A Comprehensive Monograph on Idursulfase (Elaprase®): Pharmacology, Clinical Efficacy, and Therapeutic Context in Mucopolysaccharidosis Type II

Executive Summary

Idursulfase, marketed under the brand name Elaprase®, represents a landmark achievement in the treatment of rare genetic disorders. As the first-in-class enzyme replacement therapy (ERT) for Mucopolysaccharidosis Type II (MPS II), or Hunter syndrome, it has fundamentally altered the clinical course for a generation of patients. Idursulfase is a recombinant form of the human lysosomal enzyme iduronate-2-sulfatase (I2S), produced in a human cell line to ensure structural and functional fidelity to the endogenous enzyme. Its mechanism of action is direct and intuitive: by providing an exogenous source of the deficient enzyme, it facilitates the catabolism of accumulated glycosaminoglycans (GAGs)—dermatan sulfate and heparan sulfate—within cellular lysosomes, thereby mitigating the systemic pathology of the disease.

Clinical trials have unequivocally demonstrated the somatic benefits of Idursulfase, most notably a significant improvement in physical endurance, as measured by the 6-minute walk test, and a reduction in organomegaly. These benefits have translated into a profound impact on the non-neurological aspects of Hunter syndrome, improving mobility and likely extending the lifespan of many patients. However, the therapeutic reach of Idursulfase is critically constrained by its molecular properties. As a large glycoprotein, it is unable to cross the blood-brain barrier (BBB), leaving the progressive and devastating neurological manifestations of severe Hunter syndrome untreated. This limitation is the single most important factor defining its clinical role and has become the primary driver for the development of next-generation therapies.

The safety profile of Idursulfase is characterized by a high incidence of infusion-associated hypersensitivity reactions, necessitating a U.S. Food and Drug Administration (FDA) boxed warning for life-threatening anaphylaxis. The risk of immunogenicity, with over half of patients developing anti-drug antibodies, is a significant clinical consideration, particularly in patients with null mutations who lack any endogenous I2S protein. The complex recombinant manufacturing process and the orphan disease indication contribute to its exceptionally high cost, creating substantial economic and access challenges.

This report provides an exhaustive analysis of Idursulfase, from its intricate biochemical synthesis and mechanism of action to its global regulatory history and the pivotal clinical data supporting its use. It critically examines its efficacy and safety profiles and situates the drug within the evolving therapeutic landscape. While Idursulfase remains a cornerstone of somatic management for Hunter syndrome, it is increasingly viewed as a foundational, yet transitional, therapy. The scientific and clinical experience gained from its development and use has illuminated a clear path forward, catalyzing a new wave of innovation focused on overcoming the blood-brain barrier and offering hope for a therapy that can treat the whole patient, including the brain.

Section 1: Idursulfase: Biochemical Profile and Recombinant Synthesis

The development and production of Idursulfase represent a sophisticated application of biotechnology to address a specific molecular deficiency. Its identity as a therapeutic agent is defined by its precise biochemical structure, which mimics the natural human enzyme, and by the complex, multi-stage manufacturing process required to produce it safely and effectively at a commercial scale.

1.1 Molecular Identity and Physicochemical Properties

Idursulfase is a highly purified, biotech-derived protein therapeutic.[1] It is the recombinant form of the human lysosomal enzyme iduronate-2-sulfatase (I2S), which is functionally deficient in patients with Hunter syndrome.[2] Its primary role is to restore a specific metabolic function, classifying it pharmacologically as a Hydrolytic Lysosomal Glycosaminoglycan-specific Enzyme.[1]

Structurally, Idursulfase is a glycoprotein composed of 525 amino acids, with a calculated molecular weight of approximately 76 kilodaltons (kDa).[1] A key feature of its structure is the presence of eight asparagine-linked (N-linked) glycosylation sites. These sites are occupied by complex oligosaccharide chains, which are crucial for the protein's stability, solubility, and, most importantly, its biological targeting mechanism.[4] The enzymatic function of Idursulfase is critically dependent on a specific post-translational modification: the conversion of a cysteine residue at position 59 of the polypeptide chain into Cα-formylglycine.[4] This unique amino acid is essential for the catalytic activity of all sulfatases and is required for Idursulfase to hydrolyze its target substrates. The specific activity of the final drug product ranges from 41 to 77 units per milligram of protein, where one unit is defined by its ability to hydrolyze a specific amount of heparin disaccharide substrate under controlled assay conditions.[5]

For clinical use, Idursulfase is supplied as a sterile, nonpyrogenic, clear to slightly opalescent, and colorless solution intended for intravenous infusion. The commercial formulation, Elaprase®, has a concentration of 2.0 mg/mL at a pH of approximately 6. It is formulated in a buffered saline solution containing sodium chloride, sodium phosphate monobasic monohydrate, sodium phosphate dibasic heptahydrate, and polysorbate 20 as a stabilizer. The product is preservative-free and supplied in single-use vials, which must be diluted in 0.9% Sodium Chloride Injection, USP, prior to administration.[5]

Table 1: Key Physicochemical and Regulatory Identifiers of Idursulfase

Parameter	Identifier/Value	Source(s)
Drug Name (INN)	Idursulfase	6
Brand Name	Elaprase®	8
DrugBank ID	DB01271	8
Type	Biotech	1
CAS Number	50936-59-9	8
FDA UNII	5W8JGG251	1
ATC Code	A16AB09	1
Molecular Weight	~76 kDa	1
Amino Acid Count	525	1
Company	Takeda Pharmaceuticals U.S.A., Inc. (via acquisition of Shire plc)	1

1.2 Recombinant Manufacturing and Synthesis

The production of Idursulfase is a complex, multi-step process grounded in recombinant DNA technology, cell culture, and protein purification. The entire process is designed to yield a therapeutic protein that is as close as possible to the native human enzyme in both structure and function.

A pivotal decision in the development of Idursulfase was the selection of a continuous human cell line for its production.[1] Specifically, a human HT-1080 fibrosarcoma cell line was utilized.[7] This choice was not merely a matter of technical convenience but a fundamental design element aimed at optimizing the drug's therapeutic properties. The mechanism of action for Idursulfase relies on its recognition and uptake by the mannose-6-phosphate (M6P) receptor on target cells.[1] The addition of M6P moieties to the oligosaccharide chains is a complex post-translational modification. Utilizing a human cell line ensures that these modifications, along with the overall glycosylation profile, are authentically human. This is intended to produce a recombinant enzyme that is structurally and functionally "indistinguishable from the endogenous form," thereby maximizing its ability to reach its lysosomal target and theoretically minimizing its immunogenic potential.[7]

The manufacturing process, as detailed in patent documentation, can be broken down into several key stages [11]:

1. Gene Cloning and Vector Construction: The process begins with the isolation of the human IDS gene from a cDNA library. This gene is then inserted into a specialized expression vector, such as pJK-dhfr-Or2-IDS, which contains the necessary genetic elements to drive high-level protein expression in a mammalian host cell system.[11]
2. Transfection and Cell Line Selection: The expression vector is introduced (transfected) into a host cell line, such as Chinese Hamster Ovary (CHO-DG44) cells, which are deficient in the dihydrofolate reductase (dhfr) gene. A rigorous, multi-step selection process follows. Cells that successfully incorporate the vector are first selected using an antibiotic resistance marker like geneticin (G418). Subsequently, the cells are exposed to increasing concentrations of methotrexate (MTX). MTX inhibits the DHFR enzyme, and only cells that amplify the dhfr gene—which is linked to the IDS gene in the vector—can survive. This process selects for cell clones that have amplified the gene of interest, leading to very high levels of Idursulfase expression. A final step of limiting dilution is used to isolate a single, stable, high-producing cell clone (e.g., strain NI4-S46) to serve as the master cell bank for all subsequent manufacturing.[11]
3. Large-Scale Cell Culture: The selected master cell clone is expanded in a series of progressively larger culture vessels, moving from small shaker flasks to large, industrial-scale bioreactors with volumes up to 650 liters. The cells are grown in a chemically defined, serum-free medium under precisely controlled conditions of temperature, pH, and dissolved oxygen to maximize cell density and protein production over a period of approximately 10 days.[11]
4. Purification and Formulation: After the culture period, the Idursulfase enzyme is secreted into the culture medium. The cells are removed, and the medium containing the crude protein is harvested. This is followed by an extensive downstream purification cascade designed to isolate Idursulfase from host cell proteins and other impurities. This cascade includes:

• Ultrafiltration/Diafiltration: To concentrate the protein and exchange the buffer.
• Chromatography: A sequence of at least four distinct chromatography steps is employed, including anion exchange, hydrophobic interaction, cation exchange, and affinity chromatography. Each step separates the protein based on different physicochemical properties (charge, hydrophobicity, etc.), resulting in a highly purified product.
• Viral Inactivation and Removal: A low-pH hold step is used to inactivate potential enveloped viruses, and a nanofiltration step is performed to physically remove any remaining viral particles.
• Final Formulation: The purified protein is concentrated and formulated into the final buffer solution, sterile-filtered, and aseptically filled into single-use vials.[11]

The sheer complexity of this manufacturing process, with its multiple chromatography steps, stringent quality control requirements, and use of specialized equipment and materials, is a primary driver of the high production cost. For an orphan drug with a small patient population, this high per-unit cost of goods translates directly into the exceptionally high per-patient annual treatment cost, making Idursulfase one of the world's most expensive medicines and creating significant challenges for healthcare systems and patient access.[8]

Section 2: Pathophysiology of Hunter Syndrome and Mechanism of Action

The therapeutic rationale for Idursulfase is rooted in a direct intervention at the molecular level of Hunter syndrome. Understanding the pathophysiology of the disease is essential to appreciate how the replacement enzyme works and to recognize the inherent limitations of this therapeutic approach.

2.1 The Molecular Basis of Mucopolysaccharidosis Type II (Hunter Syndrome)

Mucopolysaccharidosis Type II (MPS II), or Hunter syndrome, is a rare, progressive, and often life-threatening lysosomal storage disorder.[14] It is an X-linked recessive genetic condition, a mode of inheritance that explains its overwhelming prevalence in males.[5] The underlying genetic defect resides in the

IDS gene, which codes for the lysosomal enzyme iduronate-2-sulfatase (I2S).[2] Mutations in this gene lead to the production of a non-functional or completely absent I2S enzyme.[5]

The I2S enzyme plays a critical housekeeping role within the lysosome, the cell's recycling center. Its specific function is to catalyze a key step in the stepwise degradation of two complex sugar molecules known as glycosaminoglycans (GAGs): dermatan sulfate and heparan sulfate.[1] Specifically, it cleaves the terminal 2-O-sulfate moieties from these GAG chains.[5]

In the absence of functional I2S enzyme, the degradation of dermatan sulfate and heparan sulfate is halted. As a result, these GAGs progressively accumulate within the lysosomes of virtually every cell type in the body.[1] This relentless accumulation leads to a cascade of pathological consequences. The lysosomes swell, causing cellular engorgement and disrupting normal cellular function. On a larger scale, this leads to tissue destruction, organomegaly (particularly of the liver and spleen), and widespread, multi-systemic organ dysfunction.[5] The clinical manifestations of Hunter syndrome are a direct result of this systemic GAG storage, affecting the skeleton, heart, lungs, joints, and, in severe cases, the central nervous system.[15]

2.2 Mechanism of Action: Reversing Lysosomal Storage

Idursulfase is designed as an enzyme replacement therapy (ERT), a strategy that aims to correct the primary biochemical defect by supplying the missing enzyme from an external source.[2] The mechanism of action is a multi-step process that relies on the body's natural cellular trafficking pathways to deliver the therapeutic protein to its site of action within the lysosome.

1. Intravenous Administration and Systemic Distribution: Idursulfase is administered by intravenous infusion, introducing the recombinant enzyme directly into the patient's bloodstream.[1] From the circulation, it is distributed throughout the body to various tissues and organs.
2. Receptor-Mediated Cellular Uptake: The key to the drug's efficacy is its ability to enter target cells. This process is not passive but is actively mediated by specific receptors on the cell surface. The mannose-6-phosphate (M6P) residues, which are added to the enzyme's oligosaccharide chains during its manufacturing in a human cell line, act as a biological "zip code." These M6P tags are recognized by and bind with high affinity to M6P receptors located on the plasma membrane of cells.[1]
3. Internalization and Lysosomal Targeting: The binding of Idursulfase to the M6P receptor triggers a process called receptor-mediated endocytosis. The cell membrane invaginates to form a vesicle (an endosome) containing the enzyme-receptor complex, effectively internalizing the drug into the cell. This vesicle is then trafficked along the endocytic pathway. As the endosome matures, its internal environment becomes more acidic. This drop in pH causes the Idursulfase enzyme to dissociate from the M6P receptor, which is then recycled back to the cell surface. The vesicle containing the free enzyme continues its journey and ultimately fuses with a lysosome, delivering its cargo to the precise subcellular compartment where it is needed.[1]
4. Restoration of GAG Catabolism: Once inside the lysosome, the exogenous Idursulfase is in its correct environment and can perform its intended enzymatic function. It cleaves the accumulated dermatan sulfate and heparan sulfate, restoring the GAG degradation pathway and reducing the lysosomal storage that drives the disease's pathology.[1]

The very mechanism that makes Idursulfase effective in somatic tissues also dictates its most significant limitation. Idursulfase is a large glycoprotein with a molecular weight of ~76 kDa.[1] The blood-brain barrier (BBB) is a highly specialized and selective physiological barrier that rigorously controls the passage of substances from the bloodstream into the central nervous system (CNS), effectively preventing large molecules like Idursulfase from reaching the brain and spinal cord in therapeutic concentrations.[7] Consequently, while intravenous ERT can successfully address GAG accumulation in peripheral organs like the liver, spleen, and connective tissues, it cannot treat the neurological aspects of the disease. This inability to cross the BBB means that Idursulfase does not halt or reverse the cognitive decline and neurodegeneration characteristic of the severe phenotype of Hunter syndrome, a fundamental limitation that has defined the clinical use of the drug and spurred the search for next-generation therapies.[7]

Section 3: Clinical Pharmacology: Pharmacodynamics and Pharmacokinetics

The clinical pharmacology of Idursulfase describes the relationship between the drug's dose, its concentration in the body over time (pharmacokinetics), and its resulting biological and therapeutic effects (pharmacodynamics). This profile provides the scientific basis for its dosing regimen and for monitoring its activity in patients.

3.1 Pharmacodynamic Effects

The pharmacodynamic effects of Idursulfase are the direct, measurable consequences of its enzymatic activity within the body. These effects serve as biomarkers of the drug's action and provide evidence that it is reaching its target and functioning as intended.

