Miglustat in patients with Niemann-Pick disease Type C (NP-C): A ...

Miglustat in patients with Niemann-Pick disease Type C (NP-C): A multicenter
observational retrospective cohort study
M. Pineda a, *, J.E. Wraith b , E. Mengel c , F. Sedel d , W.-L. Hwu e , M. Rohrbach f , B. Bembi g , M. Walterfang h ,
G.C. Korenke i , T. Marquardt j , C. Luzy k , R. Giorgino k , M.C. Patterson l
a
Hospital Sant Joan de Deu, Barcelona, Spain
b
Royal Manchester Children’s Hospital, UK
c
Villa Metabolica, University of Mainz, Mainz, Germany
d
Hôpital Pitié Salpêtrière and Reference Centre for Lysosomal Diseases, Paris, France
e
National Taiwan University Hospital, Taipei, Taiwan
f
Kinderspital, Zürich, Switzerland
g
Regional Coordinator Centre for Rare Diseases, University Hospital, Udine, Italy
h
Royal Melbourne Hospital, Melbourne, Australia
i
Elisabeth Kinderkrankenhaus, Oldenburg, Germany
j
Universität Münster, Münster, Germany
k
Actelion Pharmaceuticals Ltd., Allschwil, Switzerland
l
Mayo Clinic, Rochester, MN, USA
article info
Article history:
Received 15 May 2009
Received in revised form 2 July 2009
Accepted 3 July 2009
Available online 4 August 2009
Keywords:
Niemann-Pick disease Type C
Miglustat
Observational
Cohort
Progression
Disability
Introduction
abstract
Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive
disorder characterized by progressive neurological deterioration
and invariably leading to premature death [1,2]. The disease
is caused by mutations in either one of the two genes, NPC1 or
NPC2 [3–6], which encode proteins involved in the regulation of
normal intracellular lipid trafficking through sequential activities
within a common pathway [7]. Expression of the mutant genes
* Corresponding author. Address: Hospital Sant Joan de Déu, Passeig de Sant Joan
de Déu No. 2, Esplugues, Barcelona 8950, Spain. Fax: +34 93 203 3959.
E-mail address: pineda@hsjdbcn.org (M. Pineda).
1096-7192/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.ymgme.2009.07.003
Molecular Genetics and Metabolism 98 (2009) 243–249
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism
journal homepage: www.elsevier.com/locate/ymgme
Miglustat has been shown to stabilize disease progression in children, juveniles and adults with Niemann-Pick
disease type C (NP-C), a rare genetic disorder characterized by progressive neurological deterioration.
We report findings from a retrospective observational cohort study assessing the effects of
miglustat on neurological disease progression in patients treated in the clinical practice setting. Data
from all NP-C patients prescribed miglustat at 25 expert centers were evaluated using a disease disability
scale. The scale analyzed four key parameters of neurological disease progression in NP-C (ambulation,
manipulation, language, swallowing). Mean individual parameter scores and a composite score were calculated
at baseline (time of diagnosis) and up to 4 follow-up visits. Overall, 66 patients were included
(mean [SD] age at diagnosis, 9.7 [7.6] years, and at treatment start, 12.8 [9.5] years). The median (range)
miglustat exposure was 1.46 (0.05–4.51) years. Mean annual progression was +0.11 score units/year from
diagnosis to treatment start, indicating disease progression prior to therapy, and decreasing to 0.01
score units/year from treatment start to last clinic visit, indicating stabilization. Stabilization of neurological
disease on miglustat was observed in all age groups, but the magnitude of the effect was greater in
patients diagnosed in late childhood and in juveniles and adults. Stabilization of neurological disease was
also observed in a subset of 19 patients with extended pre-treatment information. Overall, these data
support previous clinical trial findings indicating clinically relevant beneficial effects of miglustat on neurological
disease progression in patients with NP-C.
Ó 2009 Elsevier Inc. All rights reserved.
leads to severely impaired intracellular lipid transport and marked
accumulation of both unesterified cholesterol and several glycosphingolipids
in a variety of tissue and organs, in particular the
brain [6,8,9]. NPC1 and NPC2 mutations are inherited in an autosomal
recessive manner, and generally occur sporadically across populations,
regardless of race. Estimates of the frequency of NP-C
vary, but an incidence of 1 in every 150,000 live births has been
calculated [10–14].
