Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD)

A Phase I/II Multicenter Open-label Dose Escalation Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy

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. The study also includes the assessment of HGT-1110 drug product produced with a revised drug substance manufacturing process (referred to as Process B) in a fourth cohort (Cohort 4). Approximately 24 patients will be enrolled and will receive treatment of HGT-1110. Patients will be sequentially enrolled into 4 dose cohorts, approximately 6 patients each. Patient enrollment will be staggered in this study to facilitate adequate safety monitoring per dose cohort.

Inclusion

For Cohorts 1-4:

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.

   For Cohorts 1-3 only:

3. Ambulatory at the time of screening. The minimum level of function required to meet this criterion is defined as the ability to walk forward 10 steps with one hand held.

4. The patient is less than 12 years of age at the time of screening.

   For Cohort 4 only:

   3.1 Minimum motor function requirements:

   1. A total GMFM-88 (percent) score ≥40 at the screening examination and a total GMFM-88 (percent) score ≥35 at the baseline examination, AND
   2. GMFM-88 Dimension E: Walking, Running & Jumping, item 68 ("walk forward 10 steps with one hand held") score of at least 1 "initiates" at the screening and baseline examinations (if applicable).

   4.1 The patient is less than 8 years of age at the time of screening.

   For Cohorts 1-4:

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(s) 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:

Patients will be excluded from the study if there is evidence or history of any of the following criteria at screening:

For Cohorts 1-4:

1. History of hematopoietic stem cell transplantation (HSCT).
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.
5. The patient is pregnant or breastfeeding.
6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT

Mini S IDDD Instructions for Use (IFU), including:

1. The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device.
2. The patient's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the Investigator.
3. The patient has a known or suspected local or general infection.
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy.
5. The patient has one or more spinal abnormalities that could complicate safe implantation or fixation.
6. The patient has a functioning CSF shunt device.
7. The patient has shown an intolerance to an implanted device.