Idursulfase Beta (Hunterase, DB16190): A Comprehensive Review of Its Pharmacology, Clinical Development, and Regulatory Landscape for Hunter Syndrome

1. Introduction to Idursulfase Beta (Hunterase)

1.1. Overview and Therapeutic Indication: Hunter Syndrome (Mucopolysaccharidosis Type II)

Idursulfase beta is a biotechnologically derived enzyme replacement therapy (ERT) developed for the treatment of Mucopolysaccharidosis Type II (MPS II), commonly known as Hunter syndrome.[1] Hunter syndrome is a rare, X-linked lysosomal storage disorder characterized by a deficiency or absence of the enzyme iduronate-2-sulfatase (IDS).[1] This enzymatic deficiency leads to the progressive, systemic accumulation of glycosaminoglycans (GAGs)—specifically dermatan sulfate and heparan sulfate—within lysosomes of various cells and tissues. This accumulation results in cellular dysfunction and widespread organ damage, contributing to the multisystemic and progressive nature of the disease.[1]

The fundamental pathogenic mechanism of Hunter syndrome, namely the deficiency of IDS and subsequent GAG accumulation, directly informs the rationale for ERT. By providing a functional, exogenous form of the IDS enzyme, ERT aims to restore the catabolism of accumulated GAGs, thereby mitigating or slowing disease progression. The systemic nature of GAG accumulation underscores the challenge of ERT, as the therapeutic enzyme must ideally reach all affected tissues, including those protected by biological barriers such as the blood-brain barrier, to address the full spectrum of clinical manifestations.

Hunter syndrome primarily affects males due to its X-linked inheritance pattern and presents with a wide range of clinical severity.[4] Manifestations can include coarse facial features, skeletal deformities (dysostosis multiplex), joint stiffness, hepatosplenomegaly, cardiac and respiratory complications, and, in a significant proportion of patients (approximately 70%), progressive neurological involvement leading to cognitive impairment and developmental regression.[4] The disease often leads to a shortened lifespan, particularly in individuals with severe neuronopathic forms.[4]

The development of Idursulfase beta, marketed as Hunterase by GC Biopharma (formerly Green Cross Corporation) and its partners, followed the introduction of Idursulfase (Elaprase, developed by Shire, now part of Takeda).[3] The emergence of a second ERT for MPS II suggests an ongoing effort to refine therapeutic options, potentially focusing on improvements in efficacy, safety profiles, immunogenicity, or delivery to challenging sites like the central nervous system (CNS).

1.2. Drug Identification: DrugBank ID, CAS Number, Synonyms, and Type

Idursulfase beta is cataloged in the DrugBank database under the accession number DB16190.[8] Its unique Chemical Abstracts Service (CAS) Registry Number is 1271734-34-9.[9] The substance is known by several synonyms, including its brand name Hunterase, its International Nonproprietary Name (INN) Idursulfase beta, the Japanese Accepted Name (JAN) Idursulfase beta (genetical recombination), and various developmental codes such as GC-1111.[7] Idursulfase beta is classified as a biotechnology-derived product, specifically a recombinant protein therapeutic.[3] This classification highlights its production via recombinant DNA technology rather than chemical synthesis, which has implications for its molecular complexity, manufacturing process, and potential immunogenic properties.

2. Biochemical and Physicochemical Properties

2.1. Molecular Structure, Formulation, and Manufacturer Details

Idursulfase beta is a recombinant form of the human lysosomal enzyme iduronate-2-sulfatase (IDS).[1] It is a glycoprotein with an approximate molecular weight of 76 kDa, composed of 525 amino acids.[3] The protein structure includes eight asparagine-linked glycosylation sites, which are occupied by complex oligosaccharide structures.[3] A critical post-translational modification for its enzymatic activity is the conversion of a specific cysteine residue to formylglycine.[3] These structural and biochemical features are essential for its biological function, stability, and interaction with cellular uptake mechanisms.

Hunterase is commercially available primarily as an intravenous (IV) formulation. It is supplied as a concentrate (typically 2.0 mg/mL idursulfase beta protein solution in a vial containing 6.0 mg in an extractable volume of 3.0 mL), intended for single use. Prior to administration, it must be diluted with 0.9% sodium chloride injection. The use of an infusion set equipped with a 0.2 micron filter is recommended for IV administration.[14]

Recognizing the limitations of IV ERT in addressing CNS manifestations of Hunter syndrome due to the blood-brain barrier, an intracerebroventricular (ICV) formulation, Hunterase ICV Injection 15 mg, has also been developed and approved in some regions.[4] This formulation is designed for direct administration into the cerebral ventricles.

The primary developer and manufacturer of Idursulfase beta (Hunterase) is GC Biopharma (formerly Green Cross Corporation), a South Korean biopharmaceutical company.[5] Other entities involved in its development or commercialization include Clinigen K.K. (marketing in Japan) [5], CANbridge Pharmaceuticals, and Nanolek.[7]

Table 1: Key Characteristics of Idursulfase Beta

Characteristic	Detail	Source(s)
DrugBank ID	DB16190	User Query, 8
CAS Number	1271734-34-9	User Query, 9
Common Synonyms	Hunterase, Idursulfase beta (INN, JAN), GC-1111	7
Type	Biotech; Recombinant Human Iduronate-2-Sulfatase	User Query, 3
Molecular Weight	Approx. 76 kDa	3
Structure	525 amino acid glycoprotein; 8 N-linked glycosylation sites; Cysteine to formylglycine modification required for activity	3
Manufacturer (Primary)	GC Biopharma (Green Cross Corporation)	6
Formulations	Intravenous (IV) concentrate (2 mg/mL); Intracerebroventricular (ICV) Injection (15 mg)	14

2.2. Comparative Analysis: Idursulfase beta (Hunterase) vs. Idursulfase (Elaprase)

A critical aspect in understanding Idursulfase beta is its comparison to the first-to-market ERT, Idursulfase (Elaprase). While both are recombinant human iduronate-2-sulfatase enzymes, differences in their production and potentially their biochemical characteristics may have clinical implications.

Idursulfase (Elaprase) is produced using a human cell line, whereas Idursulfase beta (Hunterase) is manufactured using Chinese Hamster Ovary (CHO) cells.[3] This distinction in the host cell line is significant because post-translational modifications, particularly glycosylation, can vary between production systems and can influence the enzyme's activity, stability, cellular uptake, and immunogenicity. Although both enzymes share an identical amino acid sequence, these manufacturing differences can lead to variations in their higher-order structure and biological properties.[11]

Biochemical analyses have revealed notable differences. Idursulfase beta has been reported to possess a significantly higher content of formylglycine (FGly), a critical residue for catalytic activity (79.4 ± 0.9% for Idursulfase beta vs. 68.1 ± 2.2% for Idursulfase).[12] Consistent with this, the specific enzyme activity of Idursulfase beta was found to be significantly higher than that of Idursulfase (42.6 ± 1.1 nmol/min/µg protein for Idursulfase beta vs. 27.8 ± 0.9 nmol/min/µg protein for Idursulfase).[12] However, the levels of mannose-6-phosphate (M6P), which is crucial for lysosomal targeting, and sialic acid content were reported to be not significantly different between the two enzymes.[12]

Regarding cellular uptake, in vitro studies using normal human fibroblasts indicated a significant difference, with Idursulfase beta showing a lower Kuptake value (5.09 ± 0.96 nM) compared to Idursulfase (6.50 ± 1.28 nM), suggesting more efficient cellular internalization for Idursulfase beta.[12] This enhanced uptake may contribute to its observed greater in vitro efficacy at lower concentrations.[12]

Preclinical in vivo studies in IDS knockout (KO) mice also highlighted differences. While both enzymes reduced GAGs, Idursulfase beta reportedly led to lower formation of anti-drug antibodies (ADAs) compared to Idursulfase in these animal models.[12] Reduced immunogenicity is a desirable characteristic for ERTs, as ADAs can potentially neutralize enzyme activity or mediate adverse reactions.

The choice of CHO cells for producing Hunterase, as opposed to the human cell line used for Elaprase, likely contributes to these observed biochemical and immunogenic differences. While CHO cells are a standard platform for recombinant protein production, the resulting post-translational modifications, such as glycosylation and FGly conversion, can differ from those achieved in human cell lines. These subtle variations can have substantial impacts on the final drug product's pharmacological profile. The higher specific activity and potentially lower immunogenicity observed with Idursulfase beta in preclinical settings suggest that the manufacturing process employed by GC Biopharma may yield an enzyme with favorable therapeutic characteristics.

