Advances in Pulmonary Care in Duchenne Muscular Dystrophy

US Neurology, 2017;13(1):35–41 DOI: https://doi.org/10.17925/USN.2017.13.01.35

Abstract:

Duchenne muscular dystrophy (DMD) is a degenerative neuromuscular disease leading to progressive muscle weakness and loss. This review discusses advances in understanding the natural history of DMD, as well as recent pharmacotherapies. Decline in expiratory and inspiratory pulmonary function results in ineffective airway clearance, sleep-disordered breathing and nocturnal and daytime respiratory failure. Routine measures of pulmonary function include forced vital capacity (FVC) and peak expiratory flow (PEF). Both measures follow parallel trajectories and relentlessly decline, reaching the lower limit of normal of 80% of predicted at early teenage years. Moreover, decline in PEF and FVC are closely correlated with respiratory complications and clinically relevant thresholds for FVC are defined in standard of care recommendations. Glucocorticoids (GCs) delay the onset of pulmonary function decline, but once patients have reached the 80% of predicted threshold the decline of FVC and PEF in GC users and patients not using GCs is comparable. In the successful phase III DELOS trial in DMD patients not using GCs, the short-chain benzoquinone idebenone (Raxone® , Santhera Pharmaceuticals, Liestal, Switzerland) has demonstrated statistically significant and clinically relevant efficacy on expiratory and inspiratory function in patients in the pulmonary function decline stage. These results indicate that idebenone can modify the natural course of respiratory disease progression, 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, glucocorticoids, idebenone, pulmonary function, peak expiratory flow, forced vital capacity
Disclosure: All authors act as scientific consultants and advisors to Santhera Pharmaceuticals (Switzerland). Oscar H Mayer has additional consulting relationships with Bristol-Myers Squib, Marathon Pharmaceuticals, Catabasis Pharmaceuticals, Sarepta Pharmaceuticals, Fibrogen, Biogen, AveXis and Hoffman-LaRoche, and is an investigator in the SIDEROS trial. Erik K Henricson is study co-chair of the CINRG Duchenne natural history study and has served as a scientific consultant for Bristol Myers Squibb, PTC Therapeutics and Genzyme, Inc. He received travel assistance from Parent Project Muscular Dystrophy (USA). Craig M McDonald is study co-chair of the CINRG Duchenne natural history study and has served as a consultant for PTC, Prosensa, Sarepta, Eli Lilly, Pfizer, Halo Therapeutics, Cardero and Mitokyne, and serves on external advisory boards related to DMD for PTC and Eli Lilly. Gunnar M Buyse was investigator for clinical trials in Duchenne muscular dystrophy sponsored by Santhera Pharmaceuticals, Prosensa and GlaxoSmithKline, and is senior clinical investigator of the Research Foundation Flanders (FWO Vlaanderen, Belgium). He is also the inventor of relevant patent applications.
Acknowledgments: Medical writing assistance was provided by Katrina Mountfort at Touch Medical Media, London and funded by Santhera Pharmaceuticals. The authors thank Mika Leinonen (Santhera Pharmaceuticals, Switzerland) for statistical analyses and Thomas Meier (Santhera Pharmaceuticals, Switzerland) for contributing to the manuscript and supporting the preparation of analyses, figures and tables. Santhera Pharmaceuticals is the sponsor of the DELPHI, DELOS and SIDEROS trials and supported this publication.

Investigators of the Cooperative International Neuromuscular Research Group (CINRG): V Vishwanathan, S Chidambaranathan, W Douglas Biggar, Laura C McAdam, Jean K Mah, Mar Tulinius, Avital Cnaan, Lauren P Morgenroth, Robert Leshner, Carolina Tesi-Rocha, Mathula Thangarajh, Tina Duong, Andrew Kornberg, Monique Ryan, Yoram Nevo, Alberto Dubrovsky, Paula R Clemens, Hoda Abdel-Hamid, Anne M Connolly, Alan Pestronk, Jean Teasley, Tulio E Bertorini, Richard Webster, Hanna Kolski, Nancy Kuntz, Sherilyn Driscoll, John B Bodensteiner, Jose Carlo, Ksenija Gorni, Timothy Lotze, John W Day, Peter Karachunski, Erik K Henricson, Richard T Abresch and Craig M McDonald (for updated affiliations, see online version at www.ncbi.nlm.nih.gov/pubmed/28139640).

