Iduronate-2-sulfatase Enzyme Replacement Therapy in Mucopolysaccharidosis II (MPS II)

MPS II is a rare, X-linked, lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2-sulfatase. Because of this deficiency, glycosaminoglycans (GAG) accumulate in multiple tissues and organs, resulting in progressive cellular and organ system dysfunction. The purpose of this study is to determine if one year of therapy with iduronate-2-sulfatase enzyme replacement therapy, at a dose of 0.5mg/kg, weekly or every other week, is safe, and results in clinically meaningful improvement in multiple organ function, compared with a placebo group. Upon completion of the study, patients will be eligible to enroll in an open-label maintenance study.

• Iduronate-2-sulfatase enzyme replacement therapy (Biological), also known as Elaprase: Patients will receive weekly infusions of idursulfase at a dose of 0.5 mg/kg.
• iduronate-2-sulfatase enzyme replacement therapy (Biological), also known as Elaprase: Patients will receive every other week infusions of idursulfase at a dose of 0.5 mg/kg.
• Placebo (Biological): Patients will receive weekly infusions of placebo.

Primary outcomes

• Ranked Adjusted 2-Component Composite Variable Score Based on Change From Baseline to Week 53 [Baseline, Week 53]: The 2-component composite variable consists of the sum of the ranked changes from baseline to Week 53 for percent predicted Forced Vital Capacity (FVC) and 6-Minute Walking Test (6MWT) total distance walked. For the 2 treatment groups being compared, ranking occurred within the comparison treatment groups combined (idursulfase weekly and placebo treatment groups). These comparison groups were pooled and ranked for each component separately. Within each component (% predicted FVC, 6MWT), the change from baseline was then ranked. The lowest change value was assigned a rank of 1, the next lowest a rank of 2, etc. The composite score for each participant was the sum of the 2 ranked scores corresponding to the 2 individual components (% predicted FVC and 6MWT) for each participant. Thus, the greater the composite score (greater the sum of the ranks of the changes from baseline, where the lowest change was ranked as 1), the greater the improvement.

Secondary outcomes

• Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 [Baseline, Week 53]: Change was calculated at Week 53 from baseline. Global JROM (% of normal range of motion) is the average of 11 ratios multiplied by 100. Ratios are Left/Right means of passive range of motion in Shoulder (Flexion/Extension, Abduction, Internal/External Rotation), Elbow (Flexion/Extension), Wrist (Flexion/Extension), Index Finger (Flexion/Extension \[Combined Metacarpophalangeal joint (MCP), Proximal interphalangeal joint (PIP), Distal interphalangeal joint (DIP) motion\]), Hip (Flexion/Extension, Abduction, Internal/External Rotation), Knee (Flexion/Extension), and Ankle (Dorsiflexion) divided by the normal range (American Academy of Orthopedic Surgeons and American Medical Association).
• Mean Combined Liver and Spleen Volume at Baseline [Baseline]: Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI).
• Percent Change From Baseline in Mean Combined Liver and Spleen Volume at Week 53 [Baseline, Week 53]: Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI). Change was calculated at Week 53 from baseline.
• Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 [Baseline, Week 53]: Mean normalized urine GAG was analyzed using urine testing. Change was calculated at Week 53 from baseline. The urine GAG levels were normalized to urine creatinine and were reported as microgram GAG per milligram creatinine (mcg GAG/mg creatinine).
• Mean Cardiac Left Ventricular Mass Index (LVMI) at Baseline [Baseline]: Cardiac LVMI was determined by echocardiography. LVMI is the left ventricular mass (LVM, in grams \[g\]) indexed to body surface area (BSA), in square meter \[m\^2\]. LVMI (in gram per square meter \[g/m\^2\]) = LVM divided by BSA.
• Percent Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 53 [Baseline, Week 53]: Cardiac LVMI was determined by echocardiography. Change was calculated at Week 53 from baseline. LVMI is the LVM, in grams indexed to BSA, in square meter \[m\^2\]. LVMI in g/m\^2 = LVM divided by BSA.

