Clinical UM Guideline

Subject: Idursulfase (Elaprase®)
Guideline #:  CG-DRUG-57 Current Effective Date:    06/28/2017
Status: Revised Last Review Date:    05/04/2017


This document addresses idursulfase (Elaprase® [Shire Human Genetic Therapies Inc., Cambridge, MA]), a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme approved by the U.S. Food and Drug Administration (FDA) for treatment of mucopolysaccharidosis II. Mucopolysaccharidosis II is a lysosomal storage disease caused by an absence or a deficiency of the iduronate-2-sulfatase enzyme.

Clinical Indications

Medically Necessary:

  1. Idursulfase is considered medically necessary for the treatment of mucopolysaccharidosis II (MPS II, Hunter syndrome) in individuals who meet both (I and II):
    1. Documented deficiency in iduronate 2-sulfatase enzyme activity as measured in fibroblasts or leukocytes combined with normal enzyme activity level of another sulfatase; or
    2. Documented pathologic iduronate 2-sulfatase gene mutation; and
  2. The individual to be treated has symptoms attributable to MPS II such as:
    1. Developmental delay or cognitive impairment; or
    2. Frequent infections; or
    3. Hearing loss; or
    4. Hepatosplenomegaly; or
    5. Hernias; or
    6. Impaired respiratory function; or
    7. Joint pain; or
    8. Skeletal deformities; or
    9. Sleep apnea; or
    10. Valvular heart disease.

Not Medically Necessary:

Idursulfase is considered not medically necessary when the criteria above are not met and for all other indications.


The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

J1743 Injection, idursulfase, 1 mg [Elaprase]
S9357 Home infusion therapy, enzyme replacement intravenous therapy, (e.g., Imiglucerase); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-10 Diagnosis  
E76.1 Mucopolysaccharidosis, type II (Hunter's syndrome)
Discussion/General Information

Description of the Condition
Mucopolysaccharidosis II (MPS II, MPS 2, Hunter syndrome) is a rare disease resulting from an inborn error of metabolism characterized by the inadequate production of iduronate-2 sulfatase. Iduronate-2 sulfatase is an enzyme which accelerates the catabolism of the GAGs dermatan sulfate and heparan sulfate. Due to the absent or deficient iduronate-2-sulfatase enzyme, the GAGs accumulate within tissues of the body affecting physiologic systems and multiple organs. Clinical manifestations of the syndrome include developmental delay, hearing loss, enlarged tongue, coarse facial features, abnormal dentition, upper airway obstruction, restrictive lung disease, hepatosplenomegaly, valvular heart disease, decreased range of joint motion, poor endurance, hernias, short stature, skeletal deformities and reduced quality of life.

MPS II is classified into two categories: mild and severe types. While both the mild and severe types affect many various organs and tissues of the body, individuals with severe MPS II typically experience intellectual deterioration and a more rapid disease progression (regressing developmentally between the ages of 6 and 8 years). The life expectancy of these individuals ranges from 10 to 20 years. In contrast, individuals with mild MPS II also have a shortened lifespan but their intelligence is not affected and they typically live into adulthood. MPS II has a variable age of onset and variable rate of progression, even in affected siblings. Typically, if clinical symptoms present early in life it is more likely that disease progression will be rapid and brain involvement is more likely to occur. MPS II is an X-linked recessive disorder, typically affects males and occurs in approximately 1 out of 140,000-156,000 male live births. Generally speaking, female carriers are usually asymptomatic (Parini, 2015).

Diagnosis of MPS II
Some cases of MPS II are initially identified as a result of newborn screening. A comprehensive biochemical evaluation is typically carried out on individuals who present early in the course of disease. Tests used in the diagnosis of MPS II may include urinary GAG concentration measurement, iduronate 2-sulfatase enzymatic activity measurement and molecular genetic testing to identify a pathogenic iduronate 2- sulfatase variant.

Management of MPS II
Currently, there is no curative therapy for MPS II. Treatment of symptoms related to MPS II varies depending upon the specific symptoms that need to be addressed. For example, hernias and joint contractures may be corrected surgically, a ventricular shunt may be implanted to manage hydrocephalus and hearing devices may be prescribed as a means to treat hearing loss. Commonly used interventions include but are not limited to: occupational and physical therapy; tonsillectomy and adenoidectomy; continuous positive airway pressure (CPAP) or tracheostomy; shunting for hydrocephalus; carpal tunnel release; cardiac valve replacement; inguinal hernia repair; and hip replacement. According to the American College of Medical Genetics (ACMG) guidelines on lysosomal storage diseases, hematopoietic stem cell transplantation (HSCT) has been used in the past to successfully eliminate hepatosplenomegaly, reduce cardiac valvular thickening, improve joint mobility, and normalized coarse facies. However, HSCT for MPS II does not preserve neurocognitive outcome and is associated with a high mortality rate. Due to the severe loss of neurocognitive functioning, the high mortality rate and the advent of enzyme replacement therapy (ERT), HSCT is no longer considered an acceptable treatment modality for any form of MPS II. Standard therapy for MPS II includes ERT (Scarpa, 2011; Wang, 2011).