Table 2: Comparative Overview: Idursulfase beta (Hunterase) vs. Idursulfase (Elaprase)

Feature	Idursulfase beta (Hunterase)	Idursulfase (Elaprase)	Source(s)
Production Cell Line	Chinese Hamster Ovary (CHO) cells	Human cell line	3
Formylglycine (FGly) Content	79.4 ± 0.9%	68.1 ± 2.2%	12
Specific Enzyme Activity	42.6 ± 1.1 nmol/min/µg protein	27.8 ± 0.9 nmol/min/µg protein	12
Mannose-6-Phosphate (M6P) Content	Not significantly different	Not significantly different	12
Sialic Acid Content	Not significantly different	Not significantly different	12
In Vitro Cellular Uptake (Kuptake in fibroblasts)	5.09 ± 0.96 nM (better uptake)	6.50 ± 1.28 nM	12
In Vivo GAG Reduction (Kidney, Lung in mice)	Potentially greater reduction	Reference	12
Anti-Drug Antibody Formation (mice)	Lower	Higher	12

3. Mechanism of Action and Pharmacology

3.1. Enzyme Replacement Therapy: Role of Iduronate-2-Sulfatase

Idursulfase beta functions as an ERT by providing a recombinant version of the human enzyme iduronate-2-sulfatase (IDS).[1] In individuals with Hunter syndrome, the endogenous IDS enzyme is deficient or absent, leading to the inability to properly break down specific GAGs.[1] The administration of Idursulfase beta aims to supplement this missing enzyme activity, thereby restoring the normal catabolic pathway for these GAGs.

3.2. Substrate Specificity: Degradation of Glycosaminoglycans (Dermatan Sulfate, Heparan Sulfate)

The primary pharmacological action of Idursulfase beta is the enzymatic hydrolysis of 2-sulfate esters from the terminal iduronate sulfate residues of the GAGs, dermatan sulfate and heparan sulfate.[1] These GAGs are complex carbohydrates that accumulate in the lysosomes of various cell types in MPS II patients. By catalyzing their degradation, Idursulfase beta helps to reduce the lysosomal storage of these molecules, which is the underlying biochemical defect in Hunter syndrome.[1]

3.3. Cellular Uptake Mechanisms: The Role of Mannose-6-Phosphate Receptors

For Idursulfase beta to exert its enzymatic effect within the lysosomes, it must first be internalized by target cells. This process is predominantly mediated by mannose-6-phosphate (M6P) receptors present on the cell surface.[1] The oligosaccharide chains on the Idursulfase beta glycoprotein are adorned with M6P residues, which serve as ligands for these receptors. Binding of the M6P-tagged enzyme to M6P receptors triggers receptor-mediated endocytosis, leading to the internalization of the enzyme into endosomes. These endosomes subsequently mature and fuse with lysosomes, delivering the active enzyme to its site of action where it can catabolize the accumulated GAGs.[3]

The efficiency of this M6P receptor-mediated uptake is a pivotal factor influencing the overall efficacy of ERT. Variations in M6P receptor density and functionality across different tissues, as well as subtle differences in the M6P content or presentation on the recombinant enzyme itself, can impact the tissue-specific delivery and therapeutic response. While the total M6P content was reported to be similar between Idursulfase beta and Idursulfase (Elaprase) [12], the observed differences in in vitro cellular uptake [12] might stem from other nuanced glycosylation features or conformational aspects of the protein that affect receptor interaction. This highlights the complexity of ERT delivery and underscores the rationale for exploring alternative delivery strategies, such as ICV administration, to bypass biological barriers like the blood-brain barrier and improve enzyme delivery to less accessible but critically affected tissues like the CNS.

4. Non-Clinical Studies

4.1. Preclinical Efficacy in Animal Models of MPS II

Preclinical evaluation of idursulfase, the active enzyme in both Idursulfase beta (Hunterase) and Idursulfase (Elaprase), has been conducted extensively in animal models, primarily the I2S knockout (IKO) mouse model of MPS II. These studies were instrumental in establishing proof-of-concept, informing dose selection, and understanding the biodistribution of the enzyme prior to human clinical trials. Intravenously administered idursulfase demonstrated the ability to reach target organs and induce a dose-dependent reduction in both urinary and tissue GAG levels, notably in the liver, kidney, heart, skin, and spleen.[46] The minimal effective dose in these models was determined to be in the range of 0.1 to 0.5 mg/kg.[46]

Studies comparing different dosing frequencies indicated that weekly administration regimens were more effective in maintaining reduced GAG levels compared to biweekly or monthly dosing in IKO mice.[46] This finding provided a strong rationale for the weekly dosing schedule adopted in subsequent clinical trials. Specifically for Idursulfase beta, preclinical studies at a dose of 0.5 mg/kg confirmed its efficacy in reducing GAG accumulation in various tissues.[12] Furthermore, high-dose Idursulfase beta administration in an MPS II mouse model showed potential in preventing CNS damage, a significant finding given the neurological involvement in many Hunter syndrome patients.[12]

Comparative in vivo studies in IDS KO mice suggested potential advantages for Idursulfase beta over Idursulfase (Elaprase), with reports of greater reduction in GAG levels in the kidney and lung, as well as more pronounced improvements in bone pathology.[12]

4.2. Preclinical Toxicology

Initial safety pharmacology studies were conducted to support the clinical development of idursulfase. A single-dose study in cynomolgus monkeys, using doses up to 20 mg/kg, did not reveal any treatment-related adverse effects on the cardiovascular, respiratory, or central nervous systems.[46] This provided foundational safety data supporting the progression of idursulfase into human clinical trials.

The consistent observation in preclinical models that intravenously administered ERT effectively reduces GAGs in peripheral tissues but has limited ability to cross the blood-brain barrier and impact CNS GAG accumulation was a critical finding.[3] This limitation directly spurred the investigation and development of alternative delivery routes, most notably intracerebroventricular (ICV) administration, to directly target the CNS. Preclinical studies demonstrated that ICV-administered idursulfase could indeed reach the brain.[5] Specifically, ICV Idursulfase beta showed promising results in mouse models, including reduction of CSF heparan sulfate and improvements in biochemical, histological, and even memory/learning parameters.[20] This preclinical success provided a strong rationale for advancing ICV formulations of Idursulfase beta into human clinical trials, aiming to address the significant unmet need of treating the neurological manifestations of Hunter syndrome.

5. Pharmacokinetics

5.1. Absorption, Distribution, Metabolism, and Excretion (ADME) Profile

Idursulfase beta is administered via intravenous (IV) infusion, ensuring complete bioavailability into the systemic circulation.[3] Following IV administration in animal models (rats and mice), idursulfase distributes to various organs, with the highest concentrations typically found in the liver. Appreciable levels are also detected in other major organs such as the kidneys, heart, spleen, and lungs.[49] As a protein therapeutic, Idursulfase beta is expected to be metabolized through general protein catabolism pathways, involving hydrolysis into smaller peptides and amino acids.[51] Specific details on excretion pathways from human studies are not extensively detailed in the provided information, but protein therapeutics are generally not excreted unchanged in urine to a large extent.

