1. FRESH FROM THE PIPELINE
Galsulfase
John J. Hopwood, Guy Bate and Peter Kirkpatrick Galsulfase
In May 2005, galsulfase (Naglazyme;
BioMarin), a recombinant form of human
N-acetylgalactosamine 4-sulfatase, was
approved by the US FDA for the treatment
of patients with mucopolysaccharidosis
type VI, a rare lysosomal storage disorder
caused by a deficiency ofN–acetylga-
lactosamine 4-sulfatase. It is the first
approved product for the treatment of
mucopolysaccharidosis type VI, and has
been granted orphan drug status.
Lysosomal storage disorders are genetic
diseases that are caused by a deficiency of one
or more degradative enzymes necessary for
normal cell metabolism (TABLE 1)1
.In mucopol-
ysaccharidosis type VI (MPS-VI; Maroteaux–
Lamy syndrome), an autosomal recessive
disease, deficiency of N-acetylgalactosamine-
4-sulfatase leads to the accumulation of its
substrate, dermatan sulfate,in the lysosomes of
many cell types2
. Patients show severe skeletal
abnormalities as well as widespread soft-tissue
pathology, such as heart valvethickening, and
severely affected patients usually die between
late childhoodand early adulthood from
cardiac or respiratory complications2
.
For the majority of lysosomal storage
disorders, the only treatment option available
is bone-marrow transplantation (BMT)1,2
.
However, in the early 1990s, following
decades of research, it was demonstrated
that replacement of the deficient enzyme
involved in the lysosomal storage disorder
Gaucher disease, β-glucocerebrosidase,
could successfully treat the disease1
. This
provided the impetus for the development
of enzyme-replacement therapies for other
lysosomal storage disorders, such as the
mucopolysaccharidoses.
Basis of discovery
Mucopolysaccharides, also known as
glycosaminoglycans (GAGs), are linear
polymers of modified aminosugars and
acidic sugars that are important for the
structure and function of all tissues. GAGs
are recycled by uptake into the lysosome,
where they are degraded sequentially by
specific enzymes. Deficiency in any one of
these enzymes leads to accumulation of the
respective GAG substrate, and causes the
various mucopolysaccharidoses, such as
MPS-VI2
(TABLE 1).
In contrast to some lysosomal storage
disorders, MPS-VI is not characterized by
significant neurological involvement, and
so it is a possible candidate for enzyme-
replacement therapy. This led researchers
to assess the potential of recombinant
N-acetylgalactosamine-4-sulfatase,
referred to as galsulfase, for the treatment
of MPS-VI3
. After uptake, the enzyme was
processed normally in both normal and
MPS-VI fibroblasts, and was shown both to
correct the enzymatic defect and to initiate
degradation of dermatan sulfate in MPS-VI
fibroblasts3
. Studies in a cat model of MPS-
VI also indicated that enzyme-replacement
therapy would result in a significant
reduction in disease progression and tissue
pathology in patients with MPS-VI, and
that early intervention would be more
successful4,5
.
Drug properties
Galsulfase is a normal variant form of
human N-acetylgalactosamine 4-sulfatase
that is produced by recombinant DNA
technology in a Chinese hamster ovary
cell line6
. Galsulfase is a glycoprotein
comprising 495 amino acids, and contains
six asparagine-linked glycosylation sites,
four of which carry a bis-mannose-6-
phosphate mannose7
oligosaccharide
for specific cellular recognition6
. Post-
translational modification of cysteine-53
produces the catalytic amino acid residue
Cα-formylglycine, which is required for
enzyme activity6
.
Clinical data
Galsulfase has been studied in several
trials involving patients with MPS-VI6,7
.
The majority of patients had severe
manifestations of the disease, as evidenced
by poor performance on tests of physical
endurance6
.
In a randomized, double-blind,
placebo-controlled trial, 39 patients (aged
5–29 years) with MPS-VI received either
galsulfase (1 mg per kg as an intravenous
infusion) or placebo once-weekly for
24 weeks6
. After this time, patients that
received galsulfase showed greater mean
increases in the distance walked in 12
minutes (109 ± 154 m) and in the rate of
stair climbing in a 3-minute stair
climbing test (7.4 ± 9.9 stairs per minute)
compared with those receiving placebo
(26 ± 122 m and 2.7 ± 6.9 stairs per minute,
respectively)6
. Urinary GAG levels, which
were used as a measure of bioactivity,
decreased in patients treated with galsulfase
compared with those treated with placebo6
.