Idursulfase, a purified form of human iduronate-2-sulfatase, was approved by the FDA as an orphan drug for individuals with MPS II. According to the idursulfase product information (PI) label (revised 6/2013) Indications and Usage:

ELAPRASE has been shown to improve walking capacity in patients 5 years and older. In patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long term clinical outcome; however, treatment with ELAPRASE has reduced spleen volume similarly to that of adults and children 5 years of age and older. The safety and efficacy of ELAPRASE have not been established in pediatric patients less than 16 months of age.

Idursulfase PI includes the following Boxed Warning:

Life-threatening anaphylactic reactions have occurred in some patients during and up to 24 hours after ELAPRASE infusions. Anaphylaxis, presenting as respiratory distress, hypoxia, hypotension, urticaria and/or angioedema of throat or tongue have been reported to occur during and after ELAPRASE infusions, regardless of duration of the course of treatment. Closely observe patients during and after ELAPRASE administration and be prepared to manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions, and require additional monitoring.

Idursulfase PI includes the following Warnings and Precautions:

Idursulfase PI includes the following information regarding Use in Specific Populations:

ELAPRASE is dosed at 0.5 mg per kg of body weight and administered once every week as an intravenous infusion over a minimum of 1-3 hours based on fluid volume. Individuals may require longer infusion times due to infusion reactions; however, infusion times should not exceed 8 hours.

Idursulfase does not cross the blood-brain barrier and therefore will not affect the behavioral or cognitive manifestations of MPS II. Because idursulfase does not penetrate the blood-brain barrier, researchers are conducting clinical trials which explore intrathecal administration of idursulfase.

The FDA approval of idursulfase was based on the results of a randomized, double-blinded, placebo controlled trial that evaluated the safety and efficacy of idursulfase over a period of 53 weeks. The study included a total of 96 participants between the ages of 5-31 years with a deficiency in iduronate-2-sulfatase enzyme activity and a percent predicted forced vital capacity (% predicted FVC) less than 80%. A total of 94 of the 96 participants completed the study. Participants received idursulfase 0.5 mg/kg every week (n=32), idursulfase 0.5 mg/kg every other week (n=32) or placebo (n=32). The primary efficacy outcome assessment was a two-component composite score based on the change from baseline to week 53 in distance walked during a 6-minute walk test and the change in forced vital capacity percentages. The primary endpoints demonstrated the greatest statistically significant difference between the weekly idursulfase treated cohort and the placebo cohort (p=0.0049). Participants in the idursulfase weekly group demonstrated a 35 meter mean increase in distance walked versus the placebo group. There was not a statistically significant difference in forced vital capacity percentages between the groups. Pharmacodynamic assessments included monitoring urinary GAG levels and changes in liver and spleen size. Urinary GAG levels were elevated in all study participants at baseline. Following 53 weeks of treatment, mean urinary GAG levels were reduced in the idursulfase once weekly cohort, although GAG levels still remained above the upper limit of normal in half of the participants treated with idursulfase. Urinary GAG levels remained elevated and basically unchanged in the placebo cohort. Sustained reductions in both spleen and liver volumes were observed in the idursulfase once weekly cohort through week 53 compared to placebo. There were fundamentally no changes in spleen and liver volumes in the placebo cohort. IgG antibodies to idursulfase developed in 47% of the study participants. Although those with antibodies had a lower reduction in urinary GAG excretion, no differences in clinical outcomes were observed compared with the participants without antibodies. The percentage of individuals with antibodies decreased to 32% by the end of the trial. The most common infusion-related reactions included cutaneous reaction, headache, fever, and hypertension. The frequency of infusion-related reactions diminished with time (Muenzer, 2006).

In an extension study, Muenzer and colleagues (2011a) further evaluated the clinical outcomes and safety of long-term ERT with idursulfase in individuals with MPS II. All 94 participants who completed a 53-week double-blinded study of idursulfase were enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years. No change in percent predicted forced vital capacity was observed, but absolute forced vital capacity exhibited sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were seen at most time points. Mean liver and spleen volumes remained reduced all through the 2-year extension study. Mean joint range of motion remained stable for other joints but demonstrated improvement in the shoulder. Significant improvement was demonstrated in both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score. Infusion-related adverse events occurred in 53% of participants, peaked at the third month of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of participants and seemed to attenuate the improvement in pulmonary function.

