Enzyme replacement therapy for mucopolysaccharidosis VI: Evaluation of long-term pulmonary function in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase

Abstract

Pulmonary function is impaired in untreated mucopolysaccharidosis type VI (MPS VI). Pulmonary function was studied in patients during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-sulfatase). Pulmonary function tests prior to and for up to 240 weeks of weekly infusions of rhASB at 1 mg/kg were completed in 56 patients during Phase 1/2, Phase 2, Phase 3 and Phase 3 Extension trials of rhASB and the Survey Study. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and, in a subset of patients, maximum voluntary ventilation (MVV), were analyzed as absolute volume in liters. FEV1 and FVC showed little change from baseline during the first 24 weeks of ERT, but after 96 weeks, these parameters increased over baseline by 11% and 17%, respectively. This positive trend compared with baseline continued beyond 96 weeks of treatment. Improvements from baseline in pulmonary function occurred along with gains in height in the younger group (5.5% change) and in the older patient group (2.4% change) at 96 weeks. Changes in MVV occurred earlier within 24 weeks of treatment to approximately 15% over baseline. Model results based on data from all trials showed significant improvements in the rate of change in pulmonary function during 96 weeks on ERT, whereas little or no improvement was observed for the same time period prior to ERT. Thus, analysis of mean percent change data and longitudinal modeling both indicate that long-term ERT resulted in improvement in pulmonary function in MPS VI patients.

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ORIGINAL ARTICLE
Enzyme replacement therapy for mucopolysaccharidosis
VI: evaluation of long-term pulmonary function in patients
treated with recombinant human N-acetylgalactosamine
4-sulfatase
Paul Harmatz &Zi-Fan Yu &Roberto Giugliani &Ida Vanessa D. Schwartz &
Nathalie Guffon &Elisa Leão Teles &M. Clara Sá Miranda &J. Edmond Wraith &
Michael Beck &Laila Arash &Maurizio Scarpa &David Ketteridge &John J. Hopwood &
Barbara Plecko &Robert Steiner &Chester B Whitley &Paige Kaplan &
Stuart J. Swiedler &Karen Hardy &Kenneth I. Berger &Celeste Decker
Received: 22 June 2009 / Revised: 4 November 2009 / Accepted: 9 November 2009 / Published online: 6 February 2010
#The Author(s) 2010. This article is published with open access at Springerlink.com
Abstract Pulmonary function is impaired in untreated
mucopolysaccharidosis type VI (MPS VI). Pulmonary
function was studied in patients during long-term enzyme
replacement therapy (ERT) with recombinant human
arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-
sulfatase). Pulmonary function tests prior to and for up
to 240 weeks of weekly infusions of rhASB at 1 mg/kg
were completed in 56 patients during Phase 1/2, Phase 2,
Phase 3 and Phase 3 Extension trials of rhASB and the
Survey Study. Forced vital capacity (FVC), forced
expiratory volume in 1 s (FEV1) and, in a subset of
patients, maximum voluntary ventilation (MVV), were
Communicated by: Frits Wijburg
References to electronic databases: MPS VI: OMIM 253200.
The authors are reporting for the MPS VI Study Group; see
Acknowledgments for list of co-investigators.