Investigators of the DELOS study group (sorted by country): Austria: G Bernert, F Knipp (Vienna). Belgium: GM Buyse, N Goemans, M Van den Hauwe (Leuven). France: T Voit, V Doppler, T Gidaro (Paris); J-M Cuisset, S Coopman (Lille). Germany: U Schara, S Lutz (Essen); J Kirschner, S Borell, M Will (Freiburg). Italy: MG D’Angelo, E Brighina, S Gandossini (Lecco); K Gorni, E Falcier (Milan); L Politano, P D'Ambrosio, A Taglia (Naples). The Netherlands: JJGM Verschuuren, CSM Straathof (Leiden). Spain: JJ Vílchez Padilla, N Muelas Gómez (Valencia). Sweden: T Sejersen, M Hovmöller (Stockholm). Switzerland: P-Y Jeannet, C Bloetzer (Lausanne). USA: S Iannaccone, D Castro (Dallas); G Tennekoon, R Finkel, C Bönnemann (Philadelphia); C McDonald, E Henricson, N Joyce (Sacramento); S Apkon, RC Richardson (Seattle).

Authorship:All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

Received: February 07, 2017 Accepted March 13, 2017
Correspondence: Oscar H Mayer, Division of Pulmonology, The Children's Hospital of Philadelphia, 11309 Colket Center, 3510 Civic Center Boulevard, Philadelphia, PA 19104, US. E: MAYERO@email.chop.edu
Support: The publication of this article was supported by Santhera Pharmaceuticals. The views and opinions expressed are those of the authors and do not necessarily reflect those of Santhera Pharmaceuticals.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.

Duchenne muscular dystrophy (DMD), the most common and devastating type of muscular dystrophy,1 is characterised by the absence of the protein dystrophin, which causes premature muscle cell failure and leads to progressive muscle atrophy and loss. The condition is typically diagnosed at age 3–5 years when children start to show signs of physical disability including difficulty in walking. Patients experience progressive muscle weakness and become non-ambulant in early teenage years.2 From the age of 10–12 years, pulmonary function typically starts to decline3–5 and cardio-pulmonary complications are the major cause of morbidity and early mortality in DMD.6 Progressive pulmonary insufficiency requires the use of non-invasive and, in some circumstances, invasive ventilation, which, following the loss of ambulation, is the second irreversible disease milestone in DMD greatly impacting the patients’ quality of life. Although standard of care recommendations, including recommendations to monitor pulmonary function, have been proposed,2,6–8 overall compliance with these recommendations generally appears to be poor in real-world DMD care.9

DMD patients and their caregivers consider the preservation of pulmonary function, particularly maintaining effective cough and reducing the risk of airway infections, an important treatment goal,10 which at the current time represents a significant unmet need.

The aim of this review is to provide an update on advances in the understanding of DMD, its natural history and recent pharmacotherapies. We will summarize advances in the understanding of pulmonary function assessment in patients with DMD and the natural course of pulmonary function decline. We will also report clinically relevant thresholds of pulmonary morbidity in the context of standard of care recommendations. Finally, we will review the effects of glucocorticoids (GCs) on pulmonary function outcomes and present emerging evidence that the investigational drug idebenone can slow the loss of pulmonary function in DMD patients.