In another study, Muenzer and colleagues (2011b) used the Hunter Outcome Survey, an international database, to evaluate the safety and effectiveness of ERT with idursulfase in individuals with Hunter syndrome who started treatment before 6 years of age. The study population included 124 participants enrolled in the Hunter Outcome Survey who started idursulfase infusions (0.5 mg/kg every other week) prior to 6 years of age and who had at least one follow-up examination recorded. The mean duration of treatment was 22.9 ± 14.6 months. A total of 69 infusion-related reactions occurred in 33 (26.6%) subjects, including three serious infusion related reactions occurring in a single individual. After at least 6 months of idursulfase, urine GAG levels decreased from 592 ± 188 to 218 ± 115 µg/mg creatinine (p<0.0001, n=34). Estimated liver size (based on palpation) was also significantly decreased. Similar safety and effectiveness results were observed in participants who were 6 years of age or older when initiating idursulfase. The authors identified no new safety concerns in subjects younger than 6 years, and clinical benefit was suggested by the reduction in liver size. The authors also noted that it is challenging to prove the clinical benefit of therapy for disease-related symptoms in this population due to age-related compliance with evaluation techniques (for example, walking capacity evaluations, FEV).

Lampe and colleagues (2014) conducted a retrospective chart review to report the long-term experience of individuals who were treated with ERT for at least 2 consecutive years. Charts for a total of 22 individuals (18 months to 21 years of age) were reviewed. The researchers examined improvement in somatic manifestations (skeletal disease, joint range of motion, respiratory infections, liver/spleen size, cardiac disease, diarrhea, skin/hair texture, and disease-related hospitalizations). All participants demonstrated improvement in four or more somatic signs/symptoms, with the majority showing improvement in five to six of these findings. No new safety concerns were identified. The authors concluded that long-term treatment with idursulfase is associated with improvements in somatic manifestations.

Parini and colleagues (2015) reported the outcome of 17 individuals with Hunter syndrome who were treated at a single institution with ERT for 5 to 9 years. Eleven of the individuals were started on ERT in 2006, 3 individuals began ERT in 2004 and another 3 individuals were started on ERT after 2006, as soon as a diagnosis was made. All of the participants experienced a decrease in liver and spleen sizes and a decrease in and normalizing of urinary GAGs throughout the treatment. During the first 2 years, most of the improvement in joint range of motion (ROM) was seen in the elbows, shoulder, knees and hips. For 13 of the participants, at 5 years, the change from baseline was statistically significant for only the right shoulder. None of the participants experienced a worsening of joint ROM when compared to baseline measurements. No improvement in respiratory function, CNS disease, eye or skeletal disease was seen. Overall, the developmental quotient of individuals with a CNS involvement reflected a fast decline. These individuals were no longer testable after 6 years of age and, in spite of receiving ERT, their quality of life declined throughout the years. All of the participants demonstrated a consistent residual disease burden which was mainly reflected as persistent skeletal disease and a frequent need of surgery.

Initiating ERT
Idursulfase has been studied only in individuals with attenuated MPS II. Consequently, the effects of idursulfase on individuals with MPS II and central nervous system involvement have not been formally evaluated. However, because idursulfase does not cross the blood–brain barrier, it is not expected to have a significant impact on the neurological features of MPS II. Whether ERT should be offered to individuals with CNS manifestations is not clear. Wraith and colleagues (2008) advise that individuals with severe CNS manifestations be offered ERT for a trial period of 12-18 months, after which time a decision should be made whether to continue with the ERT (Burrow, 2008; Wraith, 2008).

Scarpa and colleagues (2011) discuss the initiation of idursulfase ERT. Based on consensus opinion, the authors recommend that, due in part to the heterogeneous nature of MPS II and the variable rate of progression, it would be reasonable to offer a 12-18 month trial period of ERT to all individuals with MPS II, after which time, the medical practitioner in consultation with the parents would determine whether to continue the ERT.

Muenzer and colleagues (2012) report the consensus recommendations of an expert panel regarding the role of ERT in severe Hunter syndrome. According to the consensus panel:

Before beginning ERT, it is absolutely essential that the physician and family discuss the goals of treatment, expectations for response, methods for evaluating response, and criteria for discontinuing therapy ... If the patient is newly diagnosed, they should be offered treatment, even if the rate of cognitive decline or severity of their eventual cognitive phenotype is not yet apparent... Both patients with attenuated disease (cognitively intact) and those with severe disease (cognitively impaired) experience many somatic signs and symptoms that can reduce quality of life, including hepatosplenomegaly, impaired respiratory function, sleep apnea, frequent infections, and joint pain.

