Safety and Dose Ranging Study of Insulin Receptor MAb-IDUA Fusion Protein in Patients With MPS I

Study Overview
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Brief Summary
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AGT-181 is a fusion protein containing alpha-L-Iduronidase that is intended to deliver the enzyme peripherally and to the brain, when administered intravenously. This study is a safety and dose ranging study to obtain safety and exposure data, as well as information on the biological activity of the investigational drug.

Official Title
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A Phase 1 Safety and Dose-Finding Study of a Human Insulin Receptor Monoclonal Antibody-Human Alpha-L-iduronidase (HIRMAb-IDUA) Fusion Protein, AGT-181 in Adult Patients With Mucopolysaccharidosis I (MPS I, Hurler Syndrome)

Conditions
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Mucopolysaccharidosis I

Intervention / Treatment
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* Drug: AGT-181 (HIRMAb-IDUA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male age 18 years or older Diagnosis of MPS I (documented fibroblast or leukocyte IDUA enzyme activity level of less than 10% of the lower limit of the normal range of the measuring laboratory) Voluntary written consent by patient or legally responsible representative All women of childbearing potential and sexually mature males must be advised to use a medically accepted method of contraception throughout the study. Negative pregnancy test (females) Must not have received ERT for at least 6 weeks prior to AGT-181 treatment Must have elevated urinary GAGs if no ERT has been received in the prior 3 months Exclusion Criteria: Refusal to complete baseline evaluations. Any medical condition or other circumstances that may significantly interfere with study compliance Receipt of an investigational drug within the prior 90 days History of diabetes mellitus or hypoglycemia Clinically significant spinal cord compression, evidence of cervical instability. Known hypersensitivity to alpha-L-iduronidase or any of the components of AGT-181. Known to be nonresponsive to standard ERT treatment. Previously successful (engrafted) hematopoietic stem cell transplantation that resulted in normalization of urinary GAGs. Contraindication for lumbar puncture

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>1 mg/kg AGT-181 (fusion protein of anti-human insulin receptor monoclonal antibody and alpha-L-iduronidase; HIRMAb-IDUA) administered once weekly x 8 weeks | Drug: AGT-181 (HIRMAb-IDUA)<br>* intravenous infusion over 3-4 hours<br>* Other names: fusion protein of monoclonal antibody to human insulin receptor fused to alpha-L-iduronidase;|
| Experimental: Cohort 2<br>3 mg/kg AGT-181 (HIRMAb-IDUA) administered once weekly x 8 weeks | Drug: AGT-181 (HIRMAb-IDUA)<br>* intravenous infusion over 3-4 hours<br>* Other names: fusion protein of monoclonal antibody to human insulin receptor fused to alpha-L-iduronidase;|
| Experimental: Cohort 3<br>6-9 mg/kg AGT-181 (HIRMAb-IDUA) administered once weekly x 8 weeks | Drug: AGT-181 (HIRMAb-IDUA)<br>* intravenous infusion over 3-4 hours<br>* Other names: fusion protein of monoclonal antibody to human insulin receptor fused to alpha-L-iduronidase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events as a measure of safety and tolerability |  | eight weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma pharmacokinetic parameters (maximal concentration, half-life, area under the curve, mean residence time, volume of distribution and clearance of AGT-181) |  | 8 weeks | 
| change in urinary or plasma glycosaminoglycans (GAGs) |  | 8 weeks | 
| change in liver size |  | 8 weeks | 
| change in spleen size |  | 8 weeks | 
| change in levels of heparan sulfate and dermatan sulfate in the cerebrospinal fluid |  | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MPS I