Assessment of pulmonary function in patients with Duchenne muscular dystrophy
Serial assessment of pulmonary function is a critical element of routine monitoring for patients with DMD, as it may enable early identification and treatment of pulmonary complications. In the absence of obstructive pulmonary disease, forced vital capacity (FVC, measured in litres), peak expiratory flow (PEF, measured in litres/minute), and forced expiratory volume in 1 second (FEV1, measured in litres) are well-established dynamic spirometry measures useful in the assessment of restrictive pulmonary function changes due to neuromuscular weakness. In DMD, both inspiratory and expiratory respiratory muscle weakness can be indicated by low peak inspiratory and expiratory flows.5,11 As pulmonary function is influenced by body growth and age, these measures are typically normalised relative to height and age12,13 and expressed as a percent of predicted (PEF%p, FVC%p, FEV1%p). As assessment of standing height in patients with DMD could be complicated by an inability to stand fully erect, scoliosis and joint contractures (particularly in non-ambulant patients), height can be estimated from ulna length measures.14,15 Although effort dependent, FVC%p and PEF%p can reliably be measured in school-age patients as shown by low within-subject coefficients of variation (CV) for successive measures.16

Natural course of pulmonary function decline in Duchenne muscular dystrophy
Two recent prospective studies investigated the natural course of pulmonary function loss in DMD. The Cooperative International Neuromuscular Research Group (CINRG) Duchenne natural history study (DNHS) is an ongoing, prospective international natural history study and currently represents the most comprehensive description of a longitudinal observational cohort of DMD subjects.4,17 Independently, prospective data in DMD patients were collected in the Neuromuscular Clinic at the Children’s Hospital of Philadelphia from 2005–2010 as part of an Institutional Review Board approved United Dystrophinopathy Project (UDP) cohort study.5

As Figure 1 from the CINRG-DNHS data set shows, flow-related PEF%p and volume-related FVC%p decline in a similar pattern, with decline in PEF%p slightly preceding the decline in FVC%p. At around 10–11 years of age, both parameters fall below the 80% predicted threshold, which is generally defined as the lower limit of normal and defines restrictive respiratory disease or low lung volume.7 From the 80% threshold, both PEF%p and FVC%p follow a co-linear decline, approaching a floor of approximately 20% of predicted from age 20 onwards.

This parallel and tightly correlated decline between FVC%p and PEF%p from early teenage years was independently reported from the data set collected at the Neuromuscular Clinic at the Children’s Hospital of Philadelphia.5

From this and other data collections, yearly rates of absolute decline in FVC%p and PEF%p can be extracted (Table 1). Although not directly comparable due to differences in age, GC-use status and other factors at time of assessment, these data indicate a yearly decline well above 5% absolute for both pulmonary function test (PFT) measures.

Correlation between pulmonary function and general disease stage in Duchenne muscular dystrophy
It would be of clinical relevance if loss of pulmonary function could be predicted from or at least correlated with the general disease stage of DMD. As seen from Figure 1, crossing the 80% of predicted threshold for PEF%p or FVC%p and subsequent decline generally coincides with the time DMD patients become non-ambulant during early teenage years. This is supported by baseline data from the DELOS trial18 in 10–18-year-old DMD patients (n=64) where the majority of enrolled patients (92%) were already non-ambulant and at baseline had declined in pulmonary function to PEF%p of 53.8% (standard deviation [SD] 11.8) and FVC%p of 52.8% (SD 18.1).16,18 The predictive value of the age of loss of ambulation was more systematically analysed in a French database with 278 DMD patients.23 This study separated three groups of patients according to their age when they became non-ambulant (age at loss of ambulation – group A: before 8 years; group B: 8–<11 years; group C: 11–<16 years). Longitudinal analyses indicated that early loss of ambulation correlated with patients beginning to lose lung volume sooner, or having a peak vital capacity sooner (group A: 10.26 years; group B: 12.45 years; group C: 14.58 years).23 Moreover, the annual rate of decline in FVC%p was also largest in patients who became non-ambulant at a very young age compared to patients who became non-ambulant at an older age (Table 1).