Also in their discussion of the initiation of ERT in individuals with severe Hunter syndrome, Muenzer and colleagues recommend that all previously diagnosed, symptomatic individuals, in whom there is an expectation that ERT will alter the course of the somatic involvement, be considered for a trial of idursulfase therapy and evaluated after a minimum of 6 to 12 months. The authors emphasize that prior to the initiation of therapy, discussions should address the fact that ERT cannot stop the eventual neurological decline and should at some point be discontinued (Muenzer, 2012).

Monitoring Response to ERT
One of the challenges in evaluating the response to ERT in individuals with MPSII is the lack of assessment tools that are validated in this group of individuals. Currently, there is no validated instrument that objectively measures both changes in function and quality of life in cognitively impaired individuals with MPS II. Additionally, there are no validated biomarkers that can be utilized to measure an individual's response to treatment. While some physicians have attempted to use clinical trial endpoints, these can only be developed for subjects with no cognitive involvement. Individuals with cognitive impairment are more often than not unable to comprehend and cooperate with testing and as a result, are not able to independently perform the 6-minute walk test. Similarly, pulmonary function tests like those utilized to demonstrate the clinical efficacy of idursulfase in clinical trials require the understanding and cooperation of the subject and are beyond the capabilities of severely affected individuals. However, some assessment tools may be employed by the clinician. The healthcare practitioner may be able to assess joint range-of-motion in the cognitively impaired individual and note improvements in spleen and liver size, coarseness of facial features, and macroglossia on examination. The frequency of respiratory infections and resultant hospitalizations are other factors that may be quantified. Yet, evaluating the response to ERT in individuals with MPS II is largely subjective and must, by necessity, be based upon the physician's clinical impression and parental input (Muenzer, 2012).

Discontinuing ERT
With regards to discontinuing ERT, Scarpa and colleagues (2011) indicated that:

Short- and long-term effects of treatment continuation or cessation on the patient's quality of life should be the primary concern. Thus, any evidence of central nervous system (CNS) disease progression should be taken into consideration when formulating a management strategy…Treatment should be discontinued for patients with life-threatening IRRs that are not adequately prevented or controlled by antihistamines and corticosteroids…In these circumstances, the possibility of potentially fatal sudden respiratory failure is high.

Individuals Generally Not Considered Candidates for ERT
Scarpa and colleagues (2011) state that treatment of MPS II is not indicated for individuals who are pregnant or lactating or in "individuals whose disease is so far advanced that there is little prospect of ERT having any benefit." The authors also indicate that "treatment is also not recommended if the patient has a comorbid life-threatening disease for which the prognosis is unlikely to be influenced by ERT."

Muenzer and colleagues (2012) also provide guidance with regards to which individuals with MPS II should not be considered candidates for ERT.

It is the opinion of the authors that patients who are severely neurologically impaired (such as in a vegetative state) with subsequent low expectation of benefit should not be considered for ERT. What constitutes severe neurological impairment may be the subject of some debate, but a patient who is gastrostomy fed due to an inability to swallow would likely fall into this category. Similarly, patients who have a disease manifestation or other condition that may lead to near-term death should not receive ERT.

MPS II is a progressive disease that affects multiple systems and results in irreversible organ damage over time. Many individuals with MPS II will develop potentially life-threatening manifestations by the time they reach their 2nd decade. The goal of ERT in individuals with MPS II is to stop or slow the progression of the disease, and thus, it is important to initiate treatment prior to the onset of irreversible changes. Idursulfase ERT will not alter the course of neurological decline but may produce somatic improvements such as improved mobility, reductions in liver and spleen volumes, as well as reductions in respiratory infections and resultant hospitalizations. Preferred timing of ERT initiation as it relates to stage of disease and patient age has not been clearly established. Demonstrating clinical benefit in young individuals with MPS II remains problematic, because functional testing requires the cooperation of the subject, particularly when evaluating pulmonary function or mobility. Several clinical trials have demonstrated the clinical benefits of idursulfase therapy in individuals older than 5 years of age; however studies exploring the use of ERT in younger children are limited. The safety and efficacy of idursulfase have not been established in pediatric subjects less than 16 months of age. Thus far, ERT has been largely unsuccessful in improving central nervous system manifestations of the lysosomal storage diseases, putatively due to difficulty in penetrating the blood-brain barrier. Joint disease, cardiac valve disease and skeletal disease, all of which cause significant morbidity, generally do not improve with ERT once pathological changes are already established. Because none of the therapeutic options currently available result in complete resolution of morbidity, the management of MPS II requires lifelong attention to multiple body systems and is generally provided by a team of medical specialists. Because idursulfase ERT cannot stop the eventual neurological decline, at some point, therapy is usually discontinued.