NP-C has a highly variable clinical presentation. Neurological
features include abnormal saccadic eye movements, ataxia, dystonia,
dysarthria and dysphagia [1,2,15–17]; systemic symptoms include
hepatosplenomegaly and, rarely, pulmonary infiltrates [18].
NP-C can present clinically at any age, but is most commonly diag-

244 M. Pineda et al. / Molecular Genetics and Metabolism 98 (2009) 243–249
nosed in infants (younger than 6 years) and children (aged 6–
15 years) [1,17–19]. However, patients can also first present
throughout adulthood (beyond 18 years) [11,20–22].
The symptomatology and rate of disease progression are
strongly influenced by age at disease onset [17,23]. Neonataland
early infantile-onset disease generally manifests as non-specific,
severe liver dysfunction/failure and organomegaly [17,18,
24,25], childhood-onset forms feature rapid neurological deterioration
and variable organomegaly [1,19,26–28], and late-onset patients
generally present during adolescence and adulthood with
varying combinations of slowly progressing ataxia, movement disorders,
dementia or major psychiatric illness [11,20,21,29].
There is no cure for NP-C, but palliative therapy can alleviate
some symptoms of the disease [30]. Miglustat is a small iminosugar
molecule that reversibly inhibits glucosylceramide synthase, the
enzyme that catalyzes the first committed step of glycosphingolipid
synthesis [31,32]. It was developed as a potential therapy
for NP-C based on preclinical studies demonstrating its ability to
cross the blood–brain barrier [33], and to reduce excess storage
of brain gangliosides and prolong survival in animal models of
NP-C [34]. Recent findings suggest that miglustat might also affect
other pathogenetic cellular pathways in NP-C, involved with calcium
homeostasis [35,36]. Miglustat was recently approved in Europe
for the treatment of progressive neurological manifestations in
adult and pediatric patients with NP-C [37]. Miglustat is the first
approved therapy for NP-C.
A clinical trial indicated that miglustat can stabilize neurological
disease in children, juveniles and adults with NP-C over
12 months [38], and therapeutic benefits were maintained up to
48 months during subsequent extension treatment [39,40]. Miglustat
was well tolerated up to 66 months [41]. Here, we present
findings from an observational retrospective cohort study conducted
to further assess the effects of miglustat on neurological
disease progression in NP-C patients treated with miglustat in
the clinical setting, outside the context of clinical trials.
Methods
Study design and patients
This was an international, multicenter observational study conducted
in 25 selected expert centers in Australia, Belgium, Brazil,
France, Germany, Italy, Spain, Switzerland, Taiwan, the Netherlands,
the UK and the USA. The period of observation started in
2003 and ended in July 2008. Treating physicians at each participating
center entered demographic and clinical data from all patients
with NP-C at their centers who were treated or had
previously received treatment with miglustat (outside the context
of clinical trials). The coverage of multiple international centers in
this study was aimed toward capturing a majority proportion of all
patients treated with miglustat in clinical practice, and the subsequent
size of the study cohort ensured that the patients evaluated
provided a representative sample of the overall NP-C population.
All patients were required to have a confirmed diagnosis of NP-C
based on biochemical and/or molecular genetic laboratory tests.
The recommended daily dose of miglustat in juveniles and
adults is 200 mg t.i.d. [37]. In patients under 12 years of age, miglustat
doses are calculated on the basis of body surface area.
Physicians were asked to complete a secure, web-based questionnaire
designed to collect retrospective data on demographics
at diagnosis, treatment history, neurological disease progression
and general health for each eligible patient. Information on reasons
for discontinuation of treatment in patients who were no longer on
miglustat therapy was also collected.
This study was carried out in accordance with criteria and procedures
outlined in the declaration of Helsinki, and in compliance
with US Food and Drug Administration regulations and ICH Good
Clinical Practice guidelines. Written, informed consent was obtained
from all patients or their legal representatives before any
data were supplied.