The primary pharmacodynamic effect is the catabolism of stored GAGs. This is most readily monitored by measuring the levels of GAGs excreted in the urine. In patients with Hunter syndrome, urinary GAG (uGAG) levels are significantly elevated at baseline. Treatment with Idursulfase leads to a marked reduction in these levels, providing a biochemical indication of the enzyme's activity.[19] In the pivotal clinical trial, weekly administration of Idursulfase resulted in a significant decrease in uGAG excretion. However, it is noteworthy that after 53 weeks of treatment, uGAG levels remained above the upper limit of normal in approximately half of the treated patients, suggesting that the therapy reduces but does not completely normalize GAG storage.[23] The clinical significance of this finding is still being explored, as the precise relationship between the magnitude of uGAG reduction and improvements in functional clinical outcomes has not been definitively established.[19]

A more direct clinical manifestation of GAG clearance from tissues is the reduction in organ volume. The accumulation of GAGs leads to significant hepatosplenomegaly (enlargement of the liver and spleen). Treatment with Idursulfase has been consistently shown to reduce both liver and spleen volume, providing tangible evidence of its effect on somatic GAG storage.[23] This effect was a key finding in studies of pediatric patients aged 16 months to 5 years. In this young population, where functional endpoints like walking tests are not feasible, the demonstration of spleen volume reduction similar to that seen in older patients served as crucial evidence of biological activity, supporting the drug's use in this age group.[2]

3.2 Pharmacokinetic Profile

The pharmacokinetic profile of Idursulfase describes its absorption, distribution, metabolism, and elimination. As a biologic administered intravenously, its profile differs significantly from that of a typical small-molecule oral drug.

Administration and Dosing: Idursulfase is administered exclusively as an intravenous (IV) infusion.[1] The approved and recommended dosing regimen is 0.5 mg per kg of body weight, administered once weekly.[26] The initial infusion is typically given over a period of 3 hours. If well-tolerated, the infusion duration for subsequent treatments may be gradually reduced to a minimum of 1 hour.[5]

Pharmacokinetic Parameters: Pharmacokinetic studies in Hunter syndrome patients have characterized the drug's behavior in the body. As an IV drug, its absorption is instantaneous and bioavailability is 100%. Following a 3-hour infusion of the recommended 0.5 mg/kg dose, key pharmacokinetic parameters were determined in patients aged 7.7 to 27 years.[5]

Table 2: Summary of Pharmacokinetic Parameters of Idursulfase (0.5 mg/kg weekly)

Pharmacokinetic Parameter	Week 1 (Mean, SD)	Week 27 (Mean, SD)	Unit
Cmax (Maximum Concentration)	1.5 (0.6)	1.1 (0.3)	µg/mL
AUC (Area Under the Curve)	206 (87)	169 (55)	min*µg/mL
t1/2 (Elimination Half-life)	44 (19)	48 (21)	min
Cl (Clearance)	3.0 (1.2)	3.4 (1.0)	mL/min/kg
Vss (Volume of Distribution)	21 (8)	25 (9)	% Body Weight
Data derived from a study in 10 patients aged 7.7 to 27 years receiving weekly 3-hour infusions.5

The pharmacokinetic parameters remained stable between Week 1 and Week 27 of treatment, indicating no drug accumulation or alteration in its clearance over time with chronic weekly dosing.[5] The volume of distribution at steady state (Vss) of 21-25% of body weight suggests that the drug distributes primarily within the plasma and extracellular fluid compartments, with subsequent uptake into tissues.[5]

A striking feature of the pharmacokinetic profile is the very short plasma elimination half-life (t1/2​), which is approximately 44 minutes.[1] This pronounced disparity between a half-life of less than an hour and a once-weekly dosing interval strongly suggests that the therapeutic effect of Idursulfase is not dependent on maintaining a sustained concentration in the bloodstream. Instead, the clinical efficacy is driven by the efficient and essentially irreversible uptake of the enzyme into cellular lysosomes via the M6P receptor. Once internalized, the enzyme is retained within the lysosome, where it can exert its catalytic activity for an extended period, long after it has been cleared from the plasma. The weekly infusion serves to replenish these intracellular lysosomal enzyme stores.

Studies have also shown that the area under the concentration-time curve (AUC), a measure of total drug exposure, increases in a greater than dose-proportional manner when the dose is increased from 0.15 mg/kg to 1.5 mg/kg. This suggests that the mechanisms responsible for clearing the drug from the circulation, likely receptor-mediated uptake, may become saturated at higher doses.[5] As a protein, Idursulfase is presumed to be metabolized through catabolism, where it is broken down by proteolysis into small peptides and amino acids that are then recycled by the body.

Section 4: Global Regulatory Trajectory and Approval History

The path of Idursulfase from an investigational compound to a globally approved therapy is a case study in the regulatory management of orphan drugs for rare and serious diseases. Its development and approval were expedited through special regulatory designations in both the United States and Europe, reflecting a consensus on the urgent unmet medical need for patients with Hunter syndrome.

4.1 Development Timeline and Pre-Approval Milestones

The scientific journey toward an ERT for Hunter syndrome began long before the first clinical trial. The initial characterization of the disease occurred in 1917, and the underlying "Hunter corrective factor" was identified in 1972, which was later confirmed to be the iduronate-2-sulfatase (I2S) enzyme.[2] The critical breakthrough came in the 1990s with the purification of the I2S enzyme and the subsequent cloning and sequencing of its gene, which provided the blueprint for producing a recombinant version.[2]

Preclinical development of recombinant Idursulfase began in 1996, and the clinical trial program was initiated in 2001 by Transkaryotic Therapies (TKT) under an Investigational New Drug (IND) application with the FDA.[2] Recognizing the severity of Hunter syndrome and the lack of any approved treatments, regulatory agencies granted the program several key designations to facilitate its development:

• Orphan Drug Designation: The U.S. FDA granted this status on November 28, 2001, for the "long term enzyme replacement therapy for patients with MPS II".[29] The European Medicines Agency (EMA) followed with its own orphan designation on December 11, 2001.[30] This status provides financial incentives, protocol assistance, and a period of market exclusivity upon approval.
• Fast Track Designation: The FDA granted this designation on July 14, 2004, acknowledging that Idursulfase was being developed to treat a serious condition with an unmet medical need. This allowed for more frequent communication with the FDA and eligibility for accelerated approval and priority review.[29]

These designations underscore a global regulatory philosophy that is flexible and pragmatic when faced with ultra-rare diseases. The high unmet need for Hunter syndrome patients prompted agencies to utilize pathways designed to bring promising therapies to patients as quickly as possible, even if the evidence base is necessarily smaller than for common diseases.

4.2 U.S. Food and Drug Administration (FDA) Approval

Shire plc (which later acquired TKT) submitted the Biologics License Application (BLA 125151) for Elaprase to the FDA on November 23, 2005.[3] The application was granted a priority review, shortening the target review timeline from ten months to six. The review was briefly extended in May 2006 following an FDA request for additional information regarding the occurrence of anaphylactoid and angioedema reactions observed during clinical trials.[29]

The FDA granted marketing approval for Elaprase on July 24, 2006, making it the first and only treatment ever approved for Hunter syndrome.[2] The initial approval was for the treatment of patients with Hunter syndrome, with the label specifying that Elaprase had been shown to improve walking capacity in patients aged 5 years and older, reflecting the population and primary endpoint of the pivotal clinical trial.[25]

The approval of an orphan drug often marks the beginning, not the end, of evidence generation. Following its initial approval, the clinical use and understanding of Idursulfase continued to evolve, leading to important updates to the U.S. Prescribing Information. In 2014, the label was updated to include data on its use in the younger pediatric population of children aged 16 months to 5 years.[2] This update was based on post-marketing studies designed to assess safety and pharmacodynamics in this age group. The label cautiously notes that while treatment in these young patients reduced spleen volume—a key biomarker of drug activity—an improvement in disease-related symptoms or long-term clinical outcomes had not been formally demonstrated.[2] This incremental approach to label expansion, based on post-marketing data, is a common feature in the lifecycle of orphan drugs, allowing for the gradual accumulation of evidence in populations not included in the original pivotal trials.