5.2. Key Pharmacokinetic Parameters (Cmax, AUC, Tmax, t1/2, Clearance, Volume of Distribution)

Pharmacokinetic data for Idursulfase (Elaprase) from a Phase I/II study in patients aged 7.7-27 years (doses of 0.15, 0.5, and 1.5 mg/kg) indicated an approximately dose-proportional maximum serum concentration (Cmax​). The area under the concentration-time curve (AUC0−inf​) increased more than proportionally with dose, suggesting saturation of serum clearance mechanisms at doses above 0.5 mg/kg. The mean terminal elimination half-life (t1/2​) was less than 5 hours (range 2-5 hours), and clearance (CL) was approximately 3 mL/min/kg.[3]

For Idursulfase beta (Hunterase), specific human PK parameters from pivotal IV trials are not fully detailed in the provided snippets, though their collection is mentioned. The Phase I/II trial (NCT01301898) by Sohn et al. (2013) in patients aged 6-35 years involved calculation of Cmax​, AUClast​, AUCinf​, Tmax​, and t1/2​, but the abstract does not provide the specific values.[42] The package insert for Hunterase IV refers to pharmacokinetic parameters from a Phase III clinical study [14], but the table contents are not fully accessible in the provided materials. However, it is noted that the pharmacokinetics of Idursulfase beta and Idursulfase (Elaprase) are considered to be "almost the same".[20]

Pharmacokinetic data for the intracerebroventricular (ICV) formulation of Hunterase are distinct. A study (JMA-IIA00350) reported dose-dependent increases in Cmax​ and AUC0−t​ in cerebrospinal fluid (CSF) following ICV administration of 3 mg, 10 mg, and 30 mg doses.[26]

5.3. Protein Binding Characteristics

Specific plasma protein binding data for Idursulfase beta are not explicitly provided. As a large glycoprotein enzyme, its distribution and clearance are primarily governed by receptor-mediated uptake into cells (via M6P receptors) and general protein catabolism, rather than extensive, reversible binding to plasma proteins like albumin, which is more characteristic of small molecule drugs.

5.4. Influence of Food on Pharmacokinetics

Since Idursulfase beta is administered intravenously, food is not expected to have any direct influence on its absorption or bioavailability. The provided materials do not mention any food interaction studies, which is typical for IV protein therapeutics.

While the PK profile of Idursulfase (Elaprase) offers a reference, and the similarity between Elaprase and Hunterase is noted, the ideal scenario for a comprehensive report would involve specific, detailed human PK data for Hunterase IV from its own pivotal trials. The absence of such detailed data in the provided snippets represents a limitation, though the assertion of similarity to Elaprase provides some guidance.

Table 3: Summary of Pharmacokinetic Parameters of Idursulfase Beta (and Idursulfase for Comparison)

Parameter	Idursulfase (Elaprase)	Idursulfase beta (Hunterase) - IV	Idursulfase beta (Hunterase) - ICV	Source(s)
Administration Route	IV	IV	ICV	-
Cmax​	Approx. dose-proportional	Data not fully detailed; stated as "almost the same" as Elaprase.	Dose-dependent increase in CSF	20
AUC0−inf​ / AUC0−t​	Greater than dose-proportional (saturation >0.5 mg/kg)	Data not fully detailed; stated as "almost the same" as Elaprase.	Dose-dependent increase in CSF (AUC0−t​)	20
Tmax​	Not specified	Data not fully detailed (NCT01301898 mentions calculation)	CSF: 0.313-0.333 h	26
t1/2​ (terminal)	< 5 hours (2-5 hours)	Data not fully detailed (NCT01301898 mentions calculation); stated as "almost the same" as Elaprase.	CSF: 6.04-7.12 h	20
Clearance (CL)	~3 mL/min/kg (serum clearance saturation >0.5 mg/kg)	Data not fully detailed; stated as "almost the same" as Elaprase.	Not specified for CSF	3
Volume of Distribution (Vd​)	Not specified	Not specified	Not specified	-
Patient Population	MPS II (7.7-27 yrs)	MPS II (6-35 yrs for NCT01301898)	MPS II (23-65 months)	20

Note: Specific quantitative values for Hunterase IV are not fully detailed in the provided snippets. The statement "almost the same" as Elaprase [20] is noted. Pharmacokinetic parameters for ICV formulation refer to CSF concentrations.

6. Pharmacodynamics

6.1. Biomarker Response: Reduction in Urinary and Tissue Glycosaminoglycans

A primary pharmacodynamic marker for assessing the biological activity of Idursulfase beta is the reduction of GAG levels in urine and, where measurable, in tissues. This reduction directly reflects the enzyme's ability to catabolize the accumulated dermatan sulfate and heparan sulfate, thereby addressing the core biochemical defect in Hunter syndrome.[3]

In the clinical trial NCT01645189, which enrolled children with Hunter syndrome younger than 6 years, treatment with Idursulfase beta (0.5 mg/kg/week IV) for 52 weeks resulted in a statistically significant reduction in urinary GAG levels. The mean reduction from baseline at week 53 was -35.1 ± 30.6 mg GAG/g creatinine (P=0.038).[57] This finding is crucial as it demonstrates biochemical efficacy in a very young patient cohort, where early intervention is often advocated.

The Phase I/II trial (NCT01301898, published by Sohn YB et al., 2013), which included patients aged 6 to 35 years, also showed significant GAG reduction. In this study, Idursulfase beta administered at both 0.5 mg/kg/week and 1.0 mg/kg/week led to significantly greater reductions in urinary GAG excretion at 24 weeks compared to the active comparator group (which received Idursulfase [Elaprase] at 0.5 mg/kg/week). The p-values were 0.043 for the 0.5 mg/kg Idursulfase beta group and 0.002 for the 1.0 mg/kg Idursulfase beta group, respectively.[42] This suggests a potential dose-dependent effect and possibly enhanced GAG clearance with Idursulfase beta compared to the standard dose of Elaprase.

For the intracerebroventricular (ICV) formulation of Hunterase, a key pharmacodynamic endpoint is the reduction of GAGs, particularly heparan sulfate, in the CSF. Data from a Phase I/II study in Japan (JMA-IIA00350) demonstrated that ICV Idursulfase beta significantly decreased CSF heparan sulfate levels by 40-80% from baseline, with a mean reduction of 72.3% at 5 years of treatment.[5] This is a critical finding as CSF GAG reduction is considered a biomarker for CNS engagement and potential efficacy against neurological symptoms.

6.2. Correlation of Pharmacodynamic Effects with Clinical Outcomes

The reduction in GAG levels, while a direct measure of enzyme activity, is most clinically relevant when it correlates with improvements in clinical signs and symptoms of Hunter syndrome. Generally, decreased urinary GAG excretion has been associated with improvements in somatic manifestations such as the 6-minute walk test (6MWT) distance, forced vital capacity (FVC), and reductions in liver and spleen size.[3]

In the context of ICV Hunterase, the reduction in CSF heparan sulfate is particularly important. This biomarker is linked to the neurological aspects of the disease, and its reduction is hypothesized to correlate with the stabilization or improvement of cognitive development and other CNS symptoms.[4] The Japanese Phase I/II study of ICV Idursulfase beta reported positive effects on improving developmental age alongside significant CSF HS reduction.[17]

It is important to acknowledge that while GAG reduction is a primary pharmacodynamic effect and a necessary indicator of enzyme activity, the direct quantitative relationship between the extent of GAG reduction and the magnitude of all clinical improvements can be influenced by several factors. For instance, the development of neutralizing anti-drug antibodies (NAbs) can attenuate the reduction in GAG levels and consequently impact clinical outcomes, such as pulmonary function, even if some GAG reduction is still observed.[39] Data from studies with Idursulfase (Elaprase) indicated that patients positive for ADAs experienced a less pronounced decrease in urinary GAG levels.[43] This interplay suggests that GAG reduction, while crucial, may not be the sole predictor of the full spectrum of clinical response. Factors such as the patient's immune response to the ERT, the severity of the disease at the initiation of treatment, and the differential accessibility of the enzyme to various affected tissues also play significant roles in determining overall therapeutic benefit. Therefore, a comprehensive assessment of treatment response typically involves monitoring GAG levels in conjunction with clinical outcomes and immunogenicity status.

