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
Abstract Background Mucopolysaccharidosis (MPS) Type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-L-iduronidase (IDUA), and a majority of patients present with severe neurodegeneration and cognitive impairment. Recombinant IDUA does not cross the blood-brain barrier (...
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doaj-63a9fb19c12247fe96