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

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.

Keywords: Cardiopulmonary exercise test; Elosulfase alfa; Endurance; Enzyme replacement therapy; Exercise capacity; Mucopolysaccharidosis IVA.

Conflict of interest statement

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.

Figures

Fig. 1

Mean (standard error) change in cardiopulmonary exercise test (CPET) outcomes from baseline to week 52 with elosulfase alfa 2 mg/kg and 4 mg/kg per week (modified intent-to-treat population). VO2 oxygen uptake