4.3 European Medicines Agency (EMA) Approval

Following the U.S. submission, Shire submitted a Marketing Authorisation Application (MAA) to the EMEA (now EMA) on December 1, 2005.[14] The Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion in October 2006, recommending the drug for approval.[32]

The European Commission granted a marketing authorisation for Elaprase, valid throughout the European Union, on January 8, 2007.[7] A significant aspect of the European approval was that it was granted under

"exceptional circumstances".[30] This regulatory provision is used when the applicant cannot provide comprehensive data on the efficacy and safety under normal conditions of use, because the condition to be treated is rare. The EMA acknowledged that due to the rarity of Hunter syndrome, it was not possible to conduct a large-scale clinical trial program. The approval was therefore based on the single pivotal trial, with the condition that the company would conduct post-marketing studies to gather additional long-term safety and efficacy data.[30] This decision highlights the balance regulators must strike between the need for robust evidence and the ethical imperative to provide access to the only available treatment for a devastating disease.

4.4 Global Reach

Following its approvals in the U.S. and Europe, Idursulfase was also approved in Japan in 2007.[7] Its availability has since expanded significantly, and as of 2020-2021, Elaprase was approved and available in 77 countries, making it the global standard of care for the somatic treatment of Hunter syndrome.[2]

Section 5: Clinical Efficacy: Analysis of Pivotal and Post-Marketing Trials

The clinical efficacy of Idursulfase is supported by a core body of evidence from a pivotal Phase II/III trial, a long-term open-label extension study, and dedicated studies in pediatric populations. A critical analysis of these trials reveals a clear, statistically significant benefit in certain somatic aspects of Hunter syndrome, while also highlighting the boundaries of its therapeutic effect.

5.1 The Pivotal Phase II/III Trial (TKT 024 / HGT-ELA-038)

The cornerstone of Idursulfase's approval was a 53-week, multicenter, randomized, double-blind, placebo-controlled clinical trial. This study enrolled 96 male patients with a confirmed diagnosis of Hunter syndrome, ranging in age from 5 to 31 years.[14] The design was robust, with patients randomized in a 1:1:1 ratio to one of three arms: Idursulfase 0.5 mg/kg administered weekly, Idursulfase 0.5 mg/kg administered every other week, or a matching placebo.[29]

The primary efficacy endpoint was designed to capture the multi-systemic nature of the disease. It was a two-component composite score based on the sum of the ranks of the change from baseline to Week 53 in two key functional measures:

1. The distance a patient could walk in 6 minutes (6-Minute Walk Test, or 6-MWT), an integrated measure of cardiac, pulmonary, and musculoskeletal function.
2. The percent predicted Forced Vital Capacity (%-FVC), a standard measure of restrictive lung disease.[14]

The trial successfully met its primary endpoint. The analysis demonstrated a statistically significant improvement in the composite score for the weekly Idursulfase group compared to the placebo group (p=0.0049), confirming the overall clinical benefit of the therapy.[14]

However, a deeper analysis of the individual components of this composite endpoint provides a more nuanced understanding of the drug's effects. The statistical success of the primary endpoint was driven almost entirely by the significant improvement in walking ability. Patients receiving weekly Idursulfase walked, on average, 37 meters farther in 6 minutes at the end of one year compared to those on placebo, a result that was both statistically significant (p=0.01) and considered clinically meaningful.[23] In contrast, the change in pulmonary function was not statistically significant. While there was a trend toward improvement in the weekly treatment group, the difference in %-predicted FVC compared to placebo did not reach the threshold for statistical significance (

p=0.07).[23] This finding indicates that while Idursulfase provides a clear benefit to physical endurance and mobility, its impact on the progression of restrictive lung disease, a major source of morbidity in Hunter syndrome, is less certain based on this pivotal evidence.

The trial also demonstrated significant effects on pharmacodynamic markers. Compared to placebo, weekly Idursulfase treatment led to substantial reductions in urinary GAG levels and in the volumes of the liver and spleen, confirming that the drug was biologically active and effectively clearing stored GAGs from these tissues.[23]

Table 3: Efficacy Outcomes of the Pivotal Phase II/III Clinical Trial (53 Weeks)

Efficacy Endpoint	Idursulfase 0.5 mg/kg Weekly (Mean Change)	Placebo (Mean Change)	Treatment Difference	P-value
6-Minute Walk Test	+35 meters	-2 meters	37 meters	0.013
%-Predicted FVC	+2.8%	+0.8%	2.0%	0.298
Liver Volume	-20.6%	+1.3%	-21.9%	<0.001
Spleen Volume	-32.5%	+3.2%	-35.7%	<0.001
Urinary GAG	-58.4%	+29.0%	-87.4%	<0.001
Note: Specific values may vary slightly between different regulatory summaries. The overall direction and statistical significance of the findings are consistent. Data adapted from FDA Medical Reviews and product information.23

5.2 Long-Term Open-Label Extension (OLE) Study

To assess the durability of the treatment effect, 94 of the 96 patients from the pivotal trial enrolled in a 24-month open-label extension study. In this phase, all patients, including those previously on placebo, received Idursulfase 0.5 mg/kg weekly.[23] The results of the OLE demonstrated that the clinical benefits observed in the first year were sustained over the long term. The improvements in 6-MWT distance and the reductions in urinary GAG levels and liver and spleen volumes were maintained throughout the additional 24 months of treatment. The data for pulmonary function remained ambiguous, with no further improvement observed.[23]

5.3 Studies in Pediatric Populations (<7 years)

Treating a progressive genetic disease as early as possible is a clinical imperative. However, the initial approval of Idursulfase was limited to patients aged 5 and older. To address the need for data in younger children, an open-label study (NCT00607386) was conducted in 28 patients aged 16 months to 7.5 years.[24]

In this very young population, functional endpoints like the 6-MWT were impractical to perform.[24] The study therefore focused on safety and pharmacodynamic surrogate markers. The results showed that Idursulfase was biologically active in these children, producing reductions in spleen volume and urinary GAG levels that were comparable to those seen in the pivotal trial of older patients.[2] This reliance on surrogate markers in the absence of a viable functional endpoint exemplifies a "benefit-of-the-doubt" principle often applied in orphan diseases. While a direct link to long-term clinical benefit could not be formally proven in this study, the combination of a demonstrated biological effect and an acceptable safety profile was deemed sufficient by regulators to support the drug's use in this younger age group, leading to the 2014 label update.[25]

Section 6: Comprehensive Safety and Immunogenicity Profile

While Idursulfase offers significant clinical benefits, its use is associated with considerable risks, primarily related to hypersensitivity reactions and the development of anti-drug antibodies. A thorough understanding of this safety and immunogenicity profile is essential for the safe administration of the therapy and for managing patient care.