References:
1. Mah JK, Korngut L, Dykeman J, et al., A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy, Neuromuscul Disord, 2014;24:482–-91.
2. 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.
3. Gayraud J, Ramonatxo M, Rivier F, et al., Ventilatory parameters and maximal respiratory pressure changes with age in Duchenne muscular dystrophy patients, Pediatr Pulmonol, 2010;45:552–9.
4. 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.
5. Mayer OH, Finkel RS, Rummey C, et al., Characterization of pulmonary function in Duchenne Muscular Dystrophy, Pediatr Pulmonol, 2015;50:487–94.
6. Bushby K, Finkel R, Birnkrant DJ, et al., Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care, Lancet Neurol, 2010;9:177–89.
7. 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.
8. Birnkrant DJ, Ashwath ML, Noritz GH, et al., Cardiac and pulmonary function variability in Duchenne/Becker muscular dystrophy: an initial report, J Child Neurol, 2010;25:1110–5.
9. Landfeldt E, Lindgren P, Bell CF, et al., Compliance to care guidelines for Duchenne muscular dystrophy, J Neuromuscul Dis, 2015;2:63–72.
10. Hollin IL, Peay H, Apkon SD, et al., Patient-centered benefit-risk assessment in Duchenne muscular dystrophy, Muscle Nerve, 2016, doi: 10.1002/mus.25411. [Epub ahead of print]
11. Buyse GM, Gueven N, McDonald C, Idebenone as a novel therapeutic approach for Duchenne muscular dystrophy, European Neurological Review, 2015;10:189–94.
12. Quanjer PH, Stocks J, Polgar G, et al., Compilation of reference values for lung function measurements in children, Eur Respir J Suppl, 1989;4:184S–261S.
13. Hankinson JL, 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.
14. Gauld LM, Kappers J, Carlin JB, et al., Height prediction from ulna length, Dev Med Child Neurol, 2004;46:475–80.
15. Gauld LM, Kappers J, Carlin JB, et al., Prediction of childhood pulmonary function using ulna length, Am J Respir Crit Care Med, 2003;168:804–9.
16. Meier T, Rummey C, Leinonen M, et al., Characterization of pulmonary function in 10–18 year old patients with Duchenne muscular dystrophy, Neuromuscular Disorders, 2017;27:307-314.Muscle Nerve, 2013;48:32–54.
18. 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, 2015;385:1748–57.
19. Connolly AM, Florence JM, Zaidman CM, et al., Clinical trial readiness in non-ambulatory boys and men with duchenne muscular dystrophy: MDA-DMD network follow-up, Muscle Nerve, 2016;54:681–9.
20. Connolly AM, Malkus EC, Mendell JR, et al., Outcome reliability in non-ambulatory boys/men with Duchenne muscular dystrophy, Muscle Nerve, 2015;51:522–32.
21. Khirani S, Ramirez A, Aubertin G, et al., Respiratory muscle decline in Duchenne muscular dystrophy, Pediatr Pulmonol, 2014;49:473–81.
22. 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;23:738–852 (P.11.12).
23. 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.
24. Brooke MH, Fenichel GM, Griggs RC, et al., Duchenne muscular dystrophy: patterns of clinical progression and effects of supportive therapy, Neurology, 1989;39:475–81.
25. Mellies U, Ragette R, Schwake C, et al., Daytime predictors of sleep disordered breathing in children and adolescents with neuromuscular disorders, Neuromuscul Disord, 2003;13:123–8.
26. Ragette R, Mellies U, Schwake C, et al., Patterns and predictors of sleep disordered breathing in primary myopathies, Thorax, 2002;57:724–8.
27. Hoque R, Sleep-disordered breathing in Duchenne muscular dystrophy: an assessment of the literature, J Clin Sleep Med, 2016;12:905–11.
28. Sawnani H, Thampratankul L, Szczesniak RD, et al., Sleep disordered breathing in young boys with Duchenne muscular dystrophy, J Pediatr, 2015;166:640-5 e1.
29. Hukins CA, Hillman DR, Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy, Am J Respir Crit Care Med, 2000;161:166–70.
30. Phillips MF, Quinlivan RC, Edwards RH, et al., 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.
31. 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, Chest, 2007;132:1977–86.

