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

• Sponsor: ArmaGen, Inc
• Information provided by (Responsible Party): ArmaGen, Inc

Study Description

Brief Summary:

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 is a safety and tolerability study to obtain safety and exposure data as well as information on the biological activity of the investigational drug.

This is a two-stage, sequential, single and multi-dose study of AGT-181 in patients with MPS I. The first stage will be an open-label, single-dose, dose-escalation cohort study and the second stage will be an open-label, multi dose, adaptive dose escalation cohort study.

Condition or disease	Intervention/treatment	Phase
Mucopolysaccharidosis I	Drug: AGT-181	Phase 1; Phase 2

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	21 participants
Allocation:	Non-Randomized
Intervention Model:	Sequential Assignment
Intervention Model Description:	Stage 1: 6 adults will be given a single dose, assigned to 0.3, 1.0 or 3.0 mg/kg (with cohort assignment based on order of study entry) Stage 2: up to 15 children will be given repeat weekly doses for 26 weeks, assigned to 1.0, 3.0 and 6.0 or 9.0 mg/kg (with cohort assignment based on order of study entry). Early term
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Two-Stage, Phase 1/2, Open-Label Study of the Human Insulin Receptor Monoclonal Antibody-Human Alpha-L-iduronidase (HIRMAb-IDUA) Fusion Protein, AGT-181 in Patients With Mucopolysaccharidosis I (MPS I, Hurler Syndrome)
Actual Study Start Date :	October 2015
Actual Primary Completion Date :	February 1, 2018
Actual Study Completion Date :	February 1, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Stage 1 (adult); AGT-181	Drug: AGT-181; Human Insulin Receptor Monoclonal Antibody-Human alpha-L-iduronidase (HIRMAb-IDUA) Fusion Protein
Experimental: Stage 2 (children); AGT-181	Drug: AGT-181; Human Insulin Receptor Monoclonal Antibody-Human alpha-L-iduronidase (HIRMAb-IDUA) Fusion Protein

Outcome Measures

Primary Outcome Measures :

1. Stage 1: number of patients with adverse events as a measure of safety and tolerability of a single dose [ Time Frame: 4 weeks ]
2. Stage 2: number of patients with adverse events as a measure of safety and tolerability of repeat weekly doses [ Time Frame: 26 weeks ]

Secondary Outcome Measures :

1. PK parameters (maximal concentration, half-life, AUC, distribution and clearance) of AGT-181 [ Time Frame: 26 weeks ]
2. change in total urinary glycosaminoglycans (GAGs) [ Time Frame: 26 weeks ]
3. change in functional capacity (6-minute walk test) or lung function (forced vital capacity) [ Time Frame: 26 weeks ]
4. change in shoulder range of motion (ROM) [ Time Frame: 26 weeks ]
5. change in liver and/or spleen volume (measured by MRI) [ Time Frame: 26 weeks ]

Other Outcome Measures:

1. change in levels of heparan sulfate and/or dermatan sulfate in cerebrospinal fluid (CSF) [ Time Frame: 26 weeks ]
2. change in levels of heparan sulfate and/or dermatan sulfate in plasma [ Time Frame: 26 weeks ]
3. change in neurocognition (measured by VABS-II and BSID-III or KABC-II) [ Time Frame: 26 weeks ]
4. change in CNS neuroimaging (brain volumetric MRI and diffusion tensor imaging, DTI) [ Time Frame: 26 weeks ]

Eligibility Criteria

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Ages Eligible for Study:	2 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Written consent and assent as required
• Diagnosis of MPS 1 confirmed by clinical signs and symptoms, documented fibroblast or leukocyte IDUA enzyme activity of less than 10% the lower limit of normal
• Female patients must not be pregnant, willing to utilize appropriate birth control methods and undergo pregnancy testing during the study
• if taking standard ERT, must be willing to discontinue for 1 week prior to dosing and for the study duration

Additional Inclusion Criteria, Stage 1:

• 18 years of age or older
• must have a diagnosis of Hurler-Scheie or Scheie syndrome

Additional Inclusion Criteria, Stage 2:

• 2 years of age or older (and less than 18)
• must be willing to undergo CNS testing, including assessment of CSF via lumbar puncture, MRI scans and neurocognitive testing
• must have evidence of Hurler-Scheie or Scheie with CNS involvement, as evidence by:
• score of 1 to 3 standard deviations below mean on IQ testing (i.e. IQ=55 or more) or in one domain of neuropsychological function (language, memory, non-verbal ability) OR
• documented historical evidence of a decline greater than 1 standard deviation on sequential testing, OR
• score between 0.75 and 1 standard deviation below the mean, AND cognitive deficit affects daily performance

Exclusion Criteria:

• Refusal to complete all assessments
• Pregnant or Lactating
• Received investigational drug within 1 year prior to study enrollment
• Medical condition or extenuating circumstance that, in the opinion of the investigator, may interfere with study compliance
• CSF pressure greater than 25 cm H20 (18 mm Hg)
• Known hypersensitivity to alpha-L-iduronidase (IDUA/Aldurazyme) or any components/excipients found in AGT-181
• Previous successful (engrafted) hematopoietic stem cell transplantation which has resulted in normalization of urinary glycosaminoglycans (GAGs); or major organ transplantation
• Clinically significant spinal cord compression or evidence of cervical instability (i.e. expected to require intervention during study participation)
• History of diabetes mellitus or hypoglycemia

Additional Exclusion Criteria, Stage 2:

• Has ventriculoperitoneal shunt
• IQ below 55
• Previously received AGT-181 in Stage 1 of the study

Contacts and Locations

Locations

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Brazil
HCPA - Hospital das Clinicas de Porto Alegre
Porto Alegre, RS, Brazil, 90035-903

Sponsors and Collaborators

ArmaGen, Inc

Investigators

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Study Director:	Patrice P Rioux, MD PhD	ArmaGen, Inc

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Giugliani R, Giugliani L, de Oliveira Poswar F, Donis KC, Corte AD, Schmidt M, Boado RJ, Nestrasil I, Nguyen C, Chen S, Pardridge WM. Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-2 trial. Orphanet J Rare Dis. 2018 Jul 5;13(1):110. doi: 10.1186/s13023-018-0849-8.

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Responsible Party:	ArmaGen, Inc
ClinicalTrials.gov Identifier:	NCT03053089 History of Changes
Other Study ID Numbers:	AGT-181-101
First Posted:	February 14, 2017
Last Update Posted:	September 18, 2018
Last Verified:	September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by ArmaGen, Inc:

MPS I; Hurler Syndrome

Additional relevant MeSH terms:

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Mucopolysaccharidoses; Mucopolysaccharidosis I; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases	Metabolic Diseases; Insulin; Insulin, Globin Zinc; Antibodies, Monoclonal; Hypoglycemic Agents; Physiological Effects of Drugs; Immunologic Factors