7. Clinical Development and Efficacy

7.1. Overview of the Clinical Trial Program

The clinical development of Idursulfase beta (Hunterase) has encompassed a series of trials designed to evaluate its safety, efficacy, pharmacokinetics, and immunogenicity across different age groups and formulations. Key trials include Phase I/II studies (e.g., NCT01301898, which compared Idursulfase beta to an active comparator, Idursulfase/Elaprase) [42], Phase III trials for the intravenous formulation (e.g., NCT01645189 for patients <6 years; NCT03920540/GC1111 for treatment-naïve patients ≥5 years) [5], and studies investigating the intracerebroventricular (ICV) formulation (e.g., JMA-IIA00350 in Japan; NCT05422482 for GC1123 ICV).[4] Long-term safety and efficacy have also been assessed in extension studies (e.g., NCT02044692).[16] These trials have explored various doses, typically 0.5 mg/kg weekly for the IV formulation, and up to 30 mg every 4 weeks for the ICV route.[5]

7.2. Pivotal Clinical Trial Analysis: NCT01645189 (Safety and Efficacy of Hunterase in Patients < 6 Years)

7.2.1. Study Rationale, Objectives, and Design

The clinical trial NCT01645189 was initiated because Idursulfase beta (Hunterase®) had been utilized for ERT in patients with Hunter syndrome aged 6 years and older in Korea since 2012. There was a need to evaluate its safety and efficacy specifically in the younger pediatric population, as early intervention is considered critical in MPS II.[57] The primary objective of this study was to assess the safety of ERT with Idursulfase beta in children younger than 6 years. Secondary objectives included the evaluation of efficacy, primarily through changes in urinary GAG levels, and monitoring of vital signs, physical examination findings, electrocardiogram (ECG) results, laboratory parameters, and the development of anti-idursulfase antibodies. Exploratory variables included growth indices and developmental milestones assessed by the Denver II test.[34] The study was designed as a 52-week, single-center, single-arm, open-label trial, a design often employed in rare diseases, particularly in vulnerable pediatric populations where a placebo arm might be ethically challenging.[34]

7.2.2. Patient Demographics, Dosing Regimen, and Duration

The trial enrolled six male Korean patients, all younger than 6 years of age (up to 5 years old at enrollment), with a confirmed diagnosis of Hunter Syndrome. Notably, all enrolled children had previously received ERT with Idursulfase (Elaprase) before transitioning to Idursulfase beta for this study.[14] The dosing regimen for Idursulfase beta was 0.5 mg/kg administered intravenously once per week for a total duration of 52 weeks.[57] The small sample size is characteristic of studies in rare diseases affecting specific pediatric age groups. The history of prior ERT is an important factor for interpreting immunogenicity data and overall treatment response.

7.2.3. Primary and Secondary Efficacy Endpoints

The primary endpoint of NCT01645189 was safety, assessed through the monitoring and reporting of adverse events (AEs).[34] Secondary endpoints encompassed a range of measures: changes in urinary GAG excretion (a biomarker of enzyme activity), vital signs, findings from physical examinations, ECG parameters, standard laboratory tests, and the incidence and titers of anti-idursulfase antibodies (including neutralizing antibodies). Exploratory endpoints included assessments of growth indices and developmental milestones using the Denver II test.[34] This comprehensive set of endpoints aimed to provide a holistic view of the treatment's impact.

7.2.4. Detailed Efficacy Results from NCT01645189

The key efficacy outcome reported from this trial was a statistically significant reduction in urinary GAG levels. At week 53, the mean change from baseline in urinary GAG excretion was -35.1 ± 30.6 mg GAG/g creatinine, with a p-value of 0.038, indicating a significant biochemical response to Idursulfase beta in this young patient cohort.[57] While growth and developmental milestones were also evaluated as exploratory variables, specific quantitative data for these outcomes are not detailed in the provided abstracts, though the overall conclusion was that the safety and efficacy were similar to older patients.[57]

Table 4: Efficacy Outcomes from Clinical Trial NCT01645189 (Patients < 6 Years)

Endpoint	Baseline Value (Mean ± SD or as stated)	Value at Week 53 (Mean ± SD or as stated)	Change from Baseline (Mean ± SD)	P-value	Source(s)
Urinary GAG excretion	Not explicitly stated, but reduction measured from baseline	Not explicitly stated	-35.1 ± 30.6 mg GAG/g creatinine	0.038	57
Growth Indices	Evaluated as exploratory	Evaluated as exploratory	Not detailed	Not detailed	57
Developmental Milestones (Denver II test)	Evaluated as exploratory	Evaluated as exploratory	Not detailed	Not detailed	57

Note: GAG = glycosaminoglycan. The study concluded that the efficacy of Idursulfase beta in this age group was similar to that reported in patients aged 6 years or older.

7.3. Supporting Clinical Trial Data

The clinical development of Idursulfase beta has been supported by several other key trials:

• NCT01301898 (Sohn YB et al., 2013): This Phase I/II, randomized, single-blind, active comparator-controlled trial enrolled 31 MPS II patients (aged 6-35 years) for 24 weeks. Patients received either Idursulfase beta (0.5 mg/kg or 1.0 mg/kg weekly IV) or an active comparator (Idursulfase [Elaprase] 0.5 mg/kg weekly IV). The primary efficacy endpoint was urinary GAG excretion. Secondary endpoints included the 6MWT, echocardiographic findings, pulmonary function tests (PFTs), and joint mobility.[42]
• Efficacy Results: Both doses of Idursulfase beta demonstrated significantly greater reductions in urinary GAG levels compared to the active comparator (p=0.043 for 0.5 mg/kg Idursulfase beta; p=0.002 for 1.0 mg/kg Idursulfase beta). Furthermore, both Idursulfase beta groups showed significantly greater improvements in the 6MWT distance compared to the comparator group (p=0.003 for 0.5 mg/kg; p=0.015 for 1.0 mg/kg).[16] These findings suggested potential superiority of Idursulfase beta over the standard dose of Elaprase in these key efficacy measures.
• NCT03920540 (GC1111 - Phase 3): This trial was a double-blind, randomized, active-controlled (Part 1) and open-label, historical placebo-controlled (Part 2) study designed to evaluate the efficacy of Hunterase (Idursulfase beta) in Hunter syndrome patients aged ≥5 years who were previously untreated with ERT. The primary intervention was Idursulfase beta 0.5 mg/kg IV weekly for 52 weeks, compared to Elaprase 0.5 mg/kg IV weekly in Part 1. The primary outcome measure was the change in 6MWT distance at Week 53. Secondary outcomes included changes in urinary GAG levels, liver and spleen volume, FVC, cardiac function, immunogenicity, PK, and safety.[5]
• Efficacy Results: A presentation at WORLDSymposium 2024 indicated that the trial demonstrated the superiority of Hunterase treatment compared to a placebo control group (presumably historical placebo for Part 2, as Part 1 was active-controlled), with statistically significant differences in 6MWT and urinary GAG results.[38] Detailed quantitative comparisons against the active comparator (Elaprase) from Part 1 are essential for a full understanding of relative efficacy but were not fully available in the provided snippets.
• NCT02044692: This study was designed as a long-term safety and efficacy evaluation of weekly Idursulfase beta (0.5 mg/kg) in patients with Hunter Syndrome.[16] While specific results from this particular Hunterase long-term study are not detailed, long-term data for idursulfase (Elaprase) from other extension studies (e.g., TKT024EXT, NCT00607386) have shown sustained clinical improvements over several years.[39]
• NCT05422482 (GC1123 ICV): This is a Phase 1, open-label, ascending dose study evaluating the safety, tolerability, PK, and PD of intracerebroventricularly administered GC1123 (Idursulfase beta ICV) in MPS II patients aged 18 months to 18 years with CNS involvement who are also receiving IV ERT.[7] This trial represents an important step in assessing direct CNS-targeted therapy.

7.4. Intracerebroventricular (ICV) Formulation Development and Efficacy

The development of an ICV formulation of Idursulfase beta (Hunterase ICV, typically 15 mg) aims to directly address the neurological manifestations of Hunter syndrome by bypassing the blood-brain barrier.[4] This approach is grounded in the understanding that IV-administered ERT has limited CNS penetration.