32. Birnkrant DJ, Bushby KM, 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.
33. Bach JR, Ishikawa Y, Kim H, Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy, Chest, 1997;112:1024–8.
34. Gauld LM, Boynton A, Relationship between peak cough flow and spirometry in Duchenne muscular dystrophy, Pediatr Pulmonol, 2005;39:457–60.
35. Tzeng AC, Bach JR, Prevention of pulmonary morbidity for patients with neuromuscular disease, Chest, 2000;118:1390–6.
36. Eagle M, Baudouin SV, Chandler C, et al., Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation, Neuromuscul Disord, 2002;12:926–9.
37. Passamano L, Taglia A, Palladino A, et al., Improvement of survival in Duchenne muscular dystrophy: retrospective analysis of 835 patients, Acta Myol, 2012;31:121–5.
38. Rall S, Grimm T, Survival in Duchenne muscular dystrophy, Acta Myol, 2012;31:117–20.
39. Calvert LD, McKeever TM, Kinnear WJ, et al., Trends in survival from muscular dystrophy in England and Wales and impact on respiratory services, Respir Med, 2006;100:1058–63.
40. Schram G, Fournier A, Leduc H, et al., All-cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy, J Am Coll Cardiol, 2013;61:948–54.
41. Matthews E, Brassington R, Kuntzer T, et al., Corticosteroids for the treatment of Duchenne muscular dystrophy, Cochrane Database Syst Rev, 2016;5:CD003725.
42. Biggar WD, Gingras M, Fehlings DL, et al., Deflazacort treatment of Duchenne muscular dystrophy, J Pediatr, 2001;138:45–50.
43. Biggar WD, Harris VA, Eliasoph L, et al., Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade, Neuromuscul Disord, 2006;16:249–55.
44. 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.
45. Houde S, Filiatrault M, Fournier A, et al., Deflazacort use in Duchenne muscular dystrophy: an 8-year follow-up, Pediatr Neurol, 2008;38:200–6.
46. Bello L, Gordish-Dressman H, Morgenroth LP, et al., Prednisone/ prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study, Neurology, 2015;85:1048–55.
47. Pane M, Fanelli L, Mazzone ES, et al., Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: a multicentric longitudinal study using the Performance of Upper Limb test, Neuromuscul Disord, 2015;25:749–53.
48. Manzur AY, Kuntzer T, Pike M, et al., Glucocorticoid corticosteroids for Duchenne muscular dystrophy, Cochrane Database Syst Rev, 2008;1:CD003725.
49. Bushby K, Lochmuller H, Lynn S, et al., Interventions for muscular dystrophy: molecular medicines entering the clinic, Lancet, 2009;374:1849–56.
50. Gloss D, Moxley RT 3rd, Ashwal S, et al., Practice guideline update summary: corticosteroid treatment of Duchenne muscular dystrophy: report of the Guideline Development Subcommittee of the American Academy of Neurology, Neurology, 2016;86:465–72.
51. Timpani CA, Hayes A, Rybalka E, Revisiting the dystrophin-ATP connection: how half a century of research still implicates mitochondrial dysfunction in Duchenne muscular dystrophy aetiology, Med Hypotheses, 2015;85:1021–33.
52. Haefeli RH, Erb M, Gemperli AC, et al., NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels, PLoS One, 2011;6:e17963.
53. Giorgio V, Petronilli V, Ghelli A, et al., The effects of idebenone on mitochondrial bioenergetics, Biochim Biophys Acta, 2012;1817:363–9.
54. 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:e36153.
55. 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, 2009;30:116–24.
56. 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 placebocontrolled trial, Neuromuscul Disord, 2011;21:396–405.
57. Buyse GM, Goemans N, van den Hauwe M, et al., Effects of glucocorticoids and idebenone on respiratory function in patients with Duchenne muscular dystrophy, Pediatr Pulmonol, 2013;48:912–20.
58. Buyse GM, Voit T, Schara U, et al., Treatment effect of idebenone on inspiratory function in patients with Duchenne muscular dystrophy, Pediatr Pulmonol, 2017;52:508-51.
59. McDonald CM, Meier T, Voit T, et al., Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy, Neuromuscul Disord, 2016;26:473–80.
60. A phase III double-blind study with idebenone in patients with Duchenne muscular dystrophy (DMD) taking glucocorticoid steroids (SIDEROS). Available at: https://clinicaltrials.gov/ct2/ show/NCT02814019 (Accessed 10/01/2017).
Keywords: Duchenne muscular dystrophy, glucocorticoids, idebenone, pulmonary function, peak expiratory flow, forced vital capacity