6.1 Boxed Warning: Anaphylaxis and Hypersensitivity Reactions

The most serious risk associated with Idursulfase is the potential for severe, life-threatening allergic reactions. This risk is significant enough that the U.S. FDA requires a boxed warning—its most stringent safety alert—in the drug's prescribing information.[25] The warning highlights that life-threatening anaphylactic reactions have occurred in patients during and up to 24 hours after Elaprase infusions. This risk is present regardless of how long a patient has been on treatment.[26]

Anaphylaxis is a rapid-onset, severe allergic reaction that can present with a constellation of symptoms, including respiratory distress, hypoxia (low oxygen levels), hypotension (low blood pressure), urticaria (hives), and/or angioedema (swelling) of the throat or tongue.[19] Patients with pre-existing compromised respiratory function or an acute respiratory illness may be at an increased risk of a serious exacerbation of their condition due to an infusion reaction.[25]

The prominence of this risk fundamentally dictates the setting and manner of the drug's administration. The prescribing information mandates that appropriate medical support, including personnel trained in emergency resuscitation and necessary equipment, must be readily available whenever Elaprase is administered.[25] This requirement effectively necessitates that infusions, especially early in the course of treatment, be conducted in a medically supervised environment such as a hospital or a specialized infusion center. This adds a significant logistical and lifestyle burden for patients and their families, who must commit to a weekly, multi-hour medical procedure.

6.2 Common Adverse Reactions

Beyond the risk of anaphylaxis, hypersensitivity reactions of varying severity are very common with Idursulfase treatment. In the pivotal clinical trial, 69% of patients in the weekly treatment arm reported a hypersensitivity reaction.[24] In the study of children under 7 years of age, the incidence was 57%.[23] These reactions are typically managed by slowing the infusion rate, temporarily interrupting the infusion, and/or administering premedications such as antihistamines and corticosteroids.

Table 4: Common Adverse Reactions Reported in Clinical Trials

Adverse Reaction	Patients ≥5 Years (Incidence %)	Patients 16 mos - 7.5 yrs (Incidence %)
Hypersensitivity Reactions (Overall)	69%	57%
Pyrexia (Fever)	Not specified as top common	36%
Rash	19% (every other week group)	32%
Urticaria (Hives)	16%	Not specified as top common
Pruritus (Itching)	25%	Not specified as top common
Headache	28%	Not specified as top common
Musculoskeletal Pain	13%	Not specified as top common
Vomiting	Not specified as top common	14%
Diarrhea	9%	Not specified as top common
Cough	9%	Not specified as top common
Incidence rates are based on adverse reactions that occurred more frequently than in the placebo group or were notably high in the pediatric population. Data adapted from.23

As shown in Table 4, the profile of common adverse reactions differs slightly with age. In patients aged 5 and older, the most frequent side effects included headache, itching, musculoskeletal pain, hives, diarrhea, and cough.[35] In the younger pediatric cohort (aged 7 years and younger), a higher incidence of fever (36%), rash (32%), and vomiting (14%) was reported.[23] The most common serious adverse events in this younger group were bronchopneumonia/pneumonia (18%), ear infection (11%), and pyrexia (11%).[23]

6.3 Immunogenicity

As a recombinant protein, Idursulfase has the potential to be recognized as foreign by the patient's immune system, leading to the formation of anti-drug antibodies (ADAs). The development of these antibodies, known as immunogenicity, is a common feature of ERT. In the pivotal clinical study of Idursulfase, 51% of patients developed immunoglobulin G (IgG) anti-idursulfase antibodies over the 53-week period.[14]

The clinical consequences of ADA development are an important consideration. Evidence suggests that the presence of ADAs can impact the drug's pharmacodynamics; patients who tested positive for antibodies experienced a less pronounced decrease in their urinary GAG levels.[23] The full impact on long-term clinical efficacy remains an area of active investigation.[36]

There appears to be a clear causal link between a patient's underlying genetic mutation and their risk of mounting an immune response. Patients with genotypes that result in a complete absence of endogenous I2S protein production—such as those with complete gene deletions, large gene rearrangements, or other null mutations—are at the highest risk. Their immune systems have no prior exposure to the I2S protein and are therefore not tolerant to it. When treated with recombinant Idursulfase, their bodies are more likely to recognize it as a foreign antigen and mount a robust immune response. This is consistent with clinical observations that these patients experience a higher incidence of both anti-idursulfase antibody development and clinically significant hypersensitivity reactions.[19] This connection suggests that genetic testing could be a valuable tool for risk-stratifying patients before initiating therapy, allowing for more vigilant monitoring and proactive management in those at highest risk.

Section 7: The Therapeutic Landscape for Hunter Syndrome: Idursulfase in Context

Idursulfase did not enter a therapeutic vacuum but rather created a new one. As the first disease-modifying therapy for Hunter syndrome, it established a standard of care while simultaneously highlighting a profound unmet need. Its position in the therapeutic landscape is best understood by analyzing its primary limitation, comparing it to alternative modalities, and considering the economic forces that shape its use.

7.1 The Critical Limitation: The Blood-Brain Barrier (BBB)

The single greatest limitation of intravenously administered Idursulfase is its inability to effectively cross the blood-brain barrier.[7] This physiological barrier, which protects the central nervous system (CNS) from toxins and pathogens in the blood, also prevents large molecules like the 76 kDa Idursulfase enzyme from reaching the brain and spinal cord in therapeutic quantities.[22]

As a result, while ERT can effectively reduce GAG accumulation in somatic tissues, it cannot address the buildup of GAGs within the CNS. This leaves the progressive neurodegeneration and cognitive impairment that characterize the severe, or "neuronopathic," phenotype of Hunter syndrome completely untreated.[7] This has created a tragic clinical paradox: ERT may allow patients with severe MPS II to live longer by improving their physical health, but they continue to suffer from an inexorable neurological decline.[21] This unmet need for a CNS-active therapy is the primary driver of all current and future research in the field. The commercial and clinical success of Idursulfase in treating the somatic aspects of the disease proved the viability of the ERT concept and created a substantial market. Simultaneously, its failure to treat the brain created a clearly defined, high-value target for innovators and competitors, paradoxically fueling the research that will ultimately lead to its replacement.

7.2 Comparative Treatment Modalities: ERT vs. Hematopoietic Stem Cell Transplantation (HSCT)

The primary alternative to ERT for Hunter syndrome, particularly for severe cases, is hematopoietic stem cell transplantation (HSCT).[39] The rationale for HSCT is that it replaces the patient's blood-forming stem cells with those from a healthy donor. These donor cells can then produce and secrete functional I2S enzyme. Crucially, some of these donor-derived cells, such as monocytes, can cross the BBB and differentiate into microglial cells within the brain, acting as a permanent, local source of the enzyme.[22]

This frames the therapeutic choice for a newly diagnosed infant with severe Hunter syndrome not as a decision between two similar drugs, but as a strategic choice between two fundamentally different philosophies:

• Enzyme Replacement Therapy (ERT): A chronic, lifelong management strategy that controls somatic symptoms but does not address the underlying genetic defect or the CNS disease. It is a continuous, lower-risk (per administration) intervention.
• Hematopoietic Stem Cell Transplantation (HSCT): A one-time, high-risk curative-intent procedure that aims to provide a permanent source of enzyme for both the body and the brain.

Direct comparative evidence, though limited, suggests that HSCT, when performed very early in life (ideally before 6 months of age), may be superior to ERT for preserving neurocognitive function. A compelling case report of two siblings with severe Hunter syndrome starkly illustrates this difference: the sibling who received early HSCT demonstrated significantly better neurocognitive outcomes, activities of daily living (ADLs), and quality of life in mid-childhood compared to his brother who was treated with both intravenous and intrathecal ERT.[22] A review of the broader literature supports this finding, with multiple studies indicating that early HSCT can stabilize CNS disease progression more effectively than ERT.[22] However, HSCT is a formidable procedure with substantial risks, including toxicity from the pre-transplant conditioning chemotherapy, graft failure, and life-threatening graft-versus-host disease.[22] The decision is therefore a complex balance of risk and potential reward, heavily influenced by the patient's age at diagnosis, the severity of their mutation, and the availability of a suitable donor.