Disease-specific disability scale
Data on the progression of neurological disease parameters specific
to NP-C were recorded using a previously published functional
disability scale, originally developed by Iturriaga et al. [23]. This
measure evaluates ambulation, manipulation, language and swallowing,
with patient performance rated on a 4- or 5-point scale
per parameter. In this study, the original scoring system was modified
by assigning scores from 0 (best) to 1 unit (worst), with equal
weighting for each parameter. Ambulation is rated across five
severity categories, from normal (score = 0) through to wheelchair-bound
(score = 1). Language is also rated across five categories,
from normal (score = 0) through to ‘absence of
communication’ (score = 1). Manipulation and swallowing are both
rated across four severity categories: normal (score = 0) to severe
dystonia/dysmetria (score = 1) for manipulation and normal
(score = 0) through to nasogastric tube or gastric button feeding
(score = 1) for swallowing. Disability scale assessments were collected
at three time points: time of diagnosis, treatment start
and at last clinical contact.
Data analysis
This was an observational study. Quantitative analyses of disability
scores were conducted based on descriptive statistics, using
both individual disability scores and a composite disability score.
The composite disability score was calculated for each patient as
the mean of all four individual disability scores. Data available at
each follow-up time point are reported (observed-case analysis),
including data from patients in whom treatment was stopped
(due either to adverse events or disease progression). Annual rates
of change in individual and composite disability scores were calculated
based on mean (95%CI) changes in absolute values from baseline
at the three follow-up assessments (baseline, treatment start
and last clinic visit), with adjustment for time intervals between
these time points.
An analysis of patient responses to treatment was undertaken
based on the number of improved or stable individual parameters
after initiation of miglustat treatment. Two patient groups were
defined: (1) patients with P3 out of four individual parameters
improved/stable after treatment with miglustat and (2) patients
with

Results
Patients and treatment
A total of 66 questionnaires corresponding to 66 patients were
collected across 25 centers covering a wide range of both EU and
non-EU countries. The numbers of patients assessed per country
were as follows: Australia (2), Belgium (1), Brazil (2), France (6),
Germany (14), Italy (2), Spain (12), Switzerland (4), Taiwan (4),
the Netherlands (2), the UK (7) and the USA (10). The demographics
and patient characteristics of this cohort are summarized in Table
1.
The mean (SD) observational period between diagnosis and
initiation of miglustat therapy was 3.1 (3.4) years. Overall, patients
had been on treatment with miglustat for a mean (SD)
duration of 1.5 (1.1) years; the median (range) miglustat
exposure was 1.5 (0.1–4.5) years. At the time of data collection,
treatment had been discontinued in 12 (18.2%) patients; reasons
for discontinuation, which could be multiple per patient, included
adverse events (n = 6), death (n = 4), perceived lack of
efficacy (n = 2) and, patients lost to follow-up (n = 1) and ‘other
reasons’ (n = 3).
Miglustat dose information was available for 61 patients. The
overall mean (95%CI) daily miglustat dose was 350.9 (303.8,
397.9) mg. Mean (95%CI) daily dose was 197.7 (138.0, 257.3) mg
among patients aged

246 M. Pineda et al. / Molecular Genetics and Metabolism 98 (2009) 243–249
Fig. 1. Disability scores for (a) ambulation, (b) manipulation, (c) language and (d) swallowing at diagnosis, treatment start and after miglustat treatment. * Percentages
calculated relative to number of evaluable patients for each parameter; n1 = total evaluated, n2 = number patients missing evaluation.
of miglustat was 453 (159) mg. At last visit, 17/19 (89%) patients
were on active treatment with miglustat, and 2/19 (11%) had discontinued
therapy.
Continuous, time-dependent progression was observed in evaluations
of mean composite disability score during the observa-
tional period prior to miglustat therapy. Mean (95%CI) composite
scores at diagnosis, Visit 2, Visit 3, and treatment start were 0.18
(0.13 0.23), 0.24 (0.18, 0.31), 0.32 (0.25, 0.40), and 0.48 (0.39
0.57), respectively; no patients exhibited spontaneous improvement.
The composite disability score indicated improvement/sta-

ilization of neurological disease after miglustat therapy (mean
[95%CI] composite score, 0.44 [0.34, 0.55] units/year).