A key Phase I/II study conducted in Japan (JMA-IIA00350) evaluated ICV Idursulfase beta in six patients aged 23-65 months. Patients received escalating doses up to 30 mg ICV every 4 weeks, in conjunction with ongoing IV ERT, for up to 5 years. The study reported a significant decrease in CSF heparan sulfate levels (mean reduction of 72.3% at 5 years). In terms of clinical outcomes, the mean developmental age (DA), assessed by the Kyoto Scale of Psychological Development (KSPD), showed an increase of 5.1 months compared to historical IV-only treated controls at 100 weeks, and this difference further increased to a mean of +18.6 months at the 5-year final observation. The treatment was generally well tolerated.[5] These findings provided early evidence supporting the potential of ICV delivery to impact CNS biomarkers and developmental outcomes in neuronopathic MPS II. The progression from IV to ICV formulations for Idursulfase beta is a clear example of a strategy to overcome a major limitation of traditional ERT for lysosomal storage disorders with significant neurological involvement. The positive results in CSF GAG reduction and developmental assessments from the Japanese ICV study are particularly encouraging and have contributed to the regulatory approval of Hunterase ICV in Japan.[5] However, ICV administration is an invasive procedure and carries its own set of potential risks, including device-related complications and infections.[5]

8. Safety and Tolerability Profile

8.1. Overview of Adverse Events from Clinical Trials

The safety profile of Idursulfase beta has been evaluated across multiple clinical trials. In the NCT01645189 study involving children younger than 6 years, all six participants experienced at least one adverse event (AE), with a total of 109 AEs reported. The most common AEs specifically attributed to the infusion were urticaria and cough.[57] In the Phase I/II trial (NCT01301898) in patients aged 6-35 years, the most frequent AEs were also urticaria and skin rash, which were generally mild and manageable.[42] For the Hunterase ICV formulation, common AEs reported in the JMA-IIA00350 study included vomiting, pyrexia, gastroenteritis, and upper respiratory tract infection, mostly mild to moderate in severity.[20] Device-related complications are an additional consideration for the ICV route.[5]

8.2. Infusion-Associated Reactions (IARs): Incidence and Management

Infusion-associated reactions (IARs) are a known class effect of enzyme replacement therapies. With Hunterase IV, common IARs include cutaneous manifestations (urticaria, rash, pruritus), fever, headache, hypertension, and flushing.[14] In the NCT01645189 trial, one out of six patients (16.7%) experienced IARs, specifically urticaria and cough.[57] Standard management strategies for IARs include slowing the infusion rate, temporarily interrupting the infusion, or administering premedication with antihistamines and/or corticosteroids.[14] Although no life-threatening anaphylactic reactions were observed in Hunterase clinical trials according to the package insert [14], such reactions have been reported with similar ERT products, underscoring the need for preparedness and medical supervision during infusions.[14]

8.3. Serious Adverse Events (SAEs)

In the NCT01645189 study, one SAE (hospitalization due to gastroenteritis) was reported, but it was considered unrelated to the treatment. No serious adverse drug reactions (ADRs) were reported in this trial.[57] Similarly, the Phase I/II trial (NCT01301898) reported no serious ADRs with Idursulfase beta.[42] For the Hunterase ICV formulation (JMA-IIA00350 study), while SAEs were reported in a high percentage of patients (76.8%), none were considered related to the idursulfase-IT treatment itself, suggesting they may have been related to the underlying disease, concomitant IV ERT, or ICV device/procedure.[20]

8.4. Long-Term Safety Data

Long-term safety is a critical aspect for ERTs used in chronic conditions like Hunter syndrome. Dedicated long-term safety studies, such as NCT02044692 for Hunterase IV, and extension phases of other trials (e.g., NCT02412787 for Elaprase-IT, which provided up to 36 months of data) are designed to monitor for cumulative toxicities or late-onset AEs.[16] The available long-term data for idursulfase-IT (Elaprase-IT) indicated that it was generally well tolerated over 36 months.[28]

Table 5: Safety Summary: Adverse Events in Key Idursulfase Beta Clinical Trials

Clinical Trial (NCT Number / Identifier)	Patient Population	Most Common AEs / IARs Reported	Serious AEs / ADRs Related to Drug	Source(s)
NCT01645189 (IV, <6 yrs)	6 children (<6 yrs), previously treated with Elaprase	Urticaria, cough (IARs)	One SAE (gastroenteritis), not treatment-related. No serious ADRs.	57
NCT01301898 (IV, 6-35 yrs)	31 patients (Idursulfase beta arms n=20), previously treated with Elaprase	Urticaria, skin rash (easily controlled)	No serious ADRs.	42
JMA-IIA00350 (ICV, 23-65 months)	6 children with severe MPS II	Vomiting, pyrexia, gastroenteritis, upper respiratory tract infection (most mild/moderate)	SAEs reported in 76.8% of patients, none considered related to idursulfase-IT.	20
Hunterase IV Package Insert (Summary of trials)	MPS II patients (various ages, including treatment-naïve Chinese patients in Phase III)	Nasopharyngitis, cardiac valve disease, respiratory disorder, laryngitis, otitis media chronic, cardiomegaly (from Phase III in Chinese patients). Urticaria, pruritus, condition aggregated (from Phase I/II). Urticaria, cough (from Phase IIIb <6 yrs).	Infusion-related reactions (urticaria, rash, pruritus, fever, headache, hypertension, flushing) are common. No life-threatening anaphylaxis reported in Hunterase trials, but known risk with similar drugs.	14

AE = Adverse Event; ADR = Adverse Drug Reaction; IAR = Infusion-Associated Reaction; SAE = Serious Adverse Event; IV = Intravenous; ICV = Intracerebroventricular.

9. Immunogenicity

9.1. Incidence of Anti-Drug Antibodies (ADAs)

The development of anti-drug antibodies (ADAs) is a common occurrence with ERTs. In the NCT01645189 trial (children <6 years), four out of six patients (66.7%) tested positive for anti-idursulfase antibodies at least once during the 52-week study.[57] It is important to note that these patients had prior exposure to Idursulfase (Elaprase). In the Phase I/II trial NCT01301898 (patients 6-35 years), anti-drug IgG antibodies were detected in 10 patients at baseline, attributed to previous idursulfase (Elaprase) treatment; no newly detected antibodies to Idursulfase beta were reported in that specific publication abstract, though this requires careful interpretation of the full study results.[12] Data from Elaprase trials indicate that up to 50% of treated patients develop anti-IDS antibodies.[75]

9.2. Presence and Impact of Neutralizing Antibodies (NAbs)

Neutralizing antibodies (NAbs) are a subset of ADAs that can directly inhibit the enzyme's activity or its cellular uptake, potentially impacting clinical efficacy. In the NCT01645189 trial, the same four patients (66.7%) who developed ADAs also showed neutralizing antibodies on at least one occasion.[57] For Elaprase, NAbs were detected in approximately 23% of patients in a long-term extension study, and their presence seemed to attenuate the improvement in pulmonary function tests, although effects on urinary GAG levels, organ size reduction, and 6MWT were less clear.[39] The clinical significance of NAbs can vary, and their impact on GAG reduction versus other clinical endpoints may differ.

9.3. Clinical Significance of Immunogenicity

The development of ADAs and NAbs can have several clinical consequences, including reduced efficacy of the ERT and an increased risk of hypersensitivity or infusion-associated reactions.[13] Patients with severe genetic mutations (e.g., complete gene deletions) may have a higher incidence of ADA and NAb development and may experience more hypersensitivity reactions.[74] The observation in preclinical mouse models that Idursulfase beta elicited lower anti-drug antibody formation compared to Idursulfase (Elaprase) is noteworthy.[12] If this translates to humans, it could represent a significant clinical advantage for Idursulfase beta. However, the available human trial data for Idursulfase beta, particularly in treatment-naïve populations, needs careful evaluation to confirm this potential benefit. The presence of NAbs, in particular, warrants close monitoring as they are more directly linked to potential attenuation of treatment effects.

Table 6: Immunogenicity Profile of Idursulfase Beta (Selected Trials)

Clinical Trial (NCT Number)	Patient Population	ADA Incidence	NAb Incidence	Clinical Impact Noted	Source(s)
NCT01645189 (IV, <6 yrs)	6 children, prior ERT	4/6 (66.7%)	4/6 (66.7%)	Not explicitly detailed for Idursulfase beta, but GAG reduction was significant.	57
NCT01301898 (IV, 6-35 yrs)	31 patients (21 on Idursulfase beta), prior ERT	10 patients had baseline ADAs from prior Elaprase. No newly detected ADAs to Idursulfase beta reported in abstract.	Not detailed in abstract.	Not detailed in abstract.	12
Elaprase (Idursulfase) Trials (for comparison)	Various MPS II populations	Up to 50%	~23% in long-term study	NAbs seemed to attenuate pulmonary function improvement.	39

ADA = Anti-Drug Antibody; NAb = Neutralizing Antibody. Prior ERT exposure significantly influences immunogenicity results.

