Multicenter Study of HGT-1110, Enzyme Replacement Therapy Administered Intrathecally, in Children With Metachromatic Leukodystrophy (MLD) (IDEAMLD)

• Clinical activity of IT administration of HGT-1110 on gross motor function [ Time Frame: 40 weeks ] [ Designated as safety issue: No ]
  Change from baseline in gross motor function
• Serum Pharmacokinetic profile of HGT-1110 after single and repeated dose administration (weeks 0 and 38) [ Time Frame: 12 time points over 48 hours post-dose ] [ Designated as safety issue: No ]
  • Cmax: maximal serum concentration
  • Tmax: time to reach Cmax in plasma
  • AUC: area under the curve
• Concentrations of HGT-1110 in CSF [ Time Frame: 40 weeks ] [ Designated as safety issue: No ]
  Concentrations of HGT-1110 in CSF prior to each IT administration

The purpose of this study is to determine the safety of ascending doses of HGT-1110 administered by intrathecal (IT) injection for 38 weeks (20 injections) in children with metachromatic leukodystrophy (MLD).

Metachromatic leukodystrophy (MLD) is an inherited, autosomal recessive disorder of lipid metabolism characterized by deficient activity of the lysosomal enzyme, arylsulfatase A (ASA). MLD is a rare disease that occurs in most parts of the world. The estimated overall incidence of the disease in the western world is approximately 1 in 100,000 live births that varies by geographic location. There are no approved therapies for MLD.

This is a multicenter, open-label, dose-escalation study designed to evaluate the safety of up to 3 dose levels (10, 30, or 100 mg) of HGT-1110 administered via an intrathecal drug delivery device (IDDD) every other week (EOW) for a total of 38 weeks (20 injections, Weeks 0 to 38) to children with MLD. Up to 18 patients will be enrolled and will receive treatment of HGT-1110. Patients will be sequentially enrolled into 3 dose cohorts, 6 patients each. Patient enrollment will be staggered in this study to facilitate adequate safety monitoring per dose cohort.

• Cohort 1 (10 mg)
  Cohort 1 (10 mg): 6 patients treated with HGT-1110 10 mg EOW by IT injection
  Intervention: Biological: Recombinant human arylsulfatase A
• Cohort 2 (30 mg)
  Cohort 2 (30 mg): 6 patients treated with HGT-1110 30 mg EOW by IT injection
  Intervention: Biological: Recombinant human arylsulfatase A
• Cohort 3 (100 mg)
  Cohort 3 (100 mg): 6 patients treated with HGT-1110 100 mg EOW by IT injection
  Intervention: Biological: Recombinant human arylsulfatase A

Inclusion Criteria:

1. Confirmed diagnosis of metachromatic leukodystrophy by both:

   • Arylsulfatase A (ASA) deficiency by assay in leukocytes AND
   • Elevated sulfatide in urine
2. Appearance of the first symptoms of disease at or before 30 months of age.
3. Ambulatory at the time of screening. The minimum level of function required to meet this criterion is defined as the ability to stand up alone and walk forward 10 steps with one hand held.
4. The patient is less than 8 years of age at the time of enrollment.
5. Neurological signs of MLD must be present at the screening examination.
6. The patient and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
7. Patient's parent or legally authorized representative(s) must provide written informed consent prior to performing any study-related activities. Study-related activities are any procedures that would not have been performed during normal management of the patient.

Exclusion Criteria:

1. History of hematopoietic stem cell transplantation.
2. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions.
3. Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial.
4. The patient is enrolled in another clinical study that involves the use of any investigational product (drug or device) other than HGT-1110 or the IDDD used in this study within 30 days prior to study enrollment or at any time during the study.