Kenneth I Berger1,2, Barbara K Burton3, Gregory D Lewis4, Mark Tarnopolsky5, Paul R Harmatz6, John J Mitchell7, Nicole Muschol8, Simon A Jones9, V Reid Sutton10, Gregory M Pastores11,12, Heather Lau11, Rebecca Sparkes13, Adam J Shaywitz14. 1. New York University School of Medicine, New York, NY, USA. Kenneth.Berger@nyumc.org. 2. André Cournand Pulmonary Physiology Laboratory, Bellevue Hospital, New York, NY, USA. Kenneth.Berger@nyumc.org. 3. Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 4. Massachusetts General Hospital, Boston, MA, USA. 5. McMaster University Medical Centre, Hamilton, ON, Canada. 6. UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA. 7. Montreal Children's Hospital, Montreal, QC, Canada. 8. University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 9. Willink Unit, St Mary's Hospital CMFT, MAHSC, University of Manchester, Manchester, UK. 10. Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA. 11. New York University School of Medicine, New York, NY, USA. 12. University College Dublin, Mater Misericordiae University Hospital, Dublin, Ireland. 13. Alberta Children's Hospital, Calgary, AB, Canada. 14. BioMarin Pharmaceutical Inc., Novato, CA, USA.
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), receivedelosulfase 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.
RCT Entities:
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.
Authors: Paul Harmatz; Karl Eugen Mengel; Roberto Giugliani; Vassili Valayannopoulos; Shuan-Pei Lin; Rossella Parini; Nathalie Guffon; Barbara K Burton; Christian J Hendriksz; John Mitchell; Ana Martins; Simon Jones; Norberto Guelbert; Ashok Vellodi; Carla Hollak; Peter Slasor; Celeste Decker Journal: Mol Genet Metab Date: 2013-02-09 Impact factor: 4.797
Authors: Christian J Hendriksz; Kenneth I Berger; Roberto Giugliani; Paul Harmatz; Christoph Kampmann; William G Mackenzie; Julian Raiman; Martha Solano Villarreal; Ravi Savarirayan Journal: Am J Med Genet A Date: 2014-10-24 Impact factor: 2.802
Authors: Christian J Hendriksz; Barbara Burton; Thomas R Fleming; Paul Harmatz; Derralynn Hughes; Simon A Jones; Shuan-Pei Lin; Eugen Mengel; Maurizio Scarpa; Vassili Valayannopoulos; Roberto Giugliani; Peter Slasor; Debra Lounsbury; Wolfgang Dummer Journal: J Inherit Metab Dis Date: 2014-05-09 Impact factor: 4.982