophy not using glucocorticoids (DELOS): a doubleblind
randomised placebo-controlled phase 3 trial, Lancet,
70. Buyse GM, Goemans N, Van Den Hauwe M, Meier T, Effects
of glucocorticoids and idebenone on respiratory function
in patients with duchenne muscular dystrophy, Pediatric
Duchenne muscular dystrophy, idebenone, respiratory function, peak expiratory flow, glucocorticoid steroid