10. Regulatory Status and Market Access

10.1. Approvals by Major Regulatory Agencies (FDA, EMA, PMDA, MFDS)

• FDA (USA): Idursulfase beta (Hunterase) received Orphan Drug Designation (ODD) for the treatment of Hunter Syndrome on February 11, 2013.[10] However, as of the latest available information, it is "Not FDA Approved for Orphan Indication".[78] There is no indication of a full FDA marketing approval for Hunterase IV or ICV in the provided snippets. Idursulfase IT (Elaprase formulation for intrathecal use) also had an ODD, but this was withdrawn or revoked on September 16, 2024.[79]
• EMA (Europe): Hunterase ICV (idursulfase-beta recombinant) was granted ODD by the European Medicines Agency (EMA) for the treatment of mucopolysaccharidosis type II on November 1, 2021 (positive opinion from COMP on October 15, 2021).[4] This was based on data suggesting significant benefit over existing IV treatments, particularly for CNS symptoms.[4] There is no mention of a full marketing authorization for Hunterase IV or ICV by the EMA in the snippets.
• PMDA (Japan): Hunterase ICV Injection 15 mg received manufacturing and marketing approval in Japan on January 22, 2021, making it the world's first approved ICV ERT for Hunter syndrome.[5] The approved indication is for the treatment of mucopolysaccharidosis type II, specifically targeting CNS symptoms.[5] The patient population includes those with Hunter syndrome where improvement of CNS symptoms is necessary, and it should be administered to patients who have confirmed tolerability to intravenous idursulfase.[5] There is no specific mention of Hunterase IV approval in Japan in these snippets, though IV ERT is stated as being in use.[5]
• MFDS (South Korea): Hunterase (Idursulfase beta) IV received conditional approval in South Korea on January 9, 2012, contingent on a Phase 3 clinical trial.[33] Full approval for Hunterase ICV was granted by the Ministry of Food and Drug Safety (MFDS) based on positive Phase 3 data demonstrating superiority over placebo in Hunter syndrome patients.[32] The approval for the IV formulation was amended to official approval in November 2023 after completion of Phase 3 trials targeting patients over 5 years with no prior ERT experience.[33] Hunter syndrome affects approximately 70-80 patients in Korea, mainly boys.[32]

10.2. Orphan Drug Designations

Idursulfase beta has received Orphan Drug Designation (ODD) in multiple regions:

• USA (FDA): Designated for "Treatment of Hunter Syndrome (mucopolysaccharidoses)" on February 11, 2013. Sponsor: Green Cross Corp..[10]
• Europe (EMA): Hunterase ICV granted ODD for "treatment of mucopolysaccharidosis type II (Hunter syndrome)" on November 1, 2021 (positive COMP opinion October 15, 2021).[4]
• Japan (MHLW/PMDA): Hunterase ICV received ODD prior to its NDA submission and approval.[5] The PMDA review report for "Izcargo" (Pabinafusp Alfa, another MPS II drug) lists Idursulfase beta (genetic recombination) as an orphan drug for mucopolysaccharidosis type II.[23]

10.3. Post-Marketing Surveillance and Commitments

Post-marketing surveillance and commitments are standard for newly approved drugs, especially ERTs for rare diseases and those with novel delivery routes like ICV. For Hunterase ICV in Japan, the PMDA approval came with conditions to further evaluate long-term efficacy and other aspects.[29] The full approval of Hunterase IV in South Korea followed the completion of a confirmatory Phase 3 trial, fulfilling earlier conditional approval requirements.[32]

Table 7: Global Regulatory Approval Status of Idursulfase Beta (Hunterase)

Region/Agency	Formulation	Indication	Patient Population	Approval Status	ODD Status	Key Dates/Notes	Source(s)
South Korea (MFDS)	IV	Hunter Syndrome (MPS II)	Patients >5 years, no prior ERT (for full approval)	Full Approval (Nov 2023, amended from conditional 2012)	Yes (Sept 2011)	Conditional approval Jan 2012. Full approval after Phase 3.	32
South Korea (MFDS)	ICV	Hunter Syndrome (MPS II)	Hunter syndrome patients	Full Approval	Yes	Based on Phase 3 data showing superiority vs placebo.	32
Japan (PMDA)	ICV (15mg)	Mucopolysaccharidosis type II (Hunter Syndrome), particularly CNS symptoms	Patients with MPS II where CNS improvement is necessary; confirmed tolerability to IV idursulfase. No specific age restriction mentioned beyond general pediatric use considerations. Phase I/II in Japan: 23-65 months.	Approved (Jan 22, 2021)	Yes (prior to approval)	World's first ICV ERT approval for MPS II.	5
USA (FDA)	IV / ICV	Treatment of Hunter Syndrome	Not specified for approval	Not FDA Approved for Orphan Indication (ODD granted Feb 11, 2013 for "idursulfase beta")	Yes (Designated)		10
Europe (EMA)	ICV	Treatment of Mucopolysaccharidosis type II	Not specified for approval	Not EMA Approved (ODD granted Nov 1, 2021)	Yes (Designated)	Positive COMP opinion noted significant benefit for ICV over IV for CNS.	4
Russia	ICV	Severe Hunter Syndrome	Not specified	Marketing Authorization Received	Not specified	Hunterase IV approved in Russia in 2018.	31

IV = Intravenous; ICV = Intracerebroventricular; ODD = Orphan Drug Designation; COMP = Committee for Orphan Medicinal Products.

11. Conclusion and Future Directions

Idursulfase beta (Hunterase) represents a significant therapeutic option for patients with Hunter syndrome (MPS II), an X-linked lysosomal storage disorder. As a recombinant form of the human iduronate-2-sulfatase enzyme, its primary mechanism involves replacing the deficient endogenous enzyme to facilitate the breakdown of accumulated glycosaminoglycans, dermatan sulfate and heparan sulfate. This ERT has demonstrated efficacy in reducing GAG levels and improving certain clinical outcomes, such as the 6-minute walk test, particularly in its intravenous formulation.

Clinical trial NCT01645189 specifically established the safety and efficacy of intravenous Idursulfase beta in children younger than 6 years, a critical patient population where early intervention is paramount. The trial confirmed significant reductions in urinary GAG levels and a safety profile consistent with that observed in older patients. Other studies, including comparative trials against Idursulfase (Elaprase), have suggested potential advantages for Idursulfase beta in terms of specific enzyme activity and immunogenicity in preclinical models, although comprehensive head-to-head clinical data in humans are essential for definitive conclusions.

A major advancement in the development of Idursulfase beta has been the creation and approval (in Japan and South Korea) of an intracerebroventricular (ICV) formulation. This route of administration aims to bypass the blood-brain barrier, a significant hurdle for IV ERTs in addressing the neurological manifestations of Hunter syndrome. Clinical data from ICV studies have shown promising reductions in CSF GAGs and some positive effects on developmental parameters, offering hope for mitigating the cognitive decline associated with neuronopathic MPS II.

Despite these advancements, challenges remain. Immunogenicity, with the development of anti-drug and neutralizing antibodies, continues to be a consideration for all ERTs, potentially impacting long-term efficacy and safety. The invasive nature of ICV administration also presents its own set of risks and logistical considerations.

Future directions for Idursulfase beta and ERT in Hunter syndrome will likely focus on:

1. Optimizing CNS Delivery: Further research into enhancing brain delivery and efficacy of ICV or other novel CNS-targeting strategies.
2. Managing Immunogenicity: Developing strategies to mitigate or manage immune responses to the recombinant enzyme.
3. Long-Term Outcomes: Continued collection and analysis of long-term data from ongoing and future studies to better understand the sustained impact on disease progression, quality of life, and survival across different patient populations and disease severities.
4. Combination Therapies: Exploring potential combination approaches that could augment the effects of ERT or address aspects of the disease not fully managed by enzyme replacement alone.
5. Global Access: Expanding regulatory approvals and patient access to both IV and ICV formulations in regions where they are not yet available.

Idursulfase beta, particularly with its ICV formulation, underscores the ongoing commitment to improving therapeutic outcomes for individuals with Hunter syndrome. Continued research and clinical experience will be crucial in defining its optimal role in the comprehensive management of this complex and devastating disorder.

12. References

(References would be compiled from the cited snippet IDs according to standard scientific citation format.)

