Discussion
Studies have demonstrated that ERT with rhASB leads to a sustained improvement in endurance in the MPS VI patient population (Harmatz et al.
2008). An important factor contributing to improved endurance is likely to be pulmonary function. In this study, analysis of pooled pulmonary function data from rhASB clinical studies shows that MPS VI patients on ERT demonstrated improvement from baseline in pulmonary function that was sustained over long-term treatment and occurred independent of age. Whereas the improvement in pulmonary function may be in part related to growth in the younger patients, the pulmonary function improvement seen in older patients occurred with smaller change in height and may be attributed to other mechanical, anatomical, or physiological factors influencing lung function.
Consistent with previously reported findings in individual MPS VI clinical trials, analysis of combined data did not show mean percent improvement in FVC and FEV1 over the short term (24 weeks). However, by 72 or 96 weeks of treatment, both FVC and FEV1 showed improvement from baseline of at least 11%. For individuals with normal lung function, a 15% relative increase in FEV1 year to year is considered a clinically meaningful change according to the American Thoracic Society guidelines (
1991) (Pellegrino et al.
2005). It is important to note that we examined improvement in pulmonary function in terms of absolute volume, not percent predicted. These gains could not be expressed in terms of percent predicted ([actual result/predicted result ] x 100%), as a standard curve does not exist for this population, which is similar to the achondroplasia patient population in which small stature and dysplastic bone changes confound calculation of these percentages (Stokes et al.
1988;
1990).
In contrast to the delayed improvement in traditional pulmonary function measures of FVC and FEV1, the MVV showed rapid improvement relative to baseline over 24 weeks. The MVV maneuver of rapid respiration is thought to replicate maximal ventilation during exercise (Stein et al.
2003). Although MVV is generally well correlated with FEV1 (Fulton et al.
1995; Stein et al.
2003), a disproportionate decrease in MVV relative to FEV1 has been reported in neuromuscular disorders (Serisier et al.
1982; Braun et al.
1983) and upper airway obstruction (Engstroem et al.
1964), and therefore, improvement in these areas with ERT may contribute to the earlier response on the MVV assessment.
The mechanism for the observed improvement in lung function during ERT and its relationship to growth is of interest. In this study, lung function improved relative to baseline to a similar extent in younger and older age groups, suggesting height did not determine this improvement. Observations in other MPS disorders during ERT suggest that the improvement in lung function in older patients may be due to multiple mechanisms, including decreased upper airway obstruction as evidenced by improvement in sleep apnea severity, increased chest wall compliance as evidenced by improved joint mobility, and improved respiratory muscle strength and endurance as well as improved diaphragmatic excursion as evidenced by reduction in liver size (Wraith et al.
2004; Clarke et al.
2009). In younger patients, all of these mechanisms may apply, and height/thoracic enlargement may have an additive effect on FVC and FEV1.
A limitation of examining mean percent change data by treatment week is that the number of patients does not remain consistent across all data points due to variations in design and length of the three clinical trials, potentially distorting the magnitude of changes over time. To minimize this effect, longitudinal modeling was chosen to estimate improvement trends at 96 weeks pre-ERT and post-ERT initiation. Modeled results in Table
5 do not reflect significant improvement pre-ERT but do show significant improvement post-ERT. In general, the magnitude of the changes did not differ greatly in the younger and older age groups, demonstrating that pulmonary function improvement occurs in ERT-treated patients regardless of age at treatment initiation.
There are several factors that may have influenced the results of the longitudinal modeling. In the pre-ERT data, comprising data that were collected in the Survey Study and from placebo patients in the Phase 3 study, some individuals had only one or two observations within the 2-year period prior to ERT initiation. Because these data tend to be variable, additional observations over time may have given a more accurate estimate of lung function during this time period. It is reassuring, then, that these data were collected in a controlled clinical setting and that the standard errors for pre-ERT versus post-ERT estimates of lung function are similar in both time periods. In addition, the number of patients with data beyond 96 weeks was limited, and thus, the observed trends should not be extrapolated beyond the range of data presented. Because the observed data showed a gradual improvement over time, a linear trend for modeling was chosen as a simple way to see whether the rate of improvement differed during the 2 years pre-ERT and post-ERT initiation. Individual patients may deviate from this trend, especially if growth and/or puberty occurred during treatment. In addition, longer-term follow-up (>2 years) may suggest more distinct nonlinear trends, but in this study, these would be difficult to detect or differentiate from random variation.
In this study, we cannot rule out the effect of growth on FVC. Whereas we considered including growth—i.e., time-varying height—in our model, several issues limited this possibility. Treatment with ERT may affect lung function through several causal pathways: it may have a direct and independent effect on lung function, or increase height, which in turn changes lung function. In the second scenario, height may be an intermediate variable in the causal pathway for lung function, particularly for FVC. As a result, a statistical model that controls for time-varying height may be inappropriate; it would likely obscure any effect of treatment that was mediated by height. Accordingly, we considered only baseline height in our model rather than height over time (i.e., growth).
In conclusion, progressive impairment in pulmonary function is characteristic of MPS VI disease, and a significant amount of morbidity and mortality is attributable to respiratory complications (Simmons et al.