P. Harmatz (*):K. Hardy
Children′s Hospital & Research Center Oakland,
747 52nd Street,
Oakland, CA 94609, USA
e-mail: Pharmatz@mail.cho.org
Z.-F. Yu
Statistics Collaborative, Inc,
Washington, DC, USA
R. Giugliani :I. V. D. Schwartz
Medical Genetics Service/ HCPA and Department of Genetics/
UFRGS,
Porto Alegre, Brazil
N. Guffon
Hôpital Femme Mère Enfant, Service Maladies Métaboliques,
Bron, France
E. L. Teles
Departamento Pediatria, Hospital de Sao João,
Unidade de Doenças Metabólicas,
Porto, Portugal
M. C. S. Miranda
Instituto de Biologia Molecular e Celular,
Unidade de Biologia do Lisossoma e Peroxisoma,
Porto, Portugal
J. E. Wraith
Royal Manchester Children′s Hosp,
Manchester, UK
M. Beck :L. Arash
Children′s Hosp, University of Mainz,
Mainz, Germany
M. Scarpa
Department of Pediatrics,
University of Padova,
Padova, Italy
D. Ketteridge
SA Pathology at Women′s and Children′s Hospital,
North Adelaide, SA, Australia
J Inherit Metab Dis (2010) 33:51–60
DOI 10.1007/s10545-009-9007-8

analyzed as absolute volume in liters. FEV1 and FVC
showed little change from baseline during the first
24 weeks of ERT, but after 96 weeks, these parameters
increased over baseline by 11% and 17%, respectively.
This positive trend compared with baseline continued
beyond 96 weeks of treatment. Improvements from
baseline in pulmonary function occurred along with gains
in height in the younger group (5.5% change) and in the
older patient group (2.4% change) at 96 weeks. Changes
in MVV occurred earlier within 24 weeks of treatment to
approximately 15% over baseline. Model results based on
data from all trials showed significant improvements in the
rate of change in pulmonary function during 96 weeks on
ERT, whereas little or no improvement was observed for
the same time period prior to ERT. Thus, analysis of mean
percent change data and longitudinal modeling both
indicate that long-term ERT resulted in improvement in
pulmonary function in MPS VI patients.
Abbreviations
MPS VI Mucopolysaccharidosis VI
rhASB Recombinant human arylsulfatase B
ERT Enzyme replacement therapy
GAG Glycosaminoglycans
FVC Forced vital capacity
FEV1 Forced expiratory volume in 1 s
MVV Maximum voluntary ventilation
LME Longitudinal linear mixed-effects model
Introduction
Mucopolysaccharidosis type VI (MPS VI; Maroteaux-
Lamy syndrome) is a lysosomal storage disease in which
deficient activity of the enzyme N-acetylgalactosamine 4-
sulfatase (arylsulfatase B, or ASB; E.C # 3.1.6.12) impairs
the stepwise degradation of the glycosaminoglycan (GAG)
dermatan sulfate (DS) (Giugliani et al. 2007). Partially
degraded GAG accumulates in lysosomes and in a wide
range of tissues, causing a chronic progressive disorder
characterized by significant functional impairment and a
shortened lifespan.
A survey of 121 MPS VI affected individuals found that
high urinary GAG values (>200 μg/mg creatinine) were
associated with an accelerated clinical course including
reduced endurance, greater pulmonary function impairment,
and lower height values for age (Swiedler et al. 2005).
Impairment in endurance based on a 6-min walk test was
observed across all age groups and levels of GAG
accumulation.
Three enzyme replacement therapy (ERT) studies using
recombinant human ASB (known as rhASB ; recombinant
human N-acetylgalactosamine 4-sulfatase; galsulfase;
Naglazyme®) to treat patients with MPS VI have been
reported. A Phase 1/2 study and a Phase 2 study both
demonstrated that weekly infusions of 1 mg/kg rhASB were
well tolerated, produced a rapid reduction in urinary GAG
levels, and improved endurance in patients with rapidly
advancing disease (Harmatz et al. 2004; Harmatz et al.
2005). A Phase 3 double-blind, placebo-controlled study
demonstrated greater improvement in endurance on the 12-
min walk test (12MWT) in patients treated with rhASB for
24 weeks compared with patients receiving placebo
(Harmatz et al. 2006). In all studies, improvement in
endurance was maintained during the open-label extension
phase for up to 240 weeks, with an acceptable safety
profile (Harmatz et al. 2008). In addition to endurance
measures, all three studies included pulmonary function
assessments. The mechanism for this improved endurance
is unknown but may relate to an impact of ERT on
pulmonary function.
