Systematic Review of the Long-Term Effectiveness and Safety of Enzyme Replacement Therapy in Mucopolysaccharidoses Disorders and Pompe Disease

Ana Pantovic (first author)
Duration: April –  September 2025 (5 PM)
Language: English (with German summary)

Background:
Lysosomal storage disorders (LSD) include rare inherited metabolic disorders involving impaired functions of specific enzymes located within the lysosomes. These disorders can be further categorized into four groups, two of which are known as glycogen storage disorders (GSD) and mucopolysaccharidoses (MPS).

Pompe disease belongs to the GSD group of lysosomal storage disorders and is known as glycogen storage disease type 2. This is a rare, inherited, progressive muscle disorder that affects mobility and breathing. It is caused by a deficiency of the enzyme acid alfa-glucosidase (GAA), leading to lysosomal glycogen accumulation and muscle damage, including the diaphragm and skeletal muscles. Incidence rates vary, with one Austrian study estimating a combined early- and late-onset incidence of 1 in 8,686 [4], and a more recent study estimated the prevalence of 1 in 350,914 [5]. Two types of Pompe disease exist. Infantile-onset Pompe disease (IOPD) involves little to no GAA activity and typically occurs in early infancy with cardiomyopathy and hypotonia, often resulting in fatal cardiorespiratory failure within the first year if untreated [6]. In contrast, late-onset Pompe disease (LOPD) retains some enzyme activity, leading to a milder but progressive course with muscle weakness and respiratory issues emerging later in life.

MPS are a group of rare inherited lysosomal storage disorders characterized by a reduced or complete inability to break down complex sugars known as glycosaminoglycans. There are several types of MPS, classified based on the specific enzyme deficiency and the resulting clinical manifestations. The project focuses on the following three types of MPS disorders:

• Mucopolysaccharidosis Type I (MPS I) results from a deficiency in the enzyme alfa-L-iduronidase, preventing lysosomes from breaking down dermatan sulphate and heparan sulphate. There are three MPS I sub-types:
  • Hurler syndrome: Most severe type, presenting in the first year of life with varied symptoms like cardiomyopathy, recurrent ear-nose-throat issues, and coarse facial features, including short stature, bony deformities, developmental delay, hepatosplenomegaly, and corneal clouding develop later. Untreated, it results in death by adolescence.
  • Hurler-Scheie syndrome: Intermediate severity.
  • Scheie syndrome: Least severe, children are intellectually normal but may face disabilities from degenerative bony disease, corneal opacity, and valvular heart disease.

The estimated prevalence is 1 in 100,000, with Hurler syndrome comprising 57% of cases, Hurler-Scheie syndrome 23%, and Scheie syndrome 20% [1].

• Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare X-linked disorder caused by a deficiency of the enzyme iduronate-2-sulfatase (I2S). Beyond neurological involvement, one of the major challenges in MPS II is the significant impact of progressive physical abnormalities on quality of life. Bone disease reduced respiratory function, and cardiac impairment lead to chronically low endurance. As the disease advances, many lose the ability to walk even short distances and eventually require a wheelchair. By the second decade of life, most individuals with central nervous system (CNS) involvement experience severe cognitive decline and are fully dependent on caregivers [2]. The incidence of MPS II ranges from 0.38 per 100,000 live births in Brazil to 1.09 per 100,000 in Portugal. In general, European countries report lower incidence rates compared to East Asian countries, where MPS II can represent up to 50% of all MPS cases [3].
• Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome or Morquio–Brailsford syndrome) is a lysosomal storage disorder inherited in an autosomal recessive pattern. It results from a deficiency of the enzyme N-acetylgalactosamine-6-sulfatase which leads to the accumulation of the glycosaminoglycans keratan sulfate and chondroitin-6-sulfate in various tissues, bones, and organs [7]. The reported prevalence of MPS IVA varies: 1 in 323,000 in Denmark, 1 in 599,000 in the UK, 1 in 926,000 in Australia, and 1 in 1,872,000 in Malaysia. Birth prevalence ranges from 1 in 71,000 in the United Arab Emirates to 1 in 500,000 in Japan [8,9]. Clinical features include waddling gait, skeletal abnormalities, genu valgum (knock knees), bell-shaped chest, joint hypermobility, spinal deformities, enlarged elbows and wrists, short stature, and short neck. Other possible symptoms include mild hepatosplenomegaly, hearing loss, respiratory issues, cardiac abnormalities, corneal clouding, and enamel hypoplasia. Unlike other forms of MPS, Morquio A typically does not involve the brain or cause significant cognitive impairment [10].