7.3 Economic Considerations and Market Position

Idursulfase is renowned for being one of the most expensive drugs in the world.[8] The annual cost of treatment is weight-based and can range from approximately $300,000 to over $657,000 per patient per year in developed markets.[12] This premium pricing is a function of several factors: the extreme complexity and high cost of manufacturing a recombinant biologic, the extensive research and development investment required to bring an orphan drug to market, and the very small patient population over which these costs must be amortized.

As the first and, for many years, only approved ERT for Hunter syndrome, Elaprase® has held a monopoly position in the market. The therapeutic ecosystem is, however, beginning to evolve. Biosimilar versions, such as Idursulfase-beta (Hunterase), have been approved in some markets, and a pipeline of next-generation, CNS-penetrant therapies is advancing rapidly, posing a direct competitive threat.[12]

The high cost of Idursulfase creates significant access and reimbursement hurdles. Payers, including government programs like Medicare and Medicaid as well as private insurers, typically require extensive documentation of medical necessity before approving coverage.[42] To address this, the manufacturer, Takeda (via its acquisition of Shire), has established comprehensive patient support programs, such as OnePathSM in the U.S., to assist patients and healthcare providers with navigating the complex processes of insurance verification, reimbursement coding, and financial assistance.[14]

Section 8: Future Directions and Next-Generation Therapies

The limitations of Idursulfase, particularly its inability to treat the central nervous system, have defined the trajectory of modern therapeutic development for Hunter syndrome. The current research landscape is vibrant and focused on two primary strategic pathways: engineering "bio-better" enzymes that can be delivered across the blood-brain barrier, and developing gene therapies that enable the patient's own cells to produce the enzyme endogenously.

8.1 Overcoming the BBB: Next-Generation ERTs

The most advanced strategy to address the neurological deficits of Hunter syndrome is to enhance the delivery of the I2S enzyme to the brain. This is being achieved by hijacking natural transport systems that exist at the BBB. The leading approach involves fusing the Idursulfase enzyme to a second molecule, typically an antibody or an antibody fragment, that binds to a receptor highly expressed on the surface of the brain's capillary endothelial cells, such as the transferrin receptor. This binding triggers receptor-mediated transcytosis, a process that actively shuttles the entire fusion protein across the barrier into the brain, acting as a "molecular Trojan horse".[38]

Several next-generation ERTs based on this principle are in late-stage clinical development:

• Tividenofusp alfa (DNL310): Developed by Denali Therapeutics, this investigational drug consists of the I2S enzyme fused to an Fc fragment of an antibody that has been engineered to bind to the transferrin receptor. It is currently in a pivotal Phase 2/3 clinical trial (NCT05371613) that is designed as an active-controlled study, directly comparing its efficacy and safety against the current standard of care, Idursulfase.[45] Early data have been promising, showing reductions in key CNS biomarkers and improvements in clinical outcomes like hearing and cognition, prompting the company to plan for accelerated approval submissions.[43]
• Pabinafusp alfa (JR-141): Developed by JCR Pharmaceuticals, this therapy fuses the I2S enzyme to a complete anti-human transferrin receptor antibody. This drug has already received marketing approval in Japan under the brand name Izcargo. It is also being evaluated in a global Phase 3 trial (the STARLIGHT study, NCT05494593) to support approvals in the U.S., Europe, and other regions.[43]

The design of these clinical trials reflects the lessons learned from the Idursulfase experience. They incorporate CNS-relevant endpoints, such as neurocognitive assessments and the measurement of GAGs in cerebrospinal fluid (CSF), and the use of an active comparator (Idursulfase) sets a higher evidentiary bar for approval, requiring the new drugs to demonstrate superiority over the existing standard of care.

8.2 The Advent of Gene Therapy: A Potential Cure

A more revolutionary approach is gene therapy, which aims to provide a one-time, permanent treatment for Hunter syndrome. Instead of repeatedly supplying the enzyme protein, gene therapy delivers a functional copy of the IDS gene itself to the patient's cells. This allows the cells to produce their own continuous supply of the I2S enzyme, potentially for the rest of the patient's life, thereby eliminating the burden of weekly infusions.[43]

The leading gene therapy candidate is:

• RGX-121: Developed by Regenxbio, this therapy uses a modified, non-pathogenic adeno-associated virus (AAV9) as a vector to deliver the human IDS gene. To address the neurological disease, RGX-121 is administered directly into the CNS via an intracisternal or intracerebroventricular injection.[43] It is being evaluated in a Phase 1/2/3 clinical trial (the CAMPSIITE study, NCT03566043) in young pediatric patients with neuronopathic MPS II.[51] Early results have been encouraging, showing a significant reduction in heparan sulfate, a key GAG biomarker in the CSF. Based on this data, the company has initiated a rolling submission to the FDA for accelerated approval.[43]

Other gene therapy approaches are also being explored, including ex vivo gene therapy, where a patient's own hematopoietic stem cells are collected, genetically modified in the laboratory to include a working copy of the IDS gene, and then infused back into the patient.[50]

8.3 Other Investigational Modalities

Beyond enhanced ERTs and gene therapy, other strategies are under investigation:

• Intrathecal/Intracerebroventricular ERT: This involves the direct administration of standard Idursulfase into the CSF to bypass the BBB. While this approach has been tested in clinical trials (e.g., NCT02055118), the results have been disappointing, failing to show a significant impact on cognitive outcomes. The invasive nature of repeated lumbar or intracerebroventricular injections also presents a significant challenge.[22]
• Substrate Reduction Therapy (SRT): This approach uses small-molecule drugs to inhibit one of the enzymes involved in the synthesis of GAGs. By reducing the production of GAGs, this therapy aims to lessen the amount of substrate that accumulates in the lysosomes. The potential advantage is that small molecules can often cross the BBB, offering a potential treatment for the neurological symptoms.[56]

Table 5: Comparison of Current and Investigational Therapies for Hunter Syndrome

Therapy Name (Brand/Code)	Company	Modality	Mechanism of Action	Route of Admin.	Key Advantage	Development Stage
Idursulfase (Elaprase®)	Takeda	ERT	Replaces deficient I2S enzyme systemically.	Intravenous	Proven somatic benefit.	Approved
Tividenofusp alfa (DNL310)	Denali	Next-Gen ERT	I2S fused to Fc fragment to cross BBB via transferrin receptor.	Intravenous	Potential to treat CNS symptoms.	Phase 3
Pabinafusp alfa (JR-141)	JCR Pharma	Next-Gen ERT	I2S fused to antibody to cross BBB via transferrin receptor.	Intravenous	Potential to treat CNS symptoms.	Phase 3 (Global); Approved (Japan)
RGX-121	Regenxbio	Gene Therapy	AAV9 vector delivers functional IDS gene directly to the CNS.	Intracisternal/ICV	One-time treatment for CNS disease.	Phase 1/2/3; Rolling BLA
HSCT	N/A	Cell Therapy	Donor cells provide a permanent source of I2S for body and brain.	Intravenous	Potential to stabilize CNS disease.	Clinical Practice

Section 9: Synthesis and Strategic Recommendations

The comprehensive analysis of Idursulfase reveals it to be a pioneering yet imperfect therapy. It stands as a testament to the power of biotechnology to address rare genetic diseases, while its limitations have clearly illuminated the path for future innovation. This concluding section synthesizes the key findings to provide an integrated assessment of its legacy and offer strategic recommendations for clinical practice and future research.

