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

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