On August 28, 2012, several amendments were made to this protocol. To view these amendments, please see the section titled “Summary of Protocol Amendments.”
Background and Objectives
Lysosomal storage disorders (LSD) comprise a group of inherited metabolic diseases (IMD) that occur secondary to genetic defects (eg, single substitutions, gene deletions) that result in the deficiency of enzymes that are needed in the catabolism of a number of biological macromolecules in lysosomes.1-3 These enzyme deficiencies cause substrates to accumulate within connective tissue, skeletal structure, and organs, resulting in progressive damage. LSDs are broadly divided into groups based on the nature of the stored substrate: mucopolysaccharidoses (MPS), lipidoses, glycogenoses, and oligosaccharidoses. LSDs are rare, with an estimated combined incidence of 1 in 1,500 to 7,000 live births. Some 50 different LSDs have been identified.3
For a majority of LSDs, therapeutic management consists of symptomatic care of disease manifestations, with no possibility for cure. Supportive care measures are disease specific, depending on the organs involved and degree of physical impairment. For example, patients with Gaucher’s Disease Type I, the most common LSD, may develop visceral problems (hepatomegaly, splenomegaly), anemia, thrombocytopenia, lung disease, severe bone pain (acute or chronic), avascular necrosis, and have growth impairment and pubertal delay.4 Supportive care may then consist of a combination of therapies that include blood transfusion, bed rest, analgesia, anti-inflammatory agents, hyperbaric oxygen, and surgery (splenectomy, orthopedic procedures). However, the advent of enzyme replacement therapy (ERT) offers an alternative to traditional management practices.5-9
The principle of ERT is to replace specific defective enzymes in LSD patients with in vitro synthesized functional enzymes. ERT products are administered by intravenous infusion, dosages determined by patient body weight, usually every other week, for the life of the patient. This approach is not curative. The infused enzymes are taken up by cells, into lysosomes, where they catabolize the substrates that have accumulated. Clinical outcomes potentially affected by ERT include survival, quality of life and ability to perform activities of daily living, cognitive development and function, neurodevelopmental function, and disease-specific symptomatic relief.
Currently, there are six ERT products that have received FDA marketing approval in the United States. Each is specific for a single disease: mucopolysaccharidosis I (Hurler disease), mucopolysaccharidosis II (Hunter disease), mucopolysaccharidosis VI (Maroteaux-Lamy syndrome), Fabry’s disease, Gaucher Type I, and Pompe disease (see Table). Accordingly, this report will focus on those six LSDs. These diseases in general do not have central nervous system manifestations, although this may vary by the severity of disease expression.
The objective of this technical brief is to provide an overview of the current state of FDA-approved ERT for the treatment of lysosomal storage disorders. The overview will present the clinical indications for each ERT, the potential benefits and harms associated with each ERT, and dosing and administration details of each ERT. This brief will also provide a discussion of the key unresolved or controversial issues surrounding the use of ERT to treat lysosomal storage diseases.
- What FDA-approved enzyme replacement therapy (ERT) products are available for lysosomal storage diseases (LSD)?
- What are the clinical indications for each FDA-approved ERT product?
- What are the theoretical benefits of ERT for LSDs?
- What are the potential safety issues and harms with ERT?
- What is the context in which each FDA-approved ERT product is used?
- What are the FDA-approved dose regimens for each ERT product?
- Where and by whom is ERT administered?
- What adjunct treatments are used with each FDA-approved ERT product?
- What published and unpublished studies have reported on the use and safety of this intervention? Provide a state of the current research for the following information on available studies:
- Type of ERT
- Indication/patient inclusion criteria
- Study design/size
- Comparator used in comparative studies
- Concurrent/prior treatments
- Length of follow up
- Outcomes measured
- Adverse events/harms/safety issues reported
- What are key unresolved or controversial issues with ERT in LSDs?
Several sources will be used to inform this technical brief. Information will be collected in a review of published medical literature, narrative review articles, a search of the grey literature, and discussions with Key Informants.
Guiding Questions 1 and 2 above will rely on information from published narrative reviews, clinical guidelines and information in the grey literature. The latter will include information culled from pharmaceutical companies, patient advocacy groups, and other sources as identified in an internet search.
Guiding Question 3 will be addressed through a review of the literature. Key Informants will provide guidance on the potential clinical outcomes of interest and the potential benefits and harms of ERT as the review is implemented.
Guiding Question 4 will rely on integrating information from Key Informants, grey literature, and narrative reviews.
1. Data Collection:
A. Discussions with Key Informants
The Key Informants include both content experts as well as patients. The content experts will include medical directors, pediatricians, neurologists, geneticists, and specialists in metabolic diseases, lysosomal storage diseases, and rare diseases.