The purpose of this paper is to evaluate pooled long-term
data from the clinical ERT trials and the Survey Study to
determine the impact of ERT on pulmonary function in
patients with MPS VI.
Methods
Study design
Detailed study design and evaluation criteria have been
reported in previous publications of the MPS VI Survey
J. J. Hopwood
Department of Genetic Medicine,
Women′s and Children′s Hospital Adelaide,
North Adelaide, SA, Australia
B. Plecko
Univ. Klinik für Kinder und Jugendheilkunde,
Graz, Austria
R. Steiner
Departments of Pediatrics and Molecular and Medical Genetics,
Oregon Health & Science University,
Portland, OR, USA
C. B. Whitley
University of Minnesota Medical School,
Minneapolis, MN, USA
P. Kaplan
Children′s Hospital of Philadelphia,
Philadelphia, PA, USA
S. J. Swiedler :C. Decker
BioMarin Pharmaceutical Inc,
Novato, CA, USA
K. I. Berger
Departments of Medicine, Physiology and Neuroscience,
New York University School of Medicine,
New York, NY, USA
52 J Inherit Metab Dis (2010) 33:51–60

Study and the Phase 1/2, Phase 2, and Phase 3 clinical
studies of rhASB (galsulfase, Naglazyme) treatment in
MPS VI, which reported results of 48 weeks of treatment
(Harmatz et al. 2004; Harmatz et al. 2005; Harmatz et al.
2006). Collection of efficacy data continued for up to
240 weeks during the extension phase of these studies.
Pretreatment data were specifically collected from patients in
the Survey Study and placebo-treated patients in the first
24 weeks of the Phase 3 clinical trial. These studies are
summarized in Table 1. An Institutional Review Board (IRB)
or Ethics Committee (EC) at each participating clinical site
approved each study. All adult patients and parent/guardians
gave written consent; patients younger than 18 years old
gave written assent according to local IRB regulations.
All patients received rhASB at 1 mg/kg/week infused over
a 4-h period, except three patients in the Phase 1/2 study who
received 0.2 mg/kg per week for the initial part of that study
and 19 patients who completed the Phase 3 study. These 19
patients received placebo during the blinded portion of the
Phase 3 study and received rhASB for the open-label
remainder of the study (weeks 24−96). These patients
underwent evaluations following 24 and 72 weeks of active
therapy, i.e., at weeks 48 and 96 of the study. Assessments
were completed for each study group as shown in Table 2.
Pulmonaryfunction parameters examined during all studies
included forced vital capacity (FVC) and forced expiratory
volume in 1 s (FEV1). Data were obtained in accord with the
American Thoracic Society guidelines (1995). The Phase 3
study also measured the maximum voluntary ventilation
(MVV), which was defined as the maximum volume of air
that can be breathed in 1 min. Data were collected while the
patients breathed as deeply and quickly as possible for 15 s
and then were extrapolated to 1 min (American Thoracic
Society guidelines 1991).
Analysis methods
This analysis focused on long-term pulmonary function
outcomes in patients receiving ERT over an extended
period. In addition, the pooled data were analyzed to
determine: (1) the importance of height change on the mean
improvement in pulmonary function during ERT, and (2)
the mean rate of increase in pulmonary function parameters
prior to and following ERT initiation. To evaluate the
improvement in pulmonary function relative to growth,
pooled data were stratified into two groups: patients
<12 years versus patients ≥12 years at treatment initiation.
The age of 12 years was chosen to approximate the
midpoint of normal pubertal development, and it is
assumed that patients who started ERT after this age are
less likely to experience significant growth. In each age
group, mean percent change in FVC, FEV1, and height
were analyzed.