Discussion and conclusion
There is agreement that disease stabilization is the best attainable
therapeutic goal in patients with NP-C exhibiting neurological
manifestations [42]. These observational cohort study data indicate
that miglustat stabilizes neurological disease in the majority
of patients with NP-C, as indicated by improvement or stabilization
of all four key parameters of neurological disease progression
(ambulation, manipulation, language and swallowing) analyzed
in this study. The data from the observational period prior to
miglustat treatment indicated a deterioration of all four neurological
parameters assessed, prior to therapy. In line with previous
data [2,17,23], disease progression was greater in the early childhood-onset
group and lower among juveniles/adults.
M. Pineda et al. / Molecular Genetics and Metabolism 98 (2009) 243–249 247
Fig. 2. Annual changes in composite disability scores by age group. * Total number of patients per age group.
Fig. 3. Annual changes in composite disability scores in all patients and those with progressive neurological disease. * Total number of patients per age group.
Overall, the pattern of changes observed on all four neurological
parameters during treatment with miglustat are consistent with
findings from the clinical trial with miglustat, which indicated
long-term therapeutic benefits in children and in juvenile/adult
patients with NP-C [38–40]. While the majority (up to 65%) of patients
in the overall cohort experienced deterioration prior to therapy,
75% were categorized as stable/improved following a mean
(SD) of 1.5 (1.1) years after miglustat treatment. The composite
disability score also indicated overall stabilization of neurological
disease.
In this cohort, patients’ response to miglustat therapy was
dependent on their age at diagnosis. Disease progression rate decreased
during miglustat treatment in all age groups. Treatment effect
appeared greatest in juveniles/adults, but a reduction in
progression rate was also observed in patients diagnosed in early
childhood. In addition, the magnitude of treatment effect was
greater in patients with progressive neurological disease between
diagnosis and treatment start. The minority of patients who

248 M. Pineda et al. / Molecular Genetics and Metabolism 98 (2009) 243–249
showed deterioration during miglustat therapy were those who
were at a more advanced stage of the disease. As suggested by findings
from a recent study modeling the disease course of NP-C [43],
these patients were less likely to benefit from miglustat owing to
significant irreversible neuronal damage that had likely occurred
before initiation of miglustat.
This retrospective observational study, conducted among international,
expert centers, is subject to a number of limitations and
inherent sources of potential bias. While it was not possible to include
a control group in the study design owing to the retrospective
nature of this analysis, the subset of 19 patients with
extended pre-treatment data could be considered as a within-subject
control group, confirming the finding from the main cohort
that invariable disease progression occurred prior to miglustat
therapy, and supporting the finding of reduced progression after
initiation of miglustat. The regional distribution of patients included
in the analysis was variable, but this is likely related to
the different national organization of healthcare for rare diseases
among the countries of the participating centers. While it is unknown
if this could have affected study outcomes, we consider this
patient cohort to be representative of the overall treated NP-C population.
Baseline patient characteristics (age at onset, gender distribution)
were comparable with those described in other studies
[1,2,17]. Moreover, the overall cohort of 66 patients represents
the majority of the estimated population of diagnosed NP-C patients
treated with miglustat in the clinical setting.
All centers known to treat NP-C patients with miglustat were
identified and invited to participate. Participation was on a voluntary
basis, and each participating center included data from all patients
undergoing treatment, without exclusion. Of note, the
discontinuation rate among patients included in this worldwide
study was comparable with that recently reported in NP-C patients
treated with miglustat as part of an ongoing European post-marketing
surveillance (PMS) program [44]. In addition, the efficacy
analysis included data from all patients in whom miglustat treatment
was stopped. It is therefore unlikely that our observational
study population was subject to selection bias based on positive
treatment benefit. Of note, standard care remained unchanged during
the pre-treatment observation period.