At least one Key Informant group conference call will be scheduled. The Key Informants will provide general guidance on the literature review, for example, years to include in the search and potential clinical outcomes. Because this technical brief involves six distinct diseases, the content experts may have additional disease-specific information to contribute. As a follow-up to the group conference call, the Key Informants will be interviewed individually by telephone, using a semi-structured interview outline which will provide the content experts the opportunity to share their experiences with patients with lysosomal storage disorders, their experience with ERT, and their opinions on unresolved or controversial issues relating to ERT.
One call with the patient advocates is planned. Because of the nature of lysosomal storage diseases, patients are predominantly children, so one adult patient and one parent of a child patient will be consulted. The patient and the parent will be asked about their experiences with the disorder prior to ERT and subsequent to ERT. They will be asked to describe symptoms, outcomes, and factors involved in the decision to begin treatment with ERT.
B. Grey Literature search
Internet searches will be conducted in the United States Food and Drug Administration website concerning the 6 ERT treatments. Information will be used in answering Guiding Questions 1, 2, and 4.
The ERT manufacturers’ websites will be searched to inform Guiding Questions 1 and 2:
Biomarin Pharmaceuticals, http://www.bmrn.com/products/naglazyme.php, http://www.bmrn.com/products/aldurazyme.php
Genzyme Corporation, http://www.aldurazyme.com/global/az_us_home.asp, http://www.fabrazyme.com/global /fz_us_hp_homepage.asp, http://www.cerezyme.com/, http://www.myozyme.com/
Shire Human Genetic Therapies Inc., www.vpriv.com,
Registries and patient advocate websites for each of the 6 LSDs will be searched. Examples include: http://www.marrow.org/PATIENT/Undrstnd_Disease_Treat/Lrn_about_Disease/Metabolic_Storage/Hurler_and_Tx/index.html, http://www.mpssociety.co.uk/index.php?page=hunter-disease,
http://www.mpssociety.org.au/MPS%20Diseases/mpsviregistry.htm, https://www.registrynxt.com/Gaucher/Pages/RegistryNXTHome.aspx, https://www.lsdregistry.net/fabryregistry/, and http://www.pompe.com/en/healthcare-professionals/pompe-registry.aspx
Current trials involving ERT will be identified by searching clinicaltrials.gov.
C. Published Literature search
A scan of published medical literature will be conducted to address Guiding Question 3. English language searches will be performed in MEDLINE, Embase, the Cochrane Database, and the Health Technology Assessment Database. The search strategies were executed September 16, 2011, as follow.
Search 1 –
"Mucopolysaccharidosis I"[Mesh] OR ("mucopolysaccharidosis" AND "type 1") OR "mucopolysaccharidosis I" OR "mucopolysaccharidosis-I" OR "MPS I" OR "Hurler disease" OR "hurler syndrome"
laronidase OR aldurazyme
English language, humans
results in PubMed = 36
29 additional studies identified using the search in EMBASE = 15 appeared to be unique and possibly relevant
Cochrane search found 4 trials – all are in the database.
Search 2 –
"Mucopolysaccharidosis II"[Mesh] OR (mucopolysaccharidosis AND "type II") OR "mucopolysaccharidosis II" OR "mucopolysaccharidosis-II" OR "MPS II" OR "Hunter disease" OR "hunter syndrome"
"idursulfase" [Supplementary Concept] OR idursulfase OR elaprase
English language, humans
Results in PubMed = 34
67 additional studies identified using the search in EMBASE = 3 appeared to be unique and possibly relevant
Cochrane search found 1 protocol and 2 trials that were unique and added to the database.
Search 3 –
"Mucopolysaccharidosis VI"[Mesh] OR (mucopolysaccharidosis AND "type VI") OR "mucopolysaccharidosis VI" OR "mucopolysaccharidosis-VI" OR "MPS VI" OR "maroteaux-lamy syndrome"
"galsulfase" [Supplementary Concept] OR galsulfase OR naglazyme
English language, humans
Results in PubMed =21
24 additional studies identified using the search in EMBASE = 6 appeared to be unique and possibly relevant
Cochrane search found 1 new technology assessment which was added. Everything else was already there.
Search 4 –
"Fabry Disease"[Mesh] OR "fabry disease" OR "alpha-Galactosidase A Deficiency"
"agalsidase beta" [Supplementary Concept] OR "agalsidase beta" OR fabrazyme
English language, humans
Results in PubMed =132
130 studies identified using the search in EMBASE = 13 appeared to be unique and possibly relevant
Cochrane search found 2 additional trials which were added.