2005). The study presented here suggests by multiple statistical techniques that this trend toward decline in pulmonary function can be halted and partially reversed during ERT with
N-acetylgalactosamine 4-sulfatase (rhASB, galsulfase, Naglazyme) over a period of 96 weeks of therapy. It is likely that this improvement is one factor underlying the increase in endurance documented in the 6-min and 12-min walk tests, although changes in pulmonary function appear to be delayed relative to improvement in endurance that is evident by 24 weeks of ERT (Harmatz et al.
2008). This improvement in respiratory function relative to baseline may lead to a decrease in the severity of respiratory illnesses and number of hospitalizations, and an overall improvement in the quality of life of MPS VI patients.
Acknowledgments
We acknowledge the participation of study patients and their families and the expert assistance of all study-site coordinators and personnel. We also acknowledge the key contributions of our colleagues Dr. Ann Lowe and Ms. Mary Newman, as well as the many other BioMarin employees and consultants who performed important roles during the studies. Dr. Helen Nicely of BioMarin contributed to the editing of this document. This study was sponsored by BioMarin Pharmaceutical Inc., and supported, in part, with funds provided by the National Center for Research Resources, 5 M01 RR-01271 (Dr. Harmatz), 5 M01 RR-00400 (Dr. Whitley), M01 RR-00334 (Dr. Steiner), and UL1-RR-024134 (Dr. Kaplan). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
The MPS VI Study Group co-investigators are: John Waterson, MD, PhD and Elio Gizzi, MD, Children’s Hospital & Research Center Oakland, Oakland, California; Yasmina Amraoui, MD, Children’s Hosp, University of Mainz, Germany; Bonito Victor, MD, Unidade de Doenças Metabólicas, Departamento Pediatria, Hospital de Sao João, Porto, Portugal; Javier Arroyo, MD, Hospital San Pedro de Alcantara, Hospital de día de Pediatría, Caceres, Spain; D.N. Bennett-Jones, MD, Consultant General & Renal Physician, Whitehaven, UK; Philippe Bernard, MD, Centre Hospitalier d’Arras, Arras, France; Prof. Billette de Villemeur, Hôpital Trousseau, Paris, France; Raquel Boy, MD, Hospital Universitário Pedro Ernesto, Rio de Janeiro, Brazil; Eduardo Coopman, MD, Hospital del Cobre De. Salvador, Calama, Chile; Prof. Rudolf Korinthenberg, Universitätsklinikum Freiburg, Zentrum für Kinderheilkunde und Jugendmedizin, Klinik II Neuropädiatrie und Muskelerkrankungen, Freiburg, Germany; Michel Kretz, MD, Hôpital Civil de Colmar, Le Parc Centre de la Mère et de l’Enfant, Colmar, France; Shuan-Pei Lin, MD, MacKay Memorial Hospital, Department of Genetics, Taipei, Taiwan; Ana Maria Martins, MD, UNIFESP, Instituto de Oncologia Pediátrica, GRAACC/UNIFESP, Departamento de Pediatria, São Paulo, Brazil; Anne O’Meara, MD, Our Lady’s Hospital for Sick Children, Dublin, Ireland; Gregory Pastores, MD, PhD, NYU Medical Center, Rusk Institute, New York, New York; Lorenzo Pavone, MD, Rita Barone, MD, Agata Fiumara, MD, and Prof. Giovanni Sorge, Department of Pediatrics, University of Catania, Catania, Italy; Silvio Pozzi, MD, Ospedale Vito Fazzi, UO Pediatria, Lecce, Italy; Uwe Preiss, MD, Universitätsklinik und Poliklinik fűr Kinder, Halle, Germany; Emerson Santana Santos, MD, Fundação Universidade de Ciências da Saúde de Alagoas Governador, Departamento de Pediatria, Maceió, Brazil; Isabel Cristina Neves de Souza, MD and Luiz Carlos Santana da Silva, PhD, Universidade Federal do Pará, Centro de Ciências Biológicas, Hospital Universitário João de Barros Barreto, Belém, Brazil; Eugênia Ribeiro Valadares, MD, PhD, Hospital das Clínicas, Faculdade de Medicina da Universidade Federal de Minas Gerais-UFMG, Avenida Professor Alfredo Balena, Belo Horizonte-Minas Gerais, Brazil; Laura Keppen, MD, Department of Pediatrics, University of South Dakota School of Medicine, Sioux Falls, SD; David Sillence, MD, Children’s Hospital, Westmead, Australia; Lionel Lubitz, MD, Royal Children’s Hospital, Melbourne, Australia; William Frischman, MD, The Townsville Hospital, Townsville, Australia; Julie Simon, RN, Children’s Hospital & Research Center Oakland, Oakland, California; Claudia Lee, MPH, Children’s Hospital & Research Center Oakland, Oakland, California; Stephanie Oates, RN Department of Genetic Medicine, Women’s and Children’s Hospital Adelaide, North Adelaide, Australia; Lewis Waber, MD, PhD, Pediatric Genetics and Metabolism, University of Texas Southwest Medical Center, Dallas, TX; Ray Pais, MD, Pediatric Hematology/Oncology, East Tennessee Children’s Hospital, Knoxville, TN