Abstract
Objective: To assess impact of a 52-week elosulfase alfa enzyme replacement therapy (ERT) on exercise capacity in Morquio A patients and analyze cardiorespiratory and metabolic function during exercise to uncover exercise limitations beyond skeletal abnormalities.
Methods: Morquio A patients aged ≥7 years, able to walk >200 m in the 6-minute walk test (6MWT), received elosulfase alfa 2.0 mg/kg/week (N = 15) or 4.0 mg/kg/week (N = 10) for 52 weeks in the randomized, double-blind MOR-008 study (ClinicalTrials.gov NCT01609062) and its extension. Exercise capacity was assessed by 6MWT, 3-minute stair climb test (3MSCT), and cardiopulmonary exercise test (CPET; N = 15 dosage groups combined).
Results: Changes over 52 weeks in 6MWT and 3MSCT were minimal. Baseline CPET results showed impaired weight-adjusted peak oxygen uptake (VO2), partly attributable to inability to increase tidal volume during exercise. CPET measures of exercise function showed significant improvement at 25 and/or 52 weeks in exercise duration, peak workload, O2 pulse, and peak tidal volume (% increases in duration, 16.9 (P = 0.0045) and 9.4 (P = 0.0807); peak workload, 26.5 (P = 0.0026) and 21.2 (P = 0.0132); O2 pulse, 10.7 (P = 0.0187) and 2.3 (P = 0.643); peak tidal volume, 11.7 (P = 0.1117) and 29.1 (P = 0.0142)). In addition, decreased VO2/work ratio was noted (% decrease −7.6 [−11.9, 1.3] and −9.2 [−25.7, 5.1]), indicating performance of work at reduced oxygen cost.
Conclusions: CPET uncovers limitation in exercise capacity in Morquio A related to reduced lung function. ERT improves exercise capacity and efficiency of oxygen utilization, not attributable to changes in cardiac or pulmonary function. Further study of the long-term impact of ERT on exercise capacity and the clinical relevance of the observed changes is warranted.
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Albouaini K, Egred M, Alahmar A, Wright DJ (2007) Cardiopulmonary exercise testing and its application. Postgrad Med J 83:675–682
American Thoracic Society (2002) ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 166:111–117
ATS and ACCP (2003) ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 167:211–277
Burton BK, Berger KI, Lewis GD et al (2015) Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: a randomized, double-blind, pilot study. Am J Med Genet A 167A:2272–2281
Charbek E (2015) Normal vital signs. Medscape. http://emedicine.medscape.com/article/2172054-overview
Crescimanno G, Modica R, Lo Mauro R, Musumeci O, Toscano A, Marrone O (2015) Role of the cardio-pulmonary exercise test and six-minute walking test in the evaluation of exercise performance in patients with late-onset Pompe disease. Neuromuscul Disord 25:542–547
Fleming TR, Powers JH (2012) Biomarkers and surrogate endpoints in clinical trials. Stat Med 31:2973–2984
Guazzi M, Dickstein K, Vicenzi M, Arena R (2009) Six-minute walk test and cardiopulmonary exercise testing in patients with chronic heart failure: a comparative analysis on clinical and prognostic insights. Circ Heart Fail 2:549–555
Harmatz P, Mengel KE, Giugliani R et al (2013) The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab 109:54–61
Hendriksz CJ, Al-Jawad M, Berger KI et al (2013) Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis 36:309–322
Hendriksz CJ, Burton B, Fleming TR et al (2014) Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis 37:979–990
Hendriksz CJ, Berger KI, Giugliani R et al (2015) International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet A 167A:11–25
Leadley RM, Lang S, Misso K et al (2014) A systematic review of the prevalence of Morquio A syndrome: challenges for study reporting in rare diseases. Orphanet J Rare Dis 9:173
Montaño AM, Tomatsu S, Gottesman GS, Smith M, Orii T (2007) International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis 30:165–174
Muenzer J (2011) Overview of the mucopolysaccharidoses. Rheumatology (Oxford) 50(Suppl 5):v4–v12
Sanford M, Lo JH (2014) Elosulfase alfa: first global approval. Drugs 74:713–718
Santuz P, Baraldi E, Filippone M, Zacchello F (1997) Exercise performance in children with asthma: is it different from that of healthy controls? Eur Respir J 10:1254–1260
Ten Harkel ADJ, Takken T, Van Osch-Gevers M, Helbing WA (2011) Normal values for cardiopulmonary exercise testing in children. Eur J Cardiovasc Prev Rehabil 18:48–54
Yasuda E, Fushimi K, Suzuki Y et al (2013) Pathogenesis of Morquio A syndrome: an autopsied case reveals systemic storage disorder. Mol Genet Metab 109:301–311
Acknowledgments
The authors are grateful to Ismar Healthcare NV for their assistance in the writing of the manuscript, which was funded by BioMarin Pharmaceutical Inc. Fred Genter is acknowledged for his work as a statistician for the study.