Search 5 –
"Gaucher Disease"[Mesh] OR "gaucher disease" OR "gaucher's disease"
(("alglucerase" [Supplementary Concept]) OR "imiglucerase" [Supplementary Concept]) OR "Velaglucerase alfa, human" [Supplementary Concept] OR alglucerase OR ceredase OR imiglucerase OR cerezyme OR velaglucerase OR "miglustat" [Supplementary Concept] OR miglustat OR zavesca
(“type 1” OR “type I”) OR various study types (RCT, meta-analysis, comparative study)
English language, humans
Results in PubMed =222
65 clinical studies identified in EMBASE = 4 appeared to be unique and possibly relevant
Cochrane search found 4 additional articles which were added.
Search 6 –
"Glycogen Storage Disease Type II"[Mesh] OR ("glycogen storage disease" AND ("type II" OR "type 2")) OR "pompe disease" OR "pompe's disease"
"GAA protein, human" [Supplementary Concept] OR "alglucosidase alfa" OR myozyme
English language, humans
Results in PubMed =99
41 clinical studies identified in EMBASE = 8 appeared to be unique and possibly relevant
Cochrane search found 2 trials – only 1 unique one – a meeting abstract – was added.
The DistillerSR Systematic Review Tool will be utilized to facilitate the screening and study selection process, as follows. Titles and abstracts will be screened to detect potential articles relevant to the topic. Full text articles of those marked as potentially relevant will be retrieved and screened for inclusion/exclusion in the review. Reports will be included if they describe clinical outcomes in patients with one of the 6 LSDs under consideration who received specific ERT for that disorder.
Due to the rarity of the diseases in this report, randomized clinical trials, simple before-after studies, case series and case reports will all be included. Reference lists of the included studies will also be reviewed to ensure that any relevant articles that may have been missed in the literature search, can then be added.
2. Data Organization and Presentation
A. Information Management
There are three main sources of information for this technical brief: published literature, grey literature, and key informants. Data from studies published in the medical literature will be abstracted and entered into the DistillerSR Systematic Review Tool. Data collected will include: study design, number of study subjects, severity of disease, ERT dosing and administration details, length of follow-up, pre-treatment physical and psychosocial measurements, post-treatment physical and psychosocial measurements, and adverse events. Information about clinical indications and dosing and administration recommendations, abstracted from guidelines and reviews in the medical literature and from pharmaceutical company websites, will be organized in a spreadsheet. Information from key informants, patient advocacy websites, and disease registries will be of a qualitative nature and will be managed in a Word document.
B. Data Presentation
There will be a graphical presentation of the level of evidence of ERT treatment for the 6 diseases, indicating the number of studies published and the number of patients included in the studies. The remaining data to be presented will be separated by disease. There will be summary tables of the published studies for each disease, which will include the following information: study design, patient population, pre-treatment physical and psychosocial measurements, post-treatment physical and psychosocial measurements, and adverse events. A narrative summary for each disease will incorporate the information gathered from the medical literature, the grey literature, and the key informants, and will describe the current state of ERT treatment, clinical indications, dosing and administration details, and a discussion of the key unresolved or controversial issues regarding the treatment.
- Burrow TA, Hopkin RJ, Leslie ND, et al. Enzyme reconstitution/replacement therapy for lysosomal storage diseases. Curr Opin Pediatr 2007 Dec;19(6):628-35. PMID: 18025928
- Heese BA. Current strategies in the management of lysosomal storage diseases. Semin Pediatr Neurol 2008 Sep;15(3):119-26. PMID: 18708002
- Staretz-Chacham O, Lang TC, LaMarca ME, et al. Lysosomal storage disorders in the newborn. Pediatrics 2009 Apr;123(4):1191-207. PMID: 19336380
- Grabowski GA. Gaucher's disease. Enzyme therapy is not enough. Lancet 2001 Dec;358 Suppl:S29. PMID: 11784578
- Beck M. Emerging drugs for lysosomal storage diseases. Expert Opin Emerg Drugs 2010 Sep;15(3):495-507. PMID: 20557271
- Beck M. Therapy for lysosomal storage disorders. IUBMB Life 2010 Jan;62(1):33-40. PMID: 20014233
- Brady RO. Enzyme replacement for lysosomal diseases. Annu Rev Med 2006;57:283-96. PMID: 16409150
- Brady RO, Schiffmann R. Enzyme-replacement therapy for metabolic storage disorders. Lancet Neurol 2004 Dec;3(12):752-6. PMID: 15556808
- Bruni S, Loschi L, Incerti C, et al. Update on treatment of lysosomal storage diseases. Acta Myol 2007 Jul;26(1):87-92. PMID: 17915580
Definition of Terms
ERT enzyme replacement therapy
GSD II glycogen storage disease type II (Pompe disease)
IMD inherited metabolic disorders
LSD lysosomal storage disorders
MPS I mucopolysaccharidosis I (Hurler disease)
MPS II mucopolysaccharidosis II (Hunter disease)
MPS VI mucopolysaccharidosis VI (Mariteaux-Lamy syndrome)
Summary of Protocol Amendments
Original study selection criteria in Protocol Methods:
During the Topic Refinement phase of this project, we did not anticipate the presence of randomized clinical trials (RCTs) for any of the LSDs or ERT products under study. However, a comprehensive electronic search of Medline, EMBASE, and the Cochrane Controlled Trials database showed that RCTs were available for all FDA-approved ERT products. There also were a number of prospective phase I and II clinical studies that complemented the RCTs. Given that RCTs comprise the best evidence in a hierarchy that takes into account risk of bias, and internal validity, we made a decision to compile the RCTs in the evidence map, supplementing them with prospective phase I and II studies that covered other clinical outcomes and patient subgroups. Given the existence of higher-level evidence, we did not include case series, case-control studies, or case reports in the evidence compilations presented in the body of the report.