Dysostosis multiplex: An autosomal recessive disease consisting of an error in the metabolism of mucopolysaccharides that result in mental retardation and skeletal, cartilage and bone abnormalities.

Enzyme replacement therapy (ERT): A treatment (usually via intravenous infusion) to provide enzymes in an individual unable to make sufficient amounts of that enzyme on their own.

Forced vital capacity (FVC): A measurement of the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible; FVC is used assess the presence and severity of lung diseases.

Glycosaminoglycans: Any of several polysaccharides derived from an amino hexose that are components of mucoproteins, glycoproteins, and blood-group substances; also known as mucopolysaccharide.

Hepatosplenomegaly: Enlargement of both the liver and the spleen.

Obstructive airway disease: Conditions that interfere with an individual's ability to exhale all the air from their lungs.

IRR: Infusion-related reactions.

6-minute walk test: A standardized test that measures how far a person can walk on a hard, flat surface in 6 minutes and has been used to assess endurance in several mucopolysaccharidosis (MPS).

Valvular heart disease: Any disease process involving one or more of the four (aortic, mitral, pulmonary and tricuspid) valves of the heart.


Peer Reviewed Publications: 

  1. da Silva EM, Strufaldi MW, Andriolo RB, Silva LA. Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome). Cochrane Database Syst Rev. 2016;(2):CD008185.
  2. Lampe C, Bosserhoff AK, Burton BK, et al. Long-term experience with enzyme replacement therapy (ERT) in MPS II patients with a severe phenotype: an international case series. J Inherit Metab Dis. 2014; 37(5):823-829.
  3. Muenzer J, Beck M, Eng CM, et al. Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Genet Med. 2011(a); 13(2):95-101.
  4. Muenzer J, Beck M, Giugliani R, et al. Idursulfase treatment of Hunter syndrome in children younger than 6 years: results from the Hunter Outcome Survey. Genet Med. 2011(b); 13(2):102-109.
  5. Muenzer J, Bodamer O, Burton B, et al. The role of enzyme replacement therapy in severe Hunter syndrome-an expert panel consensus. Eur J Pediatr. 2012; 171(1):181-188.
  6. Muenzer J, Wraith JE, Beck M, et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006; 8(8):465-473.
  7. Parini R, Rigoldi M, Tedesco L, et al. Enzymatic replacement therapy for Hunter disease: Up to 9 years experience with 17 patients. Mol Genet Metab Rep. 2015; 3:65-74.
  8. Ratko TA, Marbella A, Godfrey S, Aronson N. Enzyme-replacement therapies for lysosomal storage diseases [Internet]. 2013. Agency for Healthcare Research and Quality (US): Rockville (MD). Available at: Accessed on March 15, 2017.
  9. Raluy-Callado M, Chen WH, Whiteman DA, et al. The impact of Hunter syndrome (mucopolysaccharidosis type II) on health-related quality of life. Orphanet J Rare Dis. 2013; 8:101.
  10. Tylki-Szymanska A, Jurecka A, Zuber Z, et al. Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3-year follow-up. Acta Paediatr. 2012; 101(1):e42-e47.
  11. Wraith JE, Scarpa M, Beck M, et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008; 167(3):267-277.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Idursulfase. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated November 16, 2016. Available at: Accessed on March 15, 2017.
  2. Idursulfase Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised March 8, 2017. Accessed on March 15, 2017.
  3. Idursulfase. [Product Information] Cambridge, MA. Shire Human Genetic Therapies Inc. January 2016. Available at: Accessed on March 15, 2017.
  4. Scarpa M, Almássy Z, Beck M, et al. Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis. 2011; 6:72.
  5. Wang RY, Bodamer OA, Watson MS, et al. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011; 13(5):457-484.

Hunter syndrome
I2S deficiency
Iduronate-2-sulfatase deficiency
Mucopolysaccharidosis II

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.





Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated the medically necessary criteria so that bullet IB was changed from "documented iduronate 2-sulfatase gene mutation" to "documented pathologic iduronate 2-sulfatase mutation". Updated Discussion/General Information and References sections.
New 11/03/2016 MPTAC review. Initial document development.