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Communicated by: Roberto Giugliani, MD, PhD
Electronic Supplementary Material
Supportive online material 1
Mean (standard error) change in 6-minute walk test (6MWT) and 3-minute stair climb test (3MSCT) outcomes from baseline to week 52 with elosulfase alfa 2 mg/kg and 4 mg/kg per week (modified intent-to-treat population) (DOCX 122 kb)
Supportive online material 2
Change from resting to peak tidal volume (mL) at baseline in (A) the elosulfase alfa 2.0 mg/kg/week and (B) the elosulfase alfa 4.0 mg/kg/week treatment group (modified intent-to-treat population). Different lines represent different patients (DOCX 151 kb)
Supportive online material 3
Scatter plot of baseline change from resting to peak tidal volume (mL) by forced expiratory volume in 1 s (FEV1) revealing that the abnormal ventilatory response to exercise was correlated with FEV1 at baseline (modified intent-to-treat population) (DOCX 94 kb)
Supportive online material 4
Changes from baseline in peak workload versus Δ tidal volume during exercise at (A) week 25 and (B) week 52 (DOCX 72 kb)
Supportive online material 5
Correlations between endurance measures and peak oxygen uptake (VO2) (modified intent-to-treat population) (DOCX 13 kb)
Appendices
Take-Home Message
Morquio A patients have a limitation in exercise performance, which is related to reduced lung function; elosulfase alfa enzyme replacement therapy for 52 weeks has a positive effect on exercise capacity and efficiency of oxygen utilization, not attributable to changes in either cardiac or pulmonary function.
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Conflict of Interest
Kenneth I. Berger has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Barbara K. Burton has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Gregory D. Lewis has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Mark Tarnopolsky has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Paul R. Harmatz has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
John J. Mitchell has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Nicole Muschol has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Simon A. Jones has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Vernon R. Sutton has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Gregory M. Pastores has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Heather Lau has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Rebecca Sparkes has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.
Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc.
This study was sponsored by BioMarin Pharmaceutical Inc. and supported, in part, by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through UCSF-CTSI Grant Number UL1 TR000004 (Dr. Harmatz). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Support in the process of manuscript development was also funded by BioMarin Pharmaceutical Inc.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
Animal Rights
This article does not contain any studies with human or animal subjects performed by any of the authors.
Details of the Contributions of Individual Authors
Barbara K. Burton, Kenneth I. Berger, Gregory D. Lewis, Mark Tarnopolsky, Paul R. Harmatz, John J. Mitchell, Nicole Muschol, Simon A. Jones, Vernon R. Sutton, Gregory M. Pastores, Heather Lau, and Rebecca Sparkes were all members of the steering committee, contributed to the planning of the study, and were involved in the clinical examinations and collection of patient data and in the preparation and critical review of the manuscript.
Adam J. Shaywitz assisted with conduction of the study, data analyses, and development of the manuscript.
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Berger, K.I. et al. (2017). Cardiopulmonary Exercise Testing Reflects Improved Exercise Capacity in Response to Treatment in Morquio A Patients: Results of a 52-Week Pilot Study of Two Different Doses of Elosulfase Alfa. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 42. JIMD Reports, vol 42. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_70
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DOI: https://doi.org/10.1007/8904_2017_70
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