Peer reviewers are invited to provide written comments on the draft report based on their clinical, content, or methodologic expertise. Peer review comments on the preliminary draft of the report are considered by the EPC in preparation of the final draft of the report. Peer reviewers do not participate in writing or editing of the final report or other products. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will be published three months after the publication of the Evidence report.
Potential Reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Invited Peer Reviewers may not have any financial conflict of interest greater than $10,000. Peer reviewers who disclose potential business or professional conflicts of interest may submit comments on draft reports through the public comment mechanism.
|Disease [estimated incidence]||Symptoms||FDA-Approved Product (approval date)|
|*Beutler E, Grabowski GA. Gaucher disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds.): The Metabolic and Molecular Bases of Inherited Disease (vol. 3, 8th ed.). New York: McGraw-Hill, 2001;3635-3668.
Kishnani PS, Chen YT. Defects in Metabolism of Carbohydrates. In: Kleigman RM, Behrman RE, Jenson HB, Stanton B, ed. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, Pa: Saunders Elsevier; 2007; chap 87.
McGovern MM, Desnick RJ. Lysosomal Storage Diseases. In: Goldman L, Ausiello DA, ed. Goldman Cecil Medicine, 23rd ed. Saunders Elsevier; 2007; chap 223.
McGovern MM, Desnick RJ. Lipidoses. In: Kleigman RM, Behrman RE, Jenson HB, Stanton B, ed. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, Pa: Saunders Elsevier; 2007b; chap 86.
Spranger J. Mucopolysaccharidoses. In: Kleigman RM, Behrman RE, Jenson HB, Stanton B, ed. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, Pa: Saunders Elsevier; 2007; chap 88.
Tinkle BT, Leslie N. Glycogen Storage Disease Type II (Pompe Disease). In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2007 Aug 31 [updated 2010 Aug 12].
|MPS I (Hurler disease), 1/100,000 live births||MPS I is a variable disorder with a wide range of symptoms that differ among patients in which symptoms develop, age at onset and severity. Though the symptoms manifest in a continuous spectrum among patients, for clinical purposes, they are categorized into the following 3 groups:
||Aldurazyme® (laronidase), Genzyme Corporation
|MPS II (Hunter disease), 1/155,000 live births
(1/34,000 live births in Israeli Jewish population)
|MPS II is an X-linked disorder. The clinical symptoms of MPS II are highly variable, differing among patients in which symptoms develop, age of onset and severity. For clinical purposes, MPS II is divided into two forms, a severe form and an attenuated form.
||Elaprase® (idursulfase), Shire Human Genetic Therapies Inc
|MPS VI (Maroteaux- Lamy syndrome), 1/340,000 live births||As with the other forms of MPS, the following vary among patients: which symptoms develop, age of onset of symptoms, and severity of symptoms. An enlarged head and deformed chest may be present at birth. Growth and development can be normal the first few years of life, but appear to stop around age 6. The clinical characteristics are similar to MPS I, except with a later onset and a slower progression of symptoms. Mental development is usually normal, but psychomotor skills are affected by the physical and visual impairments of the disease. Life expectancy depends on severity of symptoms, ranging from <20 yrs to later adulthood, with cause of death usually from heart disease or airway obstruction.||NAGLAZYME® (galsulfase), BioMarin Pharmaceutical Inc
|Fabry’s disease, 1/40,000 live male births||
||Fabrazyme® (agalsidase beta), Genzyme Corporation
|Gaucher Type I, overall 1/50,000 live births (1/500-1000 live births among Ashkenazi Jewish)||
|Glycogen Storage Disease type II (Pompe disease), 1/40,000 live births||There are two forms of Pompe disease.
||Myozyme® (alglucosidase alfa), Genzyme Corporation|