Currently, enzyme replacement therapy (ERT) represents the standard of care in treating Pompe disease and MPS disorders. ERT is a systemic approach, which involves administering recombinant enzymes intravenously to replace the deficient enzyme in affected individuals. By targeting the underlying enzymatic deficiency, ERT aims to alleviate symptoms, slow disease progression, and improve quality of life for patients with LSDs. Diagnosis and initiation of ERT in Austria is usually carried out in specialized centres in hospitals. As patients require lifelong monthly infusions this significantly impacts on quality of life for patients and their caregivers. In some countries and so in Austria, eligible patients are allowed to receive their infusions at home rather than in the clinic. Home infusion of ERT has been approved for several LSD, resulting in a positive impact on the quality of life for both patients and their caregivers.

In general, ERT has demonstrated efficacy depending on the disease in improving various clinical outcomes including reductions in organ enlargement, improvements in blood counts, mitigation of skeletal and neurocognitive symptoms, and improvement of quality of life. Despite its effectiveness, ERT has limitations: it may not be effective in reversing tissue damage that has already occurred prior to treatment initiation, it requires lifelong administration, it may result in anti-drug antibodies, and its requirement for regular infusions can pose logistical challenges for patients and caregivers [12]. In addition, ERT’s limited ability to cross the blood brain barrier (BBB) reduces its capacity to reach the CNS. In addition, current knowledge about the long-term effectiveness and safety of these treatments in real-world settings is limited, highlighting the need for a systematic review. The present project focuses on real world evidence of the following selected therapies for four different LSD:

• avalglucosidase alfa and alglucosidase alfa for Pompe disease
• laronidase for Mucopolysaccharidose Type I (MPS I)
• idursulfase for Hunter Syndrome (MPS II)
• elosulfase alfa for Mucopolysaccharidose Type IVA (MPS IVA; Morquio A syndrome)

Objectives of the project:
The aim of this project is to perform a systematic search and qualitative evidence synthesis of published studies that assess the long-term effectiveness and safety of the five ERTs (laronidase, idursulfase, alglucosidase alfa, avalglucosidase alfa, elosulfase alfa) in the treatment of Pompe disease and three types of MPS disorders (MPS I, MPS II, and MPS IVA).

Non-objectives:
These are not within the scope of this project:

• to evaluate short-term efficacy and safety (less than 2 years of follow-up)
• to evaluate other ERT than the five selected treatments

Research questions (RQ)

• RQ1: What is the long-term effectivness and safety of alglucosidase alfa and avalglucosidase alfa intervention in the treatment of Pompe disease?
• RQ2: What is the long-term effectivness and safety of laronidase in the treatment of MPS I?
• RQ3: What is the long-term effectivness and safety of idursulfase in the treatment of Hunter syndrome (MPS II)?
• RQ4: What is the long-term effectivness and safety of elosulfase alfa in the treatment of MPS IVA?

Methods:
A preliminary search was conducted to identify the most recent systematic reviews that meet the present assessment’s scope. The identified systematic reviews will be evaluated based on their scope, inclusion and exclusion criteria, and methodological quality using the Risk of Bias Assessment Tool for Systematic Reviews (ROBIS). High-quality systematic reviews that align with the scope of the current research question will be updated by conducting a systematic literature search for studies published after the original search date of the respective systematic reviews. If no high-quality review is identified, or is not available, a systematic literature search of several databases for primary studies will be performed, as well as a manual search of the references of relevant published systematic reviews and journal articles. In addition, a manual search is carried out for registers and publications from these registers. Abstract and full-text screening will be performed by two authors independently. In case of a disagreement, a third author will be contacted. A hierarchical approach will be applied when selecting studies by giving preference to RCTs, Non-RCTs and observational studies with a prospective design.