9.1 Integrated Analysis: The Legacy of Idursulfase

Idursulfase will be remembered as the therapy that transformed Hunter syndrome from a purely palliative condition into a treatable disease. For patients without severe neurological involvement, it has offered profound benefits, improving mobility, reducing the burden of organomegaly, and almost certainly extending lifespan. It validated the core principle of enzyme replacement for MPS II and established a global standard of care for managing the somatic manifestations of the disease.

However, the legacy of Idursulfase is dual-sided. Its value is fundamentally constrained by its inability to address the central nervous system disease, the high risk of immunogenicity, the burdensome weekly intravenous administration schedule, and its extraordinary cost. It is, therefore, best understood as a foundational but ultimately transitional therapy. Its very existence, and the clinical experience gained over more than 15 years, has been the single most important catalyst for the development of the next generation of treatments. The therapies now poised to supersede it—CNS-penetrant ERTs and curative-intent gene therapies—were designed specifically to overcome the well-defined shortcomings of Idursulfase.

9.2 Recommendations for Clinical Practice

Based on the available evidence, the following recommendations can be made for the clinical management of patients with Hunter syndrome:

• Prioritize Early Diagnosis and Genetic Testing: The window for effective intervention, particularly for preventing irreversible neurological damage, is extremely narrow. Newborn screening and rapid diagnostic workups are critical. Genetic testing should be considered standard practice not only for diagnosis but also for risk stratification. Identifying patients with null mutations can help predict a higher risk of immunogenicity, allowing for more vigilant monitoring for hypersensitivity reactions and consideration of proactive immune management strategies.
• Set Realistic Expectations through Counseling: Clinicians must engage in transparent counseling with families regarding the expected outcomes of Idursulfase therapy. It is crucial to emphasize the strong evidence for somatic benefits (e.g., improved walking, reduced spleen size) while clearly stating that there is no evidence that standard intravenous ERT will prevent or improve the cognitive and behavioral symptoms associated with the neuronopathic phenotype.
• Adhere to Strict Infusion Safety Protocols: The boxed warning for anaphylaxis must be respected. All infusions should be administered in a medical setting equipped to manage severe, life-threatening allergic reactions. A low threshold for slowing or stopping the infusion and administering supportive care is warranted, especially in high-risk patients or those with a history of reactions.
• Engage in Shared Decision-Making for HSCT: For newly diagnosed infants with a confirmed severe, neuronopathic mutation, the decision between initiating ERT and pursuing early HSCT is complex and time-sensitive. A multidisciplinary team including geneticists, metabolic specialists, and transplant physicians should engage in a thorough shared decision-making process with the family, carefully weighing the potential for CNS benefit with HSCT against its significant morbidity and mortality risks.

9.3 Recommendations for Future Research

The field is moving rapidly, but several key areas require continued investigation to improve outcomes for all patients with Hunter syndrome:

• Focus on Long-Term Outcomes of Novel Therapies: As next-generation ERTs and gene therapies move toward approval, it will be imperative to establish robust, long-term follow-up registries. These are needed to understand the durability of their effects, monitor for any late-onset safety signals, and assess their true impact on lifespan and quality of life over decades.
• Develop and Validate CNS-Specific Biomarkers: While CSF GAG levels are a promising start, the field needs more sophisticated and validated biomarkers that correlate strongly with clinical neurocognitive outcomes. This will be essential for designing more efficient clinical trials and for monitoring the response to CNS-directed therapies in individual patients.
• Optimize Immunogenicity Management: Research into immune tolerance induction protocols should be a high priority. Developing effective strategies to prevent or mitigate the development of anti-drug antibodies could improve the efficacy and safety of all ERTs, both current and future, and may be a necessary adjunct to ensure the long-term success of gene therapies.
• Address Residual Somatic Disease: Even with CNS-active therapies, some somatic manifestations, such as skeletal and cardiac valve disease, may be difficult to reverse. Research should continue to focus on adjunctive therapies that can address this residual disease burden and improve the overall quality of life for treated patients.