Following the double-blind period, 38
patients received open-label galsulfase
for 24 weeks6
. Patients who were initially
randomized to galsulfase and who
continued to receive it showed increases
in the distance walked in 12 minutes and
in the rate of stair climbing compared
with the start of the open-label period
(36 ± 97 m and 3 ± 7 stairs per minute,
respectively), as did patients who had
been randomized initially to placebo
(66 ± 133 m and 6 ± 8 stairs per minute,
respectively)6
.
Indications
Galsulfase is approved by the FDA for
patients with MPS-VI6
. Galsulfase has
been shown to improve walking and
stair-climbing capacity6
. ▶
Table 1 | Enzyme-replacement therapies for selected LSDs
Disease Deficient enzyme Development status of ERTs
MPS type I α-l-iduronidase Marketed
MPS type II Iduronate sulfastase Filed for regulatory approval
MPS type VI N-acetylgalactosamine-4-sulfatase Marketed
GaucherdiseasetypeI β-glucocerebrosidase Marketed
Fabry disease α-galactosidase A Marketed
Pompe disease α-glucosidase Filed for regulatory approval
ERT, enzyme-replacement therapy; LSD, lysosomal storage disease; MPS, mucopolysaccharidosis.
NEWS & ANALYSIS
NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | FEBRUARY 2006 | 101

2. ANALYSIS | DRUGS FOR LYSOSOMAL STORAGE DISORDERS
In their current forms, however, each of
these therapies have significant limitations,
and several challenges remain. First is
the ability to treat all sites of pathology.
For example, intravenously administered
lysosomal enzymes are rapidly taken out of
circulation by a receptor-mediated process4
. In
addition, the transfer of administered enzyme
from the circulation to areas such as the central
nervous system (CNS) or to joint capsules is
poor because of the blood–brain barrier (BBB)
and the poor vascularization of joint tissues,
respectively. At present, only direct injection
of enzyme into the cerebrospinal fluid has
been shown to significantly reduce lysosomal
storage in the brain of MPS-I dogs8
.
Second is the ability to provide a single-
step therapy to continuously provide enzyme
to all sites of pathology. At present, ERT
requires weekly or fortnightly injections of
enzyme and up to a day-stay in hospital.
Over the long-term, this can negatively affect
therapy compliance. Gene therapy options
are considered the probable solution to this
problem, but significant technical and safety
problems need to be addressed before this
approach lives up to its promise.
Third is the ability to predict the
presence and nature of irreversible
pathology. For example, it is expected that
some CNS and skeletal pathologies may
become irreversible in MPS-I patients in
the first year of life; similarly, maximum
benefit in relief of skeletal pathology in
MPS-VI requires ERT to begin at birth in
asymptomatic cats5
. So, to maximize the
benefits of therapy in LSD it is essential that
patients are identified as early as possible,
ideally in the newborn period when most
seem asymptomatic. Several methods
using dried blood spots have recently
been proposed to enable screening of the
newborn population9,10
.
Finally, the ability to predict the rate
of clinical progression of pathology in
individuals detected during an asymptomatic
period will become an important issue for
clinicians upon the introduction of newborn
screening for these disorders and will affect
the choice of appropriate treatment and
when it should commence.
John Hopwood is at the Lysosomal Diseases Research
Unit, Women’s and Children’s Hospital, 72 King William
Road, North Adelaide, South Australia 5006, Australia.
Guy Bate is at IMS Health, 7 Harewood Avenue,
London NW1 6JB, UK. Peter Kirkpatrick is at Nature
Reviews Drug Discovery, UK.
e-mails: john.hopwood@adelaide.edu.au;
gbate@uk.imshealth.com; p.kirkpatrick@nature.com
doi:10.1038/nrd1962
1. Desnick, R. J. & Schuchman, E. H. Enzyme replacement
and enhancement therapies: lessons from lysosomal
disorders. Nature Rev. Genet. 3, 954–966 (2002).
2. Neufeld, E. F. & Muenzer, J. inThe Metabolic and
Molecular Bases of Inherited Disease (eds Scriver, C.
et al.) 3421–3452 (McGraw-Hill, New York, 2001).
3. Anson, D. S. et al. Correction of human
mucopolysaccharidosis type-VI fibroblasts with
recombinant N-acetylgalactosamine-4-sulphatase.
Biochem. J. 284, 789–794 (1992).
4. Crawley, A. C. et al. Enzyme replacement therapy in a
feline model of Maroteaux–Lamy syndrome. J. Clin.
Invest. 97, 1864–1873 (1996).
5. Crawley, A. C. et al. Enzyme replacement therapy from
birth in a feline model of mucopolysaccharidosis type
VI. J. Clin. Invest. 99, 651–662 (1997).
6. FDA labelling information [online], <http://www.fda.
gov/cder/foi/label/2005/021877lbl.pdf> (2005).