Sex: Male, ages: 5 Years to 25 Years

Inclusion Criteria:

To be eligible to participate in this study, patients must meet the following inclusion criteria prior to enrollment:

1. The diagnosis of MPS II will be determined by the investigator based upon both clinical and biochemical criteria.
2. All patients must have at least one of the following Clinical Criteria considered by the investigator to be MPS II-related:

   * Hepatosplenomegaly
   * Radiographic evidence of dysostosis multiplex
   * Valvular heart disease
   * Evidence of obstructive pulmonary disease
3. In addition, patients must have the following Biochemical Criteria:

   * Documented deficiency in iduronate-2-sulfastase enzyme activity of less than or equal to 10% of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory).
   * A normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory).
4. Must be male, 5 to 25 years of age.
5. Forced vital capacity of <80% of predicted obtained at the baseline evaluation of this study.
6. Must be able to adequately perform the testing required in this study, including reproducible pulmonary function testing by spirometry, as judged by the investigator.
7. Patient, patient's parent(s), or legally authorized guardian must have voluntarily signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient.

Exclusion Criteria:

Patients meeting any of the following criteria are not eligible for participation in this study:

1. Patient has received treatment with another investigational therapy within the past 60 days.
2. Patient, patient's parent(s), or patient's legal guardian is unable to understand the nature, scope, and possible consequences of the study.
3. Patient is unable to comply with the protocol (e.g., due to a medical condition such as cervical cord compression or uncooperative attitude) or is unlikely to complete the study, as determined by the investigator.
4. Patient has a tracheostomy.
5. Patient has received a bone marrow or cord blood transplant.
6. Patient with known hypersensitivity to any of the components of iduronate-2-sulfatase.

Participant flow

Outcome results

• Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 (Secondary), Mean, percentage of normal range of motion: Idursulfase Weekly (0.5 mg/kg) 66.86 +/- 1.85; Idursulfase EOW (0.5 mg/kg) 67.36 +/- 1.43; Placebo 67.70 +/- 1.59
• Mean Combined Liver and Spleen Volume at Baseline (Secondary), Mean, milliliter (mL): Idursulfase Weekly (0.5 mg/kg) 1578.48 +/- 80.75; Idursulfase EOW (0.5 mg/kg) 1442.2 +/- 63.54; Placebo 1485.28 +/- 70.19
• Percent Change From Baseline in Mean Combined Liver and Spleen Volume at Week 53 (Secondary), Mean, percent change: Idursulfase Weekly (0.5 mg/kg) -25.81 +/- 1.44; Idursulfase EOW (0.5 mg/kg) -23.73 +/- 1.49; Placebo 0.27 +/- 1.66
• Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 (Secondary), Mean, mcg GAG/mg creatinine: Idursulfase Weekly (0.5 mg/kg) 325.59 +/- 25.79; Idursulfase EOW (0.5 mg/kg) 338.08 +/- 21.03; Placebo 419.40 +/- 34.37
• Ranked Adjusted 2-Component Composite Variable Score Based on Change From Baseline to Week 53 (Primary), Mean, sum of the ranked scores: Idursulfase Weekly (0.5 mg/kg) 69.81 +/- 7.03; Placebo 50.86 +/- 8.07 (p 0.0049)
• Mean Cardiac Left Ventricular Mass Index (LVMI) at Baseline (Secondary), Mean, gram per square meter (g/m^2): Idursulfase Weekly (0.5 mg/kg) 105.18 +/- 6.86; Idursulfase EOW (0.5 mg/kg) 89.42 +/- 4.38; Placebo 95.55 +/- 5.96
• Percent Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 53 (Secondary), Mean, percent change: Idursulfase Weekly (0.5 mg/kg) -1.34 +/- 5.05; Idursulfase EOW (0.5 mg/kg) 6.71 +/- 4.03; Placebo 3.56 +/- 4.12

Adverse events

Time frame: 52 weeks

Serious adverse events by term

Other adverse events by term

98 more terms not shown.

• Results publication: Tandon PK, Kakkis ED. The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases. Orphanet J Rare Dis. 2021 Apr 19;16(1):183. doi: 10.1186/s13023-021-01805-5. PMID 33874971
• Results publication: Raluy-Callado M, Chen WH, Whiteman DA, Fang J, Wiklund I. The impact of Hunter syndrome (mucopolysaccharidosis type II) on health-related quality of life. Orphanet J Rare Dis. 2013 Jul 10;8:101. doi: 10.1186/1750-1172-8-101. PMID 23837440

• Study Director, Study director, Takeda