Works cited

1. What is the mechanism of Idursulfase beta? - Patsnap Synapse, accessed May 16, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-idursulfase-beta
2. What is Idursulfase beta used for? - Patsnap Synapse, accessed May 16, 2025, https://synapse.patsnap.com/article/what-is-idursulfase-beta-used-for
3. Idursulfase: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed May 16, 2025, https://go.drugbank.com/drugs/DB01271
4. GC Pharma Announces EMA Grants Orphan Drug Designation to Hunterase ICV, The World's First Enzyme Replacement Therapy for Mucopolysaccharidosis Type II Administered by ICV Injection | Financial Post, accessed May 16, 2025, https://financialpost.com/pmn/press-releases-pmn/business-wire-news-releases-pmn/gc-pharma-announces-ema-grants-orphan-drug-designation-to-hunterase-icv-the-worlds-first-enzyme-replacement-therapy-for-mucopolysaccharidosis-type-ii-administered-by-icv-injection
5. Clinigen receives marketing approval for Hunterase (Idursulfase-beta) ICV in Japan, accessed May 16, 2025, https://www.clinigengroup.com/news/news-container/2021/clinigen-receives-marketing-approval-for-hunterase-idursulfase-beta-icv-in-japan/
6. Idursulfase Beta | Green Cross Inc - Bioz, accessed May 16, 2025, https://www.bioz.com/result/idursulfase%20beta/product/Green%20Cross%20Inc
7. Idursulfase - GC Biopharma - AdisInsight, accessed May 16, 2025, https://adisinsight.springer.com/drugs/800034030
8. DrugBank - DDrare: Database of Drug Development for Rare Diseases, accessed May 16, 2025, https://ddrare.nibn.go.jp/cgi-bin/clinical_trials_e.cgi?db=drug_who_drugbank&query=DB16190
9. Idursulfase beta API Price per kg: B2B transaction history - Pharmaoffer.com, accessed May 16, 2025, https://pharmaoffer.com/api-excipient-supplier/transactions/idursulfase-beta
10. IDURSULFASE BETA - Inxight Drugs - ncats, accessed May 16, 2025, https://drugs.ncats.io/drug/5GCF8EPY6R
11. Development of idursulfase therapy for mucopolysaccharidosis type II (Hunter syndrome): the past, the present and the future - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5574592/
12. A biochemical and physicochemical comparison of two recombinant enzymes used for enzyme replacement therapies of hunter syndrome - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/261997519_A_biochemical_and_physicochemical_comparison_of_two_recombinant_enzymes_used_for_enzyme_replacement_therapies_of_hunter_syndrome
13. Comparative study of idursulfase beta and idursulfase in vitro and in ..., accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5285491/
14. Package Insert of Idursulfase β Injection - CANbridge Pharmaceuticals, accessed May 16, 2025, https://www.canbridgepharma.com/media/bfbbcxmr/hunterase-pi-en.pdf
15. Package Insert of Idursulfase β Injection - CANbridge Pharmaceuticals, accessed May 16, 2025, https://canbridgepharma.com/media/bfbbcxmr/hunterase-pi-en.pdf
16. GC Biopharma, accessed May 16, 2025, http://hunterase.com/hunterase-iv/
17. About Hunterase ICV, accessed May 16, 2025, http://www.hunterase.com/hunterase-icv/
18. GC Pharma Announces EMA Grants Orphan Drug Designation to Hunterase ICV, The World's First Enzyme Replacement Therapy for Mucopolysaccharidosis Type II Administered by ICV Injection - BioSpace, accessed May 16, 2025, https://www.biospace.com/gc-pharma-announces-ema-grants-orphan-drug-designation-to-hunterase-icv-the-world-s-first-enzyme-replacement-therapy-for-mucopolysaccharidosis-type-ii-administered-by-icv-injection
19. Clinigen and GC Pharma collaboratively submit New Drug Application for Hunterase (Idursulfase-beta) ICV in Japan, accessed May 16, 2025, https://www.clinigengroup.com/media/2062/clinigen-hunterase-announcement-01apr2020.pdf
20. Impact of intracerebroventricular enzyme replacement therapy in patients with neuronopathic mucopolysaccharidosis type II - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7957024/
21. GC Pharma Announces EMA Grants Orphan Drug Designation to Hunterase ICV, The World's First Enzyme Replacement Therapy for Mucopolysaccharidosis Type II Administered by ICV Injection - Business Wire, accessed May 16, 2025, https://www.businesswire.com/news/home/20211101006010/en/GC-Pharma-Announces-EMA-Grants-Orphan-Drug-Designation-to-Hunterase-ICV-The-Worlds-First-Enzyme-Replacement-Therapy-for-Mucopolysaccharidosis-Type-II-Administered-by-ICV-Injection
22. GC's severe hunter syndrome treatment wins orphan drug status in EU - KBR, accessed May 16, 2025, https://www.koreabiomed.com/news/articleView.html?idxno=12465
23. New Drugs Approved in FY 2020 - PMDA, accessed May 16, 2025, https://www.pmda.go.jp/files/000267879.pdf
24. Announcing Marketing Approval for Hunterase ICV Injection 15 mg, the World's First Enzyme Replacement Therapy for Mucopolysaccharidosis Type II (Hunter Syndrome) Administered by ICV Injection - Business Wire, accessed May 16, 2025, https://www.businesswire.com/news/home/20210122005255/en/Announcing-Marketing-Approval-for-Hunterase-ICV-Injection-15-mg-the-Worlds-First-Enzyme-Replacement-Therapy-for-Mucopolysaccharidosis-Type-II-Hunter-Syndrome-Administered-by-ICV-Injection
25. Announcing Marketing Approval for Hunterase ICV Injection 15 mg, the World's First Enzyme Replacement Therapy for Mucopolysaccharidosis Type II (Hunter Syndrome) Administered by ICV Injection | Business Wire, accessed May 16, 2025, https://www.businesswire.com/news/home/20210122005255/en/Announcing-Marketing-Approval-for-Hunterase-ICV-Injection-15-mg-the-World%E2%80%99s-First-Enzyme-Replacement-Therapy-for-Mucopolysaccharidosis-Type-II-Hunter-Syndrome-Administered-by-ICV-Injection
26. Hunterase ICV Injection 15 mg, accessed May 16, 2025, http://hunterase.com/assets/download/hunterase_ICV_1mL_Ins.pdf
27. Clinigen receives marketing approval for Hunterase (Idursulfase-beta) ICV in Japan, accessed May 16, 2025, https://www.clinigengroup.com/media/2196/clinigen-announcement-26jan2021.pdf
28. Intracerebroventricular enzyme replacement therapy in patients with neuronopathic mucopolysaccharidosis type II: Final report of 5-year results from a Japanese open-label phase 1/2 study - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/37922836/
29. Report on the Deliberation Results March 3, 2021 Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Hea - PMDA, accessed May 16, 2025, https://www.pmda.go.jp/files/000242410.pdf
30. Clinical data required for the approval of pediatric pharmaceuticals in Japan - PMC, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11995577/
31. GC Biopharma expands Hunterase ICV approval to Russia following Japan < Pharma < Article - KBR, accessed May 16, 2025, https://www.koreabiomed.com/news/articleView.html?idxno=25991
32. GC Pharma's Hunterase Wins Full Approval in South Korea | NAVLIN DAILY, accessed May 16, 2025, https://www.navlindaily.com/article/19546/gc-pharma-s-hunterase-wins-full-approval-in-south-korea
33. GC's Hunter syndrome treatment gets full approval in 11 years < Pharma < Article - KBR, accessed May 16, 2025, https://www.koreabiomed.com/news/articleView.html?idxno=22556
34. Idursulfase - DDrare: Database of Drug Development for Rare Diseases, accessed May 16, 2025, https://ddrare.nibn.go.jp/ddrare_Mar2023/ddrare_Mar2022/ddrare_Mar2021/cgi-bin/drug_who_e.cgi?query=idursulfase&disease_id=19
35. GC Biopharma Receives FDA Approval for its U.S. Plasma Collection Center in Calexico, California - PR Newswire, accessed May 16, 2025, https://www.prnewswire.com/news-releases/gc-biopharma-receives-fda-approval-for-its-us-plasma-collection-center-in-calexico-california-302454907.html
36. Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/36027721/
37. A Study of GC1111 in Hunter Syndrom Patients - ngram, accessed May 16, 2025, https://www.ngram.com/trials/NCT03920540
38. GC Biopharma Presents Updates on its LSD Treatments at the ..., accessed May 16, 2025, https://www.prnewswire.com/news-releases/gc-biopharma-presents-updates-on-its-lsd-treatments-at-the-worldsymposium-2024-302061569.html
39. Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/21150784/
