Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD)

A Single Center, Open-label, Non-randomized, Uncontrolled, Multiple-dose, Dose Escalation Study of the Safety, Pharmacokinetics and Efficacy of Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD)

Objectives: The overall objective is to evaluate the safety, efficacy and pharmacokinetics (PK) of rhASA treatment in patients with late infantile MLD.

Methodology: This is a single center, open-label study of patients with late infantile MLD. Twelve patients will be enrolled in this study receiving a total of thirteen intravenous infusions of Metazym. One infusion will be given every other week for a period of half a year. After the half year the subjects will continue treatment every other week until safety data is available. Safety (AE/SAE) will be monitored at every visit during this period.

Test product, dose, mode of administration, batch No.: The lowest dose level will be evaluated as a single dose of 25 U/kg. The three upper dose levels will be evaluated as repeated doses. Patients in each cohort will receive one dose of enzyme every other week for a period of eight weeks, a total of five doses. Dosing will be performed as follows: Cohort 1: 25 U/kg as a single dose - hereafter 50 U/kg; Cohort 2: 100 U/kg; Cohort 3: 200 U/kg. Patients receiving the lowest dose as a single dose will receive the next dose level as a repeated dose. After twenty six weeks the subjects will continue treatment every other week until safety data is available. Safety (AE/SAE) will be monitored at every visit during this period. The dose will be adjusted monthly to account for changes in body weight. The infusion length will be dependent on the dose. Doses of 25 U/kg, 50 U/kg and 100 U/kg will be diluted in 50 ml isotonic sodium chloride and infused over 30 minutes. Infusion of 200 U/kg will be administered in the same manner except for an infusion time of 60 minutes.

Duration of treatment: Half a year (26 weeks)

Inclusion Criteria:

1. Subject's legally authorized guardian(s) must provide signed, informed consent prior to performing any study-related activities (Trial-related activities are any procedures that would not have been performed during normal management of the subject).

2. The patient must have a confirmed diagnosis of MLD as defined by:

   ASA activity < 10 nmol/h/mg in leukocytes Presence of elevated sulfatide in urine

3. The patient must have a confirmed nerve conduction velocity < 2 standard deviations (from the appropriate age level)

4. The patient must have a residual level of voluntary function (as judged by the investigator), including presence of residual cognitive function (attention, executive and visual functions) as well as the presence of residual voluntary motor function in one upper or lower limb as a minimum.

5. The patient must have an age at the time of screening ≥ 1 year and < 6 years

6. The patient must have had onset of symptoms before the age of 4 years

7. The subject and his/her guardian(s) must have the ability to comply with the clinical protocol

8. The patients' medical record must document that the legal guardian(s) has had independent counselling or a consultation regarding stem cell transplantation in order to assure that the guardian(s) is fully informed regarding the risks and benefits of this alternative

Exclusion Criteria:

Patients will be excluded from this study if they do not meet the specific inclusion criteria, or if any of the following criteria apply:

1. Lack of voluntary function
2. Presence of severe pseudo-bulbar signs (weakness and disco-ordination of tongue and swallowing muscles leading to severe difficulty with swallowing)
3. Spasticity so severe to inhibit transportation
4. Known multiple sulfatase deficiency
5. Presence of major congenital abnormality
6. Presence of known chromosomal abnormality and syndromes affecting psychomotor development
7. History of stem cell transplantation
8. Presence of known clinically significant cardiovascular, hepatic, pulmonary or renal disease or other medical condition
9. Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial
10. Use of any investigational product within 30 days prior to study enrolment or currently enrolled in another study which involves clinical investigations
11. Received ERT with rhASA from any source
12. Planned or anticipated initiation of antispastic treatment after trial initiation