Table 1 Summary of study populations
Study Study design Study time
period (years)
Duration
of efficacy
evaluations
(weeks)
Number of
patients enrolled/
completed
Dose of
rhASB
mg/kg
Age (years)
mean±SD
(range years)
Sex
(M/F)
Height (cm)
mean±SD
Number of patients
withdrawn: time
of withdrawal
Baseline urinary
GAG (µg/mg
creatinine)
mean±SD
Phase 1/2 Double-blind, randomized,
dose comparison/
open-label extension
2001–2005 240 7/5 0.2
1.0
12.0± 3.8 (7−16 ) 4/3 107.5±21.5 1 (0.2 mg/kg)
after week 3;
1 (0.2 mg/kg)
after week 32
365± 148
Survey study
(patients not
on ERT)
Cross-sectional study
of patients not on ERT
2002–2003 123/121 None 13.9± 10 (4−56) 58/63 115± 26 321± 200
Phase 2 Open-label, nonrandomized 2002–2006 144 10/10 1.0 12.1± 5.3 (6−21) 7/3 103.7±14.4 0 336± 116
Phase 3 Double-blind, placebo-
controlled, randomized/
open-label extension
2003–2006 96 39/38 1.0 13.7± 6.5 (rhASB)
10.7± 4.4 (placebo)
(5−29)
13/26 104.4± 2.9
(rhASB)
100.3± 13.5
(placebo)
1 (placebo group)
after week 5
346± 128 (rhASB)
330± 114 (placebo)
J Inherit Metab Dis (2010) 33:51–60 53

To determine the mean rate of increase in pulmonary
function parameters prior to and following initiation of ERT,
a longitudinal linear mixed-effects model (LME) was
constructed using pooled data. The model incorporated both
pre-ERT and post-ERT data by including a linear spline for
time with a knot at treatment week 0. This formulation
allows different slopes of the mean trend before and after
ERT initiation. A random intercept gives all individuals their
own regression lines with separate intercepts that deviate
from the population line. The longitudinal model includes
repeated measures over time and allows observations within
a patient to be correlated. The model uses empirical estimates
for the standard error, which in large samples “corrects”for
misspecifying the correlation structure. The model also
includes baseline height as a covariate.
“Time”refers to time from ERT initiation. Because data
were also obtained before the start of treatment, time includes
negative values. The length of follow-up for each trial phase
differs; most patients have at least 72−96 weeks of follow-up
after ERT initiation, and the LME method is flexible in that
patients do not have to have all measurements at all time
points. The availability of pretreatment data is also limited;
analysis therefore restricts the length of time to approximately
a 2-year window on either side of ERT initiation.
Results
Baseline data
The age of patients at time of enrollment in a clinical
therapy trial ranged from 5 to 29 years; the mean age was
approximately 12 years. An overview of baseline height
and pulmonary function data is presented in Table 3.As
expected, patients <12 years were shorter on average than
patients in the older age group, with a mean height of
99.4 cm versus 105.4 cm, respectively. Pulmonary function
parameters were significantly impaired for age in compar-
ison with a healthy population (Rosenthal et al. 1993). The
younger group showed mean values for FVC and FEV1 of
0.56 L and 0.52 L, respectively, whereas the older group
showed similar mean values of 0.55 L and 0.48 L,
respectively, for the same measures.
