A Safety and Dose Ranging Study of Idursulfase (Intrathecal) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Hunter Syndrome Who Have Central Nervous System Involvement and Are Receiving Treatment With Elaprase®

• Safety of intrathecal idursulfase administration as assessed by AEs, changes in clinical laboratory testing, 12-lead electrocardiograms, CSF chemistries, and anti-idursulfase antibodies [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
• Safety, tolerability, and long term patency of the IDDD in the pediatric Hunter syndrome population [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

• Concentration of idursulfase in CSF and blood after single and repeated doses of intrathecal idursulfase-IT given in conjunction with Elaprase [ Time Frame: Weeks 3 and 23 ] [ Designated as safety issue: No ]
• Change from baseline in CSF biomarkers (eg, glycosaminoglycans [GAGs] and GAG‑degradation products, heparan sulfate [HS]/dermatan sulfate [DS] oligosaccharides, and markers of lysosomal function) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Change from baseline in urinary GAG and degradation byproducts by dose group and in comparison with untreated patients [ Time Frame: 6 months ] [ Designated as safety issue: No ]

• Single and repeated dose pharmacokinetic parameters of idursulfase-IT, given in conjunction with Elaprase, in CSF and blood [ Time Frame: Weeks 3 and 23 ] [ Designated as safety issue: No ]
• Change from baseline in CSF biomarkers by dose group and in comparison with untreated patients [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Change from baseline in urinary GAG and degradation byproducts by dose group and in comparison with untreated patients [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Elaprase, a large molecular protein, is not expected to cross the blood brain barrier when administered intravenously. A revised formulation of idursulfase, idursulfase-IT, that differs from that of the intravenous (IV) formulation, Elaprase, has been developed to be suitable for delivery into the cerebrospinal fluid (CSF) via intrathecal administration.

This Phase I/II study is designed to obtain necessary safety and exposure data, as well as secondary and exploratory outcome measures, to be interpreted and used in the design of subsequent clinical trials.

• Drug: Idursulfase-IT
  Four (4) patients will be randomized to receive 1 of 3 dose levels of idursulfase-IT (10, 30, or 100 mg) once a month via an IDDD. If the IT space is not accessible via the IDDD, idursulfase-IT may be administered via lumbar puncture up to 2 times during the first 4 treatment months.
• Other: Control
  Untreated patients will be enrolled (1-2 per dose cohort to a total of 4) and will not receive the IDDD or study drug. These patients will not undergo a second CSF sampling at Baseline but will undergo all end-of-study procedures 6 months after Baseline assessments are made.

• Control
  Untreated Patients
  Intervention: Other: Control
• Experimental: Idursulfase-IT
  intrathecal, 1 mg, monthly
  Intervention: Drug: Idursulfase-IT
• Experimental: Idursulfase IT
  intrathecal, 10 mg, monthly
  Intervention: Drug: Idursulfase-IT
• Experimental: Idursulfase -IT
  intrathecal, 30 mg, monthly
  Intervention: Drug: Idursulfase-IT

• Muenzer J, Gucsavas-Calikoglu M, McCandless SE, Schuetz TJ, Kimura A. A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). Mol Genet Metab. 2007 Mar;90(3):329-37. Epub 2006 Dec 20.
• Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, Vellodi A, Martin R, Ramaswami U, Gucsavas-Calikoglu M, Vijayaraghavan S, Wendt S, Puga AC, Ulbrich B, Shinawi M, Cleary M, Piper D, Conway AM, Kimura A. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006 Aug;8(8):465-73. Erratum in: Genet Med. 2006 Sep;8(9):599. Wendt, Suzanne [corrected to Wendt, Susanne]; Puga, Antonio [corrected to Puga, Ana Cristina]; Conway, Ann Marie [corrected to Conway, Anne Marie].

Inclusion Criteria:

1a. A deficiency in iduronate-2-sulfatase enzyme activity of ≤10 % of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory) AND

1b. A documented mutation in the iduronate-2-sulfatase gene OR A normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory).

2. The patient is male and is ≥3 and <18 years of age .

3. The patient has evidence at Screening of early stage (duration and severity metrics per protocol) Hunter syndrome-related Central Nervous System (CNS) involvement, defined as:

• The patient has an Intelligence quotient (IQ) ≤77 OR

• There is evidence of a change of ≥1 but ≤2 standard deviations decline from a previous protocol-defined neurodevelopmental assessment. The duration of protocol-defined neurologic involvement is at least 3 months but less than 36 months as documented in the patient's medical history.

  4. The patient has received and tolerated a minimum of 6 months of treatment with weekly intravenous idursulfase, and has received 80% of the total planned infusions within that time frame, including having received 100% of the planned infusions within 4 weeks immediately preceding the surgical insertion of the IDDD.

  5. The patient must have sufficient auditory capacity, with or without aids, to complete the required protocol testing, and be compliant with wearing the aid on scheduled testing days.

  6. The patient, patient's parent(s), or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board / Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient. The guardians' consent must be obtained.

Exclusion Criteria:

1. The patient has clinically significant non-Hunter syndrome-related CNS involvement which is judged by the Investigator to be likely to interfere with the accurate administration and interpretation of protocol assessments.
2. The patient has an IQ ≥78
3. The patient has a CNS shunt.
4. The patient has experienced an infusion-related anaphylactoid event or has evidence of consistent severe adverse events related to treatment with Elaprase which, in the Investigator's opinion, may pose an unnecessary risk to the patient.
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to compromised airways or other conditions
6. The patient has a history of complications from previous lumbar punctures or technical challenges in conducting lumbar punctures such that the potential risks would exceed possible benefits for the patient.
7. The patient or patient's family has a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns.
8. The patient has a history of poorly controlled seizure disorder.
9. The patient has a significant medical or psychiatric comorbidity(ies) that might affect study data or confound the integrity of study results.
10. The patient is currently receiving chronic psychotropic therapy (e.g., neuroleptics, benzodiazepines, antidepressants, anticonvulsants, stimulants, etc.) which in the Investigator's opinion would likely affect the neurocognitive assessments. Intermittent use of selected short half-life agents (benzodiazepine, sedatives, etc.) may be permitted as long as there are 5 half-lives between last drug administered and study-related procedures including neurocognitive assessments.
11. The patient has received treatment with any investigational drug or device within the 30 days prior to study entry.
12. The patient has received a cord blood or bone marrow transplant at any time, or has received blood product transfusions within 90 days prior to Screening.
13. The patient is unable to comply with the protocol, (e.g., has significant hearing or vision impairment, a clinically relevant medical condition making implementation of the protocol difficult, unstable social situation, known clinically significant psychiatric/behavioral instability, is unable to return for safety evaluations, or is otherwise unlikely to complete the study), as determined by the Investigator.
14. The patient has skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD.
15. The patient has an opening CSF pressure upon lumbar puncture that exceeds 30 cm (water)H2O.