40. JCR Pharmaceuticals' Research Presentations at WORLDSymposium™ 2025 Showcase Research from Its Investigational Treatments for Lysosomal Storage Disorders - BioSpace, accessed May 16, 2025, https://www.biospace.com/press-releases/jcr-pharmaceuticals-research-presentations-at-worldsymposium-2025-showcase-research-from-its-investigational-treatments-for-lysosomal-storage-disorders
41. REGENXBIO Announces Presentations at the 20th Annual WORLDSymposium 2024, accessed May 16, 2025, https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-presentations-20th-annual-worldsymposium/
42. (PDF) Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter Syndrome) - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/236052073_Phase_III_clinical_trial_of_enzyme_replacement_therapy_with_idursulfase_beta_in_patients_with_mucopolysaccharidosis_II_Hunter_Syndrome
43. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome) | Request PDF - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/6874230_A_phase_IIIII_clinical_study_of_enzyme_replacement_therapy_with_idursulfase_in_mucopolysaccharidosis_II_Hunter_syndrome
44. The Long-term Safety Study of Idursulfase-beta in Hunter Syndrome(Mucopolysaccharidosis II) Patients - ClinicalTrials.Veeva, accessed May 16, 2025, https://ctv.veeva.com/study/the-long-term-safety-study-of-idursulfase-beta-in-hunter-syndrome-mucopolysaccharidosis-ii-patients
45. How to launch a clinical trial in South Korea: Investigational New Drug Application Process, accessed May 16, 2025, https://www.precisionformedicine.com/blog/how-to-launch-a-clinical-trial-in-south-korea-investigational-new-drug-application-process
46. Summary Basis of Decision for Elaprase ™ - Drug and Health Products Portal, accessed May 16, 2025, https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD00049
47. Development of idursulfase therapy for mucopolysaccharidosis type II (Hunter syndrome): the past, the present and the future - Dove Medical Press, accessed May 16, 2025, https://www.dovepress.com/development-of-idursulfase-therapy-for-mucopolysaccharidosis-type-ii-h-peer-reviewed-fulltext-article-DDDT
48. Preclinical dose ranging studies for enzyme replacement therapy with idursulfase in a knock-out mouse model of MPS II - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/17459751/
49. Clinical Pharmacology Biopharmaceutics Review(s) - accessdata.fda.gov, accessed May 16, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/125151s0000_Elaprase_ClinPharmR.pdf
50. (PDF) Development of idursulfase therapy for mucopolysaccharidosis type II (Hunter syndrome): the past, the present and the future - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/319266446_Development_of_idursulfase_therapy_for_mucopolysaccharidosis_type_II_Hunter_syndrome_the_past_the_present_and_the_future
51. Profile of idursulfase for the treatment of Hunter syndrome, accessed May 16, 2025, https://www.tandfonline.com/doi/pdf/10.2147/RRED.S64347
52. Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter Syndrome) - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3614543/
53. Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter syndrome) - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/23497636/
54. Idursulfase Beta (Hunterase) Therapeutic Experience in a Patient with Mucopolysaccharidosis Type II | Vashakmadze | Current Pediatrics, accessed May 16, 2025, https://vsp.spr-journal.ru/jour/article/view/3270?locale=en_US
55. Long-term experience with idursulfase beta (Hunterase) in two adolescent patients with MPS II: A case series - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10475840/
56. Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome) - PMC - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7173756/
57. Safety and efficacy of enzyme replacement therapy with idursulfase beta in children aged younger than 6 years with Hunter syndrome - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/25219292/
58. accessed January 1, 1970, https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-42
59. Safety and efficacy of enzyme replacement therapy with idursulfase beta in children aged younger than 6 years with Hunter syndrome - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/265170554_Safety_and_efficacy_of_enzyme_replacement_therapy_with_idursulfase_beta_in_children_aged_younger_than_6_years_with_Hunter_syndrome
60. Study of Idursulfase-beta (GC1111) in Hunter Syndrome - ClinicalTrials.Veeva, accessed May 16, 2025, https://ctv.veeva.com/study/study-of-idursulfase-beta-gc1111-in-hunter-syndrome
61. Profile of idursulfase for the treatment of Hunter syndrome | RRED - Dove Medical Press, accessed May 16, 2025, https://www.dovepress.com/profile-of-idursulfase-for-the-treatment-of-hunter-syndrome-peer-reviewed-fulltext-article-RRED
62. Long-term open-label extension study of the safety and efficacy of intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/35961250/
63. Elaprase (idursulfase) C2720-A - Molina Marketplace, accessed May 16, 2025, https://www.molinamarketplace.com/marketplace/oh/en-us/Providers/-/media/D85AF9DB50334DCFA4F51A63AD283E09.ashx
64. ELAPRASE® Clinical Trial | Trial Design, Endpoints and Safety Profile, accessed May 16, 2025, https://www.elaprase.com/hcp/clinical-trial/
65. accessed January 1, 1970, https.ctv.veeva.com/study/study-of-idursulfase-beta-gc1111-in-hunter-syndrome
66. Successful reduction of high-sustained anti-idursulfase antibody titers by immune modulation therapy in a patient with severe mucopolysaccharidosis type II - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/268821854_Successful_reduction_of_high-sustained_anti-idursulfase_antibody_titers_by_immune_modulation_therapy_in_a_patient_with_severe_mucopolysaccharidosis_type_II
67. Database of Drug Development for Rare Diseases - DDrare, accessed May 16, 2025, https://ddrare.nibn.go.jp/ddrare_Mar2023/cgi-bin/disease_who_e.cgi?id=19&query=%22Hunterase%22
68. Hunterase - DDrare: Database of Drug Development for Rare Diseases, accessed May 16, 2025, https://ddrare.nibiohn.go.jp/ddrare_Mar2022/ddrare_Mar2021/cgi-bin/drug_who_e.cgi?query=hunterase&disease_id=19
69. Database of Drug Development for Rare Diseases - DDrare, accessed May 16, 2025, https://ddrare.nibn.go.jp/ddrare_Mar2023/cgi-bin/disease_who_e.cgi?id=19&query=%22GC1123%22
70. Mucopolysaccharidosis Type II (MPS II) (DBCOND0065668) | DrugBank Online, accessed May 16, 2025, https://go.drugbank.com/conditions/DBCOND0065668
71. accessed January 1, 1970, https.www.canbridgepharma.com/media/bfbbcxmr/hunterase-pi-en.pdf
72. Extension of Study TKT024 Evaluating Long-Term Safety and Clinical Outcomes in MPS II Patients Receiving Idursulfase, accessed May 16, 2025, https://clinicaltrials.takeda.com/study-detail/5f6b600f4db2bf003ab48d9e
73. Elaprase (idursulfase), accessed May 16, 2025, https://hhs.iowa.gov/media/383/download?inline
74. Elaprase (idursulfase) injection label - accessdata.fda.gov, accessed May 16, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125151s0152lbl.pdf
75. Case report of treatment experience with idursulfase beta (Hunterase) in an adolescent patient with MPS II - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/316897517_Case_report_of_treatment_experience_with_idursulfase_beta_Hunterase_in_an_adolescent_patient_with_MPS_II
76. Mean normalized uGAG (μg/mg) by visit and IgG Ab status (A) and NAb... | Download Scientific Diagram - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/figure/Mean-normalized-uGAG-mg-mg-by-visit-and-IgG-Ab-status-A-and-NAb-status-B-Ab_fig1_315368744
77. Comparative study of idursulfase beta and idursulfase in vitro and in vivo - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/309905425_Comparative_study_of_idursulfase_beta_and_idursulfase_in_vitro_and_in_vivo
78. Search Orphan Drug Designations and Approvals - FDA, accessed May 16, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=385712
79. Search Orphan Drug Designations and Approvals - FDA, accessed May 16, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=289709
80. Idursulfase beta - Orphanet, accessed May 16, 2025, https://www.orpha.net/en/drug/substance/627620?name=&mode=pat®ion=&status=all