Mean observed improvement in pulmonary function
(FEV1, FVC, and MVV) during ERT
Data showing mean percent change in FEV1, FVC, and
MVV during ERT are presented in Fig. 1. Changes from
baseline in FEV1 and FVC were minimal up to 24 weeks of
Study Evaluation Treatment week
0 24 48 72 96 144 192 240
Phase 1/2 FVC X X X X X X X
FEV1 X X X X X X X
Height X X X X X X X
Phase 2 FVC X X X X X X PSC PSC
FEV1 X X X X X X PSC PSC
Height X X X X X X PSC PSC
Phase 3 rhASB/rhASB FVC X X X X PSC PSC PSC
FEV1 X X X X PSC PSC PSC
MVV X X X X PSC PSC PSC
Height X X X X X PSC PSC PSC
Phase 3 placebo/rhASB FVC X X X PSC PSC PSC PSC
FEV1 X X X PSC PSC PSC PSC
MVV X X X PSC PSC PSC PSC
Height X X X X PSC PSC PSC PSC
Table 2 Schedule of assessments
Phase 1/2 had no week 72 but
had week 84 PFT height
assessments. PSC, post-study
completion
Table 3 Combined Phase 1, Phase 2, and Phase 3 data: baseline height and pulmonary function
All patients; mean (range) Number Age <12years; mean (range) Number Age ≥12years; mean (range) Number
Height (cm) 101.9 (81.5, 136) 54 99.4 (81.5, 133) 32 105.4 (86, 136) 22
FVC (L) 0.56 (0.16, 1.74) 53 0.56 (0.16, 1.64) 32 0.55 (0.28, 1.74) 21
FEV1 (L) 0.50 (0.16, 1.67) 53 0.52 (0.16, 1.42) 32 0.48 (0.25, 1.67) 21
54 J Inherit Metab Dis (2010) 33:51–60

treatment with rhASB but increased thereafter through
96 weeks of treatment. For FVC and FEV1, those on
treatment for 72 weeks improved 14% from baseline on
average (p<0.001) for both outcomes. Those on treatment
for 96 weeks improved approximately 17% (p= 0.009) and
11% (p= 0.014), respectively, relative to baseline. Changes
in MVV occurred earlier. At 24 weeks of treatment, MVV
increased approximately 15% over baseline (p=0.021).
Although sample sizes beyond 144 weeks of treatment were
too small to make valid inferences, this trend of pulmonary
function improvement compared with baseline appears to
continue through 240 weeks of treatment.
Pulmonary function improvement from baseline relative
to growth
In order to examine whether the observed change in
pulmonary function could be attributed to growth, we
examined pulmonary function after dividing the population
into two groups based on age at time of treatment initiation:
older or younger than 12 years (Table 4; Fig. 2). The left
panel of Fig. 2graphs data obtained in patients <12 years.
Both FEV1 and FVC showed little change from baseline
during the first 24 weeks of ERT. By 96 weeks of treatment,
these parameters showed meaningful improvement, with
increases in FEV1 and FVC averaging approximately 10%
and 13%, respectively, with respect to baseline. Height
increased concomitantly with increases in FEV1 and FVC in
the younger age group.
The right panel of Fig. 2graphs similar data in older
patients (age≥12 years). As with the younger patients,
FEV1 and FVC did not improve relative to baseline in the
first 24 weeks but showed meaningful improvement in
subsequent weeks. For those on 96 weeks of treatment,
FEV1 and FVC improved from baseline by approximately
13% and 23%, respectively. However, in contrast to the
younger patient group, improvements in FEV1 and FVC
seen in older patients occurred despite a smaller percent
increase in height.
Mean rate of increase in pulmonary function parameters
(FVC, FEV1) prior to and following ERT initiation
The observed increases over time during ERT are described
using longitudinal modeling of the absolute changes in lung
function relative to baseline, defined as the week prior to
ERT initiation. The longitudinal models used all available
pre-ERT and post-ERT data.
Regression analyses
Model results showed improvements for all patients on
ERT compared with before ERT (Table 5;Fig.3). For
FEV1, the estimated mean value for all patients at baseline
was 0.49 L. For approximately 2 years prior to ERT, mean
FEV1 increased only 0.01 L on average. In contrast, over
2 years on ERT, mean FEV1 increased 0.06 L on average
(p<0.001) (Table 5). This improvement in FEV1
corresponds to an increase of approximately 12% relative
to baseline value. When patients were subdivided into
those <12 years versus ≥12 years, the change in FEV1
post-ERT still remained, corresponding to approximately
Weeks on ERT
Percent change
0 24 48 72 96 144 192 240
n*=53 53 34 28 33 14 5 5
*N refers to the number of patients for whom data were available for that particular timepoint;
sample sizes at each timepoint do not necessaril
y
include the same patients
0
10
20
30
40
50
Changes from baseline in FVC and FEV1 -
All ERT-Treated Patients (Phase 1, 2, and 3 Data)
FVC
FEV1
Weeks on ERT
Percent change
024487296
n=34 30 16 17 14
0
10
20
30
40
50
Changes from baseline in MVV -
ERT-Treated Phase 3 Data
Fig. 1 Mean percent change in FVC, FEV1, and MVV by treatment week over all available patient data
J Inherit Metab Dis (2010) 33:51–60 55

14% in the younger group and 11% in the older group
(refer to Table 5; small differences in percentages
between text and Table 5are related to actual data versus
modeled data).