7. Harmatz, P. et al. Enzyme replacement therapy in
mucopolysaccharidosis type VI (Maroteaux–Lamy
syndrome). J. Pediatr. 144, 574–580 (2004).
8. Kakkis, E. et al. Intrathecal enzyme replacement
therapy reduces lysosomal storage in the brain and
meninges of the canine model of MPS I. Mol. Genet.
Metab. 83, 163–174 (2004).
9. Meikle, P. J. et al. Newborn screening for lysosomal
storage disorders: evaluation of protein profiling.
J. Inherit. Met. Dis. 28, 14 (2005).
10. Li, Y. et al. (2004) Direct multiplex assay of lysosomal
enzymes in dried blood spots for newborn screening.
Clin. Chem. 50, 1785–1796 (2004).
11. Meikle, P. J., Hopwood, J. J. & Clague, A. E. Prevalence
of lysosomal storage disorders. JAMA 281, 249–254
(1999).
12. Genzyme data <http://www.genzyme.com> (2006).
13. Shire data <http://www.shire.com> (2006).
Analysing clinical issues in the treatment of
lysosomal storage disorders is Professor John
Hopwood, Ph.D., Head of the Lysosomal
Diseases Research Unit, Women’s and
Children’s Hospital, North Adelaide, Australia.
What are the current needs and challenges
in the development of therapies for
lysosomal storage disorders?
The ability to treat lysosomal storage
disorders (LSD) has improved dramatically
over the past 10–15 years. Enzyme-
replacement therapy (ERT) has been trialled
and/or approved for clinical use for several
disorders, namely Gaucher disease, Fabry
disease, MPS-I, MPS-II, MPS-VI and Pompe
disease. Other forms of therapy, such as
small-molecule chaperone therapy and
substrate deprivation, are also in trials, and
are likely to provide useful adjunct methods
of treatment. One such drug, miglustat
(Zavesca; Actelion), has been approved for
the treatment of type I Gaucher disease.
Gene therapy is perhaps the ultimate
treatment method for LSD, and current
research is directed towards evaluating the
use of various types of viral vectors.
▶
Box 1 | Market analysis
Analysing the market for drugs to treat lysosomal storage disorders is Guy Bate, Ph.D., Principal,
Product & Portfolio Development, IMS Consulting & Services, IMS Health, London, UK.
Lysosomal storage disorder market.There are nearly 50 forms of LSD. Individually, these different
forms are very rare, but together they are thought to affect 1 in 7,700 newborn infants11
. The
pharmaceutical market for these disorders is niche and is currently limited to treatments for Fabry
disease, Gaucher disease and some forms of mucopolysaccharidosis (MPS). Additional treatments
are in clinical development for disorders such as Hunter syndrome, Pompe disease and Niemann–
Pick disease. We estimate that the worldwide pharmaceutical market for LSDs is worth close to
US$1.5 billion per year12,13
. Worldwide sales growth was 20% over the previous 12-month period,
associated with double-digit growth for all products12,13
.
The major companies in the field of LSDs are Genzyme, Shire and BioMarin, which markets
galsulfase. Genzyme has three key marketed enzyme replacement therapies for LSDs: imiglucerase
(Cerezyme) for type 1 Gaucher disease (which has largely replaced Genzyme’s earlier non-
recombinant form, alglucerase; Ceredase), agalsidase beta (Fabrazyme) for Fabry disease and
laronidase (Aldurazyme) for MPS -I, which is the product of a joint venture with BioMarin. This
portfolio was worth more than US$1.3 billion in the 12 months to December 2005, growing ~20%
over the previous 12-month period12
. A decision on marketing approval is pending for a fourth
treatment, alglucosidase alfa (Myozyme), for Pompe disease. Shire has one LSD treatment on the
market, agalsidase alfa (Replagal) for Fabry disease, which was added to Shire’s portfolio following
the acquisition of Transkaryotic Therapies. Agalsidase alfa could soon be joined by idusulfase
(Elaprase), which was filed in the United States and Europe for MPS-II (Hunter syndrome) in the
fourth quarter of 2005.
Galsulfase. Galsulfase is the first specific therapy for MPS-VI and received US orphan drug status,
providing 7 years of market exclusivity. The agent was launched in the United States in June 2005
and had sales of US$2.3 million in the first full quarter on the market (Q3, 2005). On 15 September
2005, BioMarin received a positive opinion from the EMEA, with European marketing approval
expected in the first quarter of 2006.
NEWS & ANALYSIS
102 | FEBRUARY 2006 | VOLUME 5 www.nature.com/reviews/drugdisc