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

NCT03053089 | Completed Phase 1 FDA Drug

• 1 other identifier: AGT-181-101
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

Mucopolysaccharidosis I

Keywords

MPS I; Hurler Syndrome

Outcome Measures

Primary Outcomes (2)

• Stage 1: number of patients with adverse events as a measure of safety and tolerability of a single dose

  4 weeks

• Stage 2: number of patients with adverse events as a measure of safety and tolerability of repeat weekly doses

  26 weeks

Secondary Outcomes (5)

• PK parameters (maximal concentration, half-life, AUC, distribution and clearance) of AGT-181

  26 weeks

• change in total urinary glycosaminoglycans (GAGs)

  26 weeks

• change in functional capacity (6-minute walk test) or lung function (forced vital capacity)

  26 weeks

• change in shoulder range of motion (ROM)

  26 weeks

• change in liver and/or spleen volume (measured by MRI)

  26 weeks

Other Outcomes (4)

• change in levels of heparan sulfate and/or dermatan sulfate in cerebrospinal fluid (CSF)

  26 weeks

• change in levels of heparan sulfate and/or dermatan sulfate in plasma

  26 weeks

• change in neurocognition (measured by VABS-II and BSID-III or KABC-II)

  26 weeks

Study Arms (2)

Stage 1 (adult)

EXPERIMENTAL

AGT-181

Drug: AGT-181

Stage 2 (children)

EXPERIMENTAL

AGT-181

Drug: AGT-181

Interventions

AGT-181 DRUG

Human Insulin Receptor Monoclonal Antibody-Human alpha-L-iduronidase (HIRMAb-IDUA) Fusion Protein

Stage 1 (adult); Stage 2 (children)

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• ArmaGen, Inc: lead

Study Sites (1)

HCPA - Hospital das Clinicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, 90035-903, Brazil

Location

Related Publications (1)

• 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.

  PMID: 29976218 RESULT

MeSH Terms

Conditions

Mucopolysaccharidosis I

Interventions

valanafusp alpha

Condition Hierarchy (Ancestors)

Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Patrice P Rioux, MD PhD

  ArmaGen, Inc

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: February 9, 2017
• First Posted: February 14, 2017
• Study Start: October 1, 2015
• Primary Completion: February 1, 2018
• Study Completion: February 1, 2018
• Last Updated: March 15, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)