For FVC, the estimated mean for all patients at baseline
was 0.54 L. In the 2 years prior to ERT, mean FVC increased
approximately 0.01 L on average. In contrast, over 2 years on
ERT, mean FVC increased 0.10 L on average (p<0.001)
(Table 5). This improvement in FVC corresponds to an
increase of approximately 19% relative to baseline value.
Both younger and older groups demonstrated improvement
in FVC after treatment (approximately 14% and 25%,
respectively) compared with lesser improvements before
treatment (refer to Table 5). For all parameters, the younger
group showed minimal or no improvement prior to treat-
ment, with significant improvement after ERT initiation.
Older patients demonstrated minor improvement in lung
function pre-ERT, with significant improvement after ERT
(Table 5).
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
Table 4 Combined Phase 1, Phase 2, and Phase 3 data: percent change height and pulmonary function from start of ERT by age group
Treatment
week
Number
a
FEV1 (L) FVC (L) Height (cm)
Observed
mean (SD)
% Change
mean (SD)
Observed
mean (SD)
% Change
mean (SD)
n Observed
mean (SD)
% Change
mean (SD)
Age <12 years
0 32 0.52 (0.26) –0.56 (0.31) –32 99.4 (11.1) –
24 32 0.52 (0.31) 0.96 (21.0) 0.57 (0.37) 1.5 (21.7) 32 101.0 (11.2) 1.6 (1.1)
48 17 0.62 (0.41) 7.1 (32.5) 0.69 (0.48) 6.8 (32.0) 30 102.9 (11.4) 3.6 (1.6)
72 20 0.55 (0.30) 15.3 (18.1) 0.57 (0.21) 17.5 (20.0) 29 103.4 (11.2) 4.9 (1.7)
96 17 0.64 (0.44) 9.6 (28.8) 0.73 (0.51) 12.5 (32.9) 27 105.7 (11.8) 5.5 (2.1)
144 7 0.75 (0.41) 11.1 (15.4) 0.91 (0.48) 17.6 (11.6) 9 110.6 (13.6) 8.6 (2.4)
192 3 0.73 (0.35) 16.4 (21.6) 0.99 (0.49) 39.6 (14.7) 3 116.2 (16.0) 8.6 (3.9)
240 3 0.70 (0.30) 13.6 (12.1) 0.98 (0.48) 39.8 (12.0) 3 120.2 (17.0) 12.2 (3.1)
Age ≥12 years
0 21 0.48 (0.30) –0.55 (0.32) –22 105.4 (12.8) –
24 21 0.49 (0.29) 2.6 (14.6) 0.54 (0.32) −2.0 (9.6) 22 106.3 (12.5) 0.9 (1.4)
48 17 0.54 (0.32) 8.2 (16.0) 0.60 (0.22) 5.2 (17.6) 20 109.1 (11.8) 1.8 (1.7)
72 8 0.47 (0.19) 9.7 (9.6) 0.52 (0.22) 6.5 (7.3) 17 109.9 (12.6) 2.7 (2.1)
96 16 0.57 (0.32) 12.9 (20.4) 0.74 (0.49) 22.6 (39.0) 19 110.2 (12.4) 2.4 (2.9)
144 7 0.49 (0.22) 17.0 (27.4) 0.57 (0.21) 20.2 (20.9) 10 107.9 (10.3) 1.2 (2.1)
192 2 0.47 (0.02) 35.9 (3.6) 0.52 (0.06) 49.0 (22.2) 2 96.5 (3.5) -1.5 (1.5)
240 2 0.39 (0.03) 14.5 (16.5) 0.46 (0.08) 30.6 (27.5) 2 100.1 (6.3) 2.0 (2.4)
Patient population will not necessarily include exactly the same patients at each timepoint.