Data will be extracted in a pre-defined tabulated form, which will contain the following information: details about the study design, the intervention (dosage, duration period), the comparator (if applicable), the duration of the follow-up, losses to follow-up, details about the patient population (age, gender, severity of the disease, disease manifestation / symptoms / conditions), and the main findings related to the outcomes of interest. The risk of bias of included studies will be assessed with Cochrane Risk of Bias 2.0 tool for randomized controlled trials (RCTs) and with the Risk Of Bias In Non-randomized controlled Studies - of Interventions (ROBINS-I) for non-randomized studies (NRSs). The certainty of the evidence will be assessed using the GRADE approach [13].

PICO - Inclusion criteria for relevant literature:

Alglucosidase alfa and avalglucosidase alfa for infant-onset Pompe disease (IOPD)

Abbreviations: ECG = Electrocardiogram, LV = left ventricular, ERT= Enzyme replacement therapy, IOPD= Infant-onset Pompe disease, n= Number of patients, NRCs= non-randomized comparative studies, RCTs= randomized controlled trials

Alglucosidase alfa and avalglucosidase alfa for late-onset Pompe disease (LOPD)

Abbreviations: 6MWT= Six-minute walk test, ERT= Enzyme replacement therapy, FEV1= Forced expiratory volume at one second, FVC= Forced vital capacity, LOPD= Late-onset Pompe disease, n= Number of patients, NRCs= non-randomized comparative studies, RCTs= randomized controlled trials

Laronidase for Mucopolysaccharidosis Type I (MPS I)

Abbreviations: 6mwt= Six-minute walk test, ERT= Enzyme replacement therapy, FEV1= Forced expiratory volume at one second, FVC= Forced vital capacity, ECG = Electrocardiogram, GAG =Glycosaminoglycan, MPS I= Mucopolysaccharidosis Type I, n= Number of patients, NRCs= non-randomized comparative studies, RCTs= randomized controlled trials

Idursulfase for Hunter syndrome (Mucopolysaccharidosis Type II)

Abbreviations: 6MWT= Six-minute walk test, ERT= Enzyme replacement therapy, FEV1= Forced expiratory volume at one second, FVC= Forced vital capacity, ECG = Electrocardiogram, GAG= Glycosaminoglycan, MPS II= Mucopolysaccharidosis Type II, n= Number of patients, NRCs= non-randomized comparative studies, RCTs= randomized controlled trials

Elosulfase alfa for Mucopolysaccharidosis Typ IVA (MPS IVA; Morquio A syndrome)

Abbreviations: ERT= Enzyme replacement therapy, FEV1= Forced expiratory volume at one second, FVC= Forced vital capacity, 3MSCT= Three-minute stair climb, 6MWT= Six-minute walk test, MPS IVA= Mucopolysaccharidosis Type IVA, n= Number of patients, NRCs= non-randomized comparative studies, RCTs= randomized controlled trials

Quality assurance:
As part of the quality assurance process, monitoring by external clinical experts is planned for the entire project process. In addition, the report will undergo an internal review by an AIHTA member and an external review by a clinical expert before project completion.

Time schedule/ milestones (in months)

References:
1]  Orphanet. Mucopolysaccharidosis type I. [cited 16.04.2025]. Available from: https://www.orpha.net/en/disease/detail/579?name=MPS1&mode=name
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[8]  Leadley RM, Lang S, Misso K, Bekkering T, Ross J, Akiyama T, et al. A systematic review of the prevalence of Morquio A syndrome: challenges for study reporting in rare diseases. Orphanet J Rare Dis. 2014;9:173. DOI: 10.1186/s13023-014-0173-x.
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