Principal Investigator: Dave Viskochil
Keywords: MPS I , ERT , Mucopolysaccharidosis type I , Hurler Scheie Department: Pediatric Genetics
IRB Number: 00088096
Specialty: Pediatric Genetics
Sub Specialties: Medical Genetics
Recruitment Status: Not yet recruiting

Contact Information

Carrie Bailey

Brief Summary

Primary Objective:
To determine a safe and well tolerated dose of AGT-181 in adults with MPS I
Secondary Objectives:
1. To determine a biologically active starting dose, based upon assessment of pharmacodynamic effects such as urinary glycosaminoglycans (GAGs), for future clinical trials
2. To evaluate the pharmacokinetics (PK) of AGT-181, where possible, in the context of the laronidase PK profile in study subjects on ERT at study entry
3. To determine the pharmacodynamic effects of AGT-181 on glycoaminoglycans -GAGs (urinary, plasma and cerebrospinal heparan sulfate and dermatan sulfate) and glycemia.
4. To evaluate the occurrence of infusion reactions
5. To determine the effect of 8 or 13 weeks (see treated groups below) of AGT-181 treatment on liver and spleen size
Study Purpose:
This is a sequential, open-label, dose-escalation, multi-dose study of AGT-181 for treatment of adult patients with MPS I.
This dose-escalation study will enroll at least two cohorts of 3 patients with MPS I age 18 or older. Two dose cohorts (1.0 and 3.0 mg/kg), will begin enrollment sequentially, with safety data from the first 4-weeks of treatment at 1.0 mg/kg being reviewed by an independent DMC prior to escalation to the 3 mg/kg cohort. Patients will be assigned to cohorts on the basis of their order of entry into the study. Dose escalation will continue until at least one dose higher than the dose determined to have biologic activity. For example, if biologic activity is deemed present at any time during treatment of the 3.0 mg/kg cohort, an additional higher dose cohort(s) of no greater than 1/2 log higher may be enrolled after DMC review. It is expected that doses will not exceed 9 mg/kg.
The first cohort will be administered an infusion of 1.0 mg/kg AGT-181 over 3-4 hours. Patients will receive 8 doses given once weekly.
Dose escalation to the higher dose cohort can occur providing < 2 patients develop the same CTCAE grade 3 event (severe or medically significant but not immediately life threatening) and no patient develops a grade 4 or higher event (life threatening, urgent intervention indicated) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Inclusion Criteria

Patients must meet all of the following criteria to be enrolled in this study:
1. Patients must be 18 years of age or older.
2. Patient must have signed and dated the informed consent document indicating that the patient has been informed of all pertinent aspects of the trial.
3. The patient must have a diagnosis of MPS I, previously confirmed by clinical signs and symptoms of MPS I, and a documented fibroblast or leukocyte IDUA enzyme activity level of less than 10% of the lower limit of the normal range of the measuring laboratory.
4. Patients must fall into one of the following groups:
a) ERT Group: Be currently receiving ERT and, for the duration of the study, be willing to discontinue current ERT and, instead receive AGT-181 for 13 weeks.
b) Washout Group: Be currently receiving ERT and be willing to discontinue ERT for 6 weeks. Patients in this Group will be treated with AGT-181 for 8 weeks.
c) Naïve/Extended Washout Group: Have never received ERT (Naïve Group) or have not received ERT for at least 90 days (Extended Washout Group), and have elevated uGAGs of at least 3-fold above normal range at screening. Patients will be treated with AGT-181 for 8 weeks.
5. A female patient of childbearing potential must have a negative pregnancy test (urine β–human chorionic gonadotropin) at entry (prior to the first infusion). All women of childbearing potential and sexually mature men must agree use a highly reliable method of birth control by using two forms of contraception (for example oral contraceptive plus condom, two barrier method, etc.). throughout the study (Refer to sections 8.9-8.10). Women of childbearing potential must be willing to undergo periodic pregnancy tests during the course of the study.

Exclusion Criteria

1. The patient has neurocognitive impairment and is not competent to give informed consent.
2. The patient refuses to complete all screening evaluations.
3. The patient has received an investigational drug within the past 90 days
4. The patient has a medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities.
5. The patient is pregnant or lactating
6. The patient has known clinically significant spinal cord compression (e.g. with planned surgery within the next 8 months) or evidence of cervical spine/atlanto-axial instability based on the screening MRI.
7. The patient has known hypersensitiviIty to alpha-L-iduronidase/Aldurazyme that has previously interferred with their ERT treatment or known clinically relevant hypersentivity to any of the components/excipients found in AGT-181.
8. The patient has previously undergone successful (engrafted) hematopoietic stem cell transplantation (i.e., bone marrow or cord blood transplantation) which has resulted in normalization of urinary GAGs.
9. The patient is known to be nonresponsive to standard ERT treatment (for example, high urine GAG levels despite full dose ERT treatment).
10. The patient has a history of diabetes mellitus or a history of hypoglycemia.
11. The patient has a contra-indication for lumbar puncture
12. The patient has previously received AGT-181