a
Percent change FEV1 and FVC have same n
56 J Inherit Metab Dis (2010) 33:51–60

is similar to the achondroplasia patient population in which
small stature and dysplastic bone changes confound calcu-
lation 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
FEV1hasbeenreportedinneuromusculardisorders
(Serisier et al. 1982; Braun et al. 1983) and upper airway
obstruction (Engstroem et al. 1964), and therefore, im-
Model Predicted mean
at baseline
Time period N Predicted change
over 2 years (SE)
Pvalue
FEV1 (L) All patients 0.49 Pre-ERT 35 0.01±0.03 0.84
Post-ERT 53 0.06 ± 0.02 <0.001
Age <12 years 0.51 Pre-ERT 22 0.00 ± 0.02 0.93
Post-ERT 32 0.07 ± 0.02 0.005
Age ≥12 years 0.46 Pre-ERT 13 0.02 ±0.07 0.81
Post-ERT 21 0.05 ± 0.02 0.027
FVC (L) All patients 0.54 Pre-ERT 35 0.01 ± 0.03 0.71
Post-ERT 53 0.10 ± 0.03 <0.001
Age <12 years 0.56 Pre-ERT 22 -0.02 ± 0.02 0.47
Post-ERT 32 0.08 ± 0.02 0.001
Age ≥12 years 0.51 Pre-ERT 13 0.07± 0.09 0.41
Post-ERT 21 0.13 ± 0.06 0.036
Table 5 Predicted changes
over 2 years based on
longitudinal model results
Percent change
0 24 48 72 96 144 192 240
n=32 32 17 20 17 7 3 3
n=32 32 30 29 27 9 3 3
0
10
20
30
40
50
Weeks on ERT
FVC, FEV1
Height
Patient age < 12 years
FVC
FEV1
Height
0 24 48 72 96 144 192 240
n=21 21 17 8 16 7 2 2
n=22 22 20 17 19 10 2 2
0
10
20
30
40
50
Weeks on ERT
FVC, FEV1
Height
Patient age >= 12 years
FVC
FEV1
Height
Fig. 2 Mean percent change in height and pulmonary function by treatment week and age group over all available patient data
J Inherit Metab Dis (2010) 33:51–60 57

provement 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 improve-
ment. 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 5do 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 improve-
ment 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. Accord-
ingly, 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
FVC (L)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
2.0
2.1
2.2
Weeks prior to ERT Weeks on ERT
-96 -72 -48 -24 0 24 48 72 96
Fig. 3 Observed FVC (L) and modeled regression line. Dots show the
scatter of all patients’FVC measurements over time
58 J Inherit Metab Dis (2010) 33:51–60

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 contribu-
tions 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, Departa-
mento de Pediatria, Maceió, Brazil; Isabel Cristina Neves de Souza,
MD and Luiz Carlos Santana da Silva,PhD,UniversidadeFederaldo
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
Conflict of interest Drs. Harmatz, Beck, Giugliani, Berger, Steiner,
and Yu have provided consulting support to BioMarin Pharmaceutical
Inc, Novato, CA, USA. Dr. Hopwood has received commercial
research project funding to assist the development of enzyme
replacement therapy for MPS VI patients. Drs. Harmatz and Arash
each report receiving a speaker′s honorarium and travel support from
BioMarin. BioMarin is a supporter of the Lysosomal Disease Network′s
WORLD Symposium organized by Dr. Whitley. Drs. Swiedler and
Decker are former and current employees of BioMarin Pharmaceutical,
Inc., respectively; both are stockholders.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
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