Presently, there are no clinical tools that have been validated for
monitoring disease progression in NP-C. The disease-specific disability
scale offered a valuable and easy-to-use tool for standardizing
clinical assessments across the participating centers. It
incorporates four well recognized parameters of neurological disease
progression in NP-C that are considered clinically relevant
across all patient age groups, and has previously been used in a
Spanish cohort of 30 patients with NP-C (three peri-natal, 13 infantile,
11 juvenile and three adult cases) [23]. In the present study,
this scale allowed the identification of distinct differences in disease
progression rate among patient subgroups, both on and off
treatment with miglustat. An international disease registry for
NP-C patients will be implemented soon and will include this scale
as one of the standard monitoring assessments. This will yield further,
valuable long-term information on the utility of this scale in
monitoring disease progression and treatment response.
An innate limitation of the disability scale is that it does not
capture psychiatric manifestations; psychiatric impairment is a
common manifestation among adolescent and adult patients
with NP-C [20,21]. However, while our cohort did contain a significant
number of such patients, inclusion of a psychiatric symptom
parameter would have skewed the composite score data
because not all patients would exhibit psychiatric symptoms,
particularly very young patients with early-onset disease. Further,
prospective studies would be required to address psychiatric
manifestations in addition to the standard four parameters
assessed here.
Based as it is on data from clinical site experience, this cohort
represents the largest sample of patients with NP-C studied to
date. There are relatively few published reports of findings from
‘real-world’ experience with miglustat. Our findings support those
from case studies. For instance, Chien et al. [45] reported improved
swallowing over a time course of 6 months in one patient, and reported
improved ambulation over 6–12 months in a second. Santos
et al. [46] reported notably improved ambulation in a Brazilian
case study following 12 months of miglustat therapy. Galanaud
et al. [47] reported general clinical improvement/stabilization
and improved brain function in three patients included in a French
case series.
Collection of data on the safety/tolerability of miglustat in NP-C
was not in the scope of this study. However, the mean dose of
miglustat used in this cohort of patients was similar to that used
in a previous clinical trial investigating the efficacy and safety of
miglustat in patients with NP-C [38,40]. The safety/tolerability of
miglustat 200 mg t.i.d. in patients with NP-C evaluated in this clinical
trial was shown to be consistent with that seen during previous
trials in Gaucher disease type 1, where half the clinical dose
(100 mg t.i.d.) is used [37]. The safety/tolerability profile of miglustat
has also been shown to be comparable between pediatric and
adult/juvenile patients with NP-C [38,40]. Further safety/tolerability
data have been collected in the ongoing miglustat PMS study.
In conclusion, there is consensus that stabilization of neurological
disease is the best attainable therapeutic goal in NP-C patients
presenting with neurological manifestations, which reflect underlying
irreversible neuronal loss/damage. This study indicates that
miglustat can stabilize neurological disease in most patients, particularly
in juveniles and adults. Age at diagnosis influenced response
to treatment, and clinical benefit (i.e. slowing of disease
progression) was also seen in the earliest childhood forms.
Acknowledgments and disclosures
The authors would like to thank Peter Schieber from Actelion
Pharmaceuticals Ltd., for his help in data collection, and extend
gratitude to the following investigators, for their contributions of
patient data: Dr. D. Cassiman, Leuven, Belgium; Dr. M. Cochran,
Tuscon, USA; Dr. P.M. Fernhoff, Atlanta, USA; Dr. R. Greenstein,
West Hartford, USA; Dr. C. Haase, Jena, Germany; Dr. B. Heron,
Paris, France; Dr. R. Lachmann, London, UK; Dr. M. Noetzel, St.
Louis, USA; Dr M. Schmitz dos Santos, Curitiba, Brazil; Dr. L.S. Smit,
Rotterdam, the Netherlands; Dr. M. Clayton, London, UK; Dr. F.A.
Wijburg, Amsterdam, the Netherlands; Dr. S. Winter, California,
USA; Dr. A.L. Yanai, Mato Grosso, Brazil.
This research was sponsored by Actelion Pharmaceuticals Ltd.
Alpha-Plus Medical Communications provided medical writing
assistance, paid for by Actelion Pharmaceuticals Ltd. Dr. Wraith is
supported by the Manchester Academic Health Sciences Centre
(MAHSC) and the NIHR Manchester Biomedical Research Centre.
All authors read, contributed to and approved this paper, and the
decision to submit this report to peer review, for publication,
was reached by consensus among all listed authors.
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