Works cited

1. Idursulfase - PubChem, accessed September 16, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Idursulfase
2. What is ELAPRASE ® (Idursulfase)?, accessed September 16, 2025, https://www.elaprase.com/what-is-elaprase/
3. Elaprase (idursulfase) FDA Approval History - Drugs.com, accessed September 16, 2025, https://www.drugs.com/history/elaprase.html
4. Recombinant Human IDS therapeutic protein(Idursulfase) - Creative BioMart, accessed September 16, 2025, https://www.creativebiomart.net/recombinant-human-ids-therapeutic-protein-idursulfase-436489.htm
5. ELAPRASE TM (idursulfase) - accessdata.fda.gov, accessed September 16, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/125151s032lbl.pdf
6. Idursulfase: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 16, 2025, https://go.drugbank.com/drugs/DB01271
7. Development of idursulfase therapy for mucopolysaccharidosis type II (Hunter syndrome): the past, the present and the future - PMC - PubMed Central, accessed September 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5574592/
8. Idursulfase - Wikipedia, accessed September 16, 2025, https://en.wikipedia.org/wiki/Idursulfase
9. Idursulfase (intravenous route) - Side effects & uses - Mayo Clinic, accessed September 16, 2025, https://www.mayoclinic.org/drugs-supplements/idursulfase-intravenous-route/description/drg-20068977
10. Idursulfase (Injection): Uses & Side Effects - Cleveland Clinic, accessed September 16, 2025, https://my.clevelandclinic.org/health/drugs/18531-idursulfase-injection
11. US9249397B2 - Composition and formulation comprising ..., accessed September 16, 2025, https://patents.google.com/patent/US9249397B2/en
12. IDURSULFASE biosimilar entry, drug patent expiry and freedom to operate - DrugPatentWatch, accessed September 16, 2025, https://www.drugpatentwatch.com/p/biologics/ingredient/idursulfase
13. CEDAC FINAL RECOMMENDATION and REASONS for RECOMMENDATION, accessed September 16, 2025, https://www.cda-amc.ca/sites/default/files/cdr/complete/cdr_complete_Elaprase_Dec-19-2007.pdf
14. Press Release Shire's ELAPRASE™ (idursulfase) Approved by the Food and Drug Administration (FDA) for Hunter Syndrome - SEC.gov, accessed September 16, 2025, https://www.sec.gov/Archives/edgar/data/936402/000095010306001827/dp03185_ex9901.htm
15. Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome) - da Silva, EMK - 2014 | Cochrane Library, accessed September 16, 2025, https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008185.pub3
16. Project Alive | A Cure Within Reach, accessed September 16, 2025, https://projectalive.org/
17. Long-term enzyme replacement therapy in a severe case of mucopolysaccharidosis type II (Hunter syndrome) - European Review for Medical and Pharmacological Sciences, accessed September 16, 2025, https://www.europeanreview.org/article/902
18. reference.medscape.com, accessed September 16, 2025, https://reference.medscape.com/drug/elaprase-idursulfase-342847#:~:text=Mechanism%20of%20Action,and%20CNS%20involvement%20also%20occur.
19. About ELAPRASE® | Mechanism of Action, accessed September 16, 2025, https://www.elaprase.com/hcp/about/mechanism-of-action/
20. Elaprase (idursulfase) dosing, indications, interactions, adverse effects, and more, accessed September 16, 2025, https://reference.medscape.com/drug/elaprase-idursulfase-342847
21. The role of enzyme replacement therapy in severe Hunter syndrome—an expert panel consensus - PMC - PubMed Central, accessed September 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3249184/
22. Efficacy of early haematopoietic stem cell transplantation versus ..., accessed September 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9160838/
23. ELAPRASE® Clinical Trial | Trial Design, Endpoints and Safety Profile, accessed September 16, 2025, https://www.elaprase.com/hcp/clinical-trial/
24. ELAPRASE® Clinical Trials, accessed September 16, 2025, https://www.elaprase.com/what-is-elaprase/clinical-trials/
25. Elaprase - FEPBlue.com, accessed September 16, 2025, https://www.fepblue.org/-/media/PDFs/Medical-Policies/2024/March/Mar-2024-Pharmacy-Policies/Remove---Replace/530008-Elaprase-idursulfase.pdf
26. Elaprase (idursulfase), accessed September 16, 2025, https://hhs.iowa.gov/media/383/download?inline
27. Idursulfase - Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Hepatic Dose | Drug Index | Pediatric Oncall, accessed September 16, 2025, https://www.pediatriconcall.com/drugs/idursulfase/165
28. ELAPRASE® history and global usage, accessed September 16, 2025, https://www.elaprase.com/hcp/about/history-and-global-usage/
29. BLA STN 125151 Elaprase (idursulfase) - CPY Document - FDA, accessed September 16, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/125151s0000_Elaprase_MedR.pdf
30. Elaprase | European Medicines Agency (EMA), accessed September 16, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/elaprase
31. Drug Approval Package: Elaprase (Indursulfase) NDA #125151, accessed September 16, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/125151s0000_ElapraseTOC.cfm
32. Shire Pharmaceuticals Group plc Release: ELAPRASE(TM) (idursulfase) Receives Positive Opinion In Europe - BioSpace, accessed September 16, 2025, https://www.biospace.com/shire-pharmaceuticals-group-plc-release-elaprase-tm-idursulfase-receives-positive-opinion-in-europe
33. Idursulfase Completed Phase 4 Trials for Mucopolysaccharidosis Type II (MPS II) Treatment, accessed September 16, 2025, https://go.drugbank.com/drugs/DB01271/clinical_trials?conditions=DBCOND0065668&phase=4&purpose=treatment&status=completed
34. Study Details | NCT00607386 | Safety and Clinical Outcomes in Hunter Syndrome Patients 5 Years of Age and Younger Receiving Idursulfase Therapy, accessed September 16, 2025, https://www.clinicaltrials.gov/study/NCT00607386
35. ELAPRASE® | Information for Patients & Families, accessed September 16, 2025, https://www.elaprase.com/
36. An Observational Study Evaluating Anti-Idursulfase Serum Antibody Response in Hunter Syndrome Patients | ClinicalTrials.gov, accessed September 16, 2025, https://www.clinicaltrials.gov/study/NCT00882921?term=idursulfase&rank=1
37. Immune Modulation for Enzyme Replacement Therapy in A Female Patient With Hunter Syndrome - Frontiers, accessed September 16, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01000/full
38. Recombinant idursulfase (JCR Pharmaceuticals/GlaxoSmithKline) - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 16, 2025, https://synapse.patsnap.com/drug/986309daebf04727bb803edc4bb0f6f4
39. www.labiotech.eu, accessed September 16, 2025, [https://www.labiotech.eu/best-biotech/hunter-syndrome-treatment-approaches/#:~:text=Hematopoietic%20stem%20cell%20transplantation%20(HSCT,Hunter%20syndrome%20through%20an%20IV.](https://www.google.com/url?q=https://www.labiotech.eu/best-biotech/hunter-syndrome-treatment-approaches/%23:~:text%3DHematopoietic%2520stem%2520cell%2520transplantation%2520(HSCT,Hunter%2520syndrome%2520through%2520an%2520IV.&sa=D&source=editors&ust=1758017237526336&usg=AOvVaw2kcjMA9nB5GsYRm2KIWPqe)
40. Hunter Syndrome (MPS 2) | UPMC Children's Hospital Pittsburgh, accessed September 16, 2025, https://www.chp.edu/our-services/rare-disease-therapy/conditions-we-treat/hunter-syndrome
41. 10 most expensive drugs in the world - BM.GE, accessed September 16, 2025, https://bm.ge/en/news/10-most-expensive-drugs-in-the-world/115224
42. ELAPRASE REIMBURSEMENT GUIDE, accessed September 16, 2025, https://www.elaprase.com/Content/pdf/resource-pdf/consumer/ELAPRASE%20Reimbursement%20Guide%20PDF.pdf
43. 3 promising biotech approaches to treat Hunter syndrome, a rare genetic disorder, accessed September 16, 2025, https://www.labiotech.eu/best-biotech/hunter-syndrome-treatment-approaches/
44. Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses - MDPI, accessed September 16, 2025, https://www.mdpi.com/1422-0067/21/2/400
45. UCSF Hunter Syndrome Clinical Trials — San Francisco Bay Area, accessed September 16, 2025, https://clinicaltrials.ucsf.edu/hunter-syndrome
46. UCSF Mucopolysaccharidosis Clinical Trials for 2025 — San Francisco Bay Area, accessed September 16, 2025, https://clinicaltrials.ucsf.edu/mucopolysaccharidosis
47. Hunter Syndrome Market Expected to Grow at a CAGR of 4.69% During 2025-2035, Impelled by Advancements in Enzyme Replacement Therapy (ERT) & Gene Therapy - BioSpace, accessed September 16, 2025, https://www.biospace.com/press-releases/hunter-syndrome-market-expected-to-grow-at-a-cagr-of-4-69-during-2025-2035-impelled-by-advancements-in-enzyme-replacement-therapy-ert-gene-therapy
48. Idursulfase Recruiting Phase 3 Trials for Mucopolysaccharidosis Type II (MPS II) Treatment, accessed September 16, 2025, https://go.drugbank.com/drugs/DB01271/clinical_trials?conditions=DBCOND0065668&phase=3&purpose=treatment&status=recruiting
49. MPS II Active Clinical Trials - Project Alive, accessed September 16, 2025, https://projectalive.org/resources/mps-ii-active-clinical-trials
50. Gene Therapy for Mucopolysaccharidosis Type II—A Review of the Current Possibilities, accessed September 16, 2025, https://www.mdpi.com/1422-0067/22/11/5490
51. CAMPSIITE™ RGX-121 Gene Therapy in Subjects With MPS II (Hunter Syndrome) - UCSF Clinical Trials, accessed September 16, 2025, https://clinicaltrials.ucsf.edu/trial/NCT03566043
52. RGX-121 Gene Therapy in Patients With MPS II (Hunter Syndrome), accessed September 16, 2025, https://www.chop.edu/research-studies/rgx-121-gene-therapy-patients-mps-ii-hunter-syndrome
53. Groundbreaking gene therapy trial for Hunter syndrome opens - The University of Manchester, accessed September 16, 2025, https://www.manchester.ac.uk/about/news/groundbreaking-gene-therapy-trial-for-hunter-syndrome-opens/
54. NCT02055118 | Study of Intrathecal Idursulfase-IT Administered in Conjunction With Elaprase® in Pediatric Patients With Hunter Syndrome and Early Cognitive Impairment | ClinicalTrials.gov, accessed September 16, 2025, https://clinicaltrials.gov/study/NCT02055118
55. Therapeutic options for mucopolysaccharidosis ii (Hunter disease) - Mayo Clinic, accessed September 16, 2025, https://mayoclinic.elsevierpure.com/en/publications/therapeutic-options-for-mucopolysaccharidosis-ii-hunter-disease
56. Clinical trials of new therapies for mucopolysaccharidoses - Medical Science Pulse, accessed September 16, 2025, https://medicalsciencepulse.com/seo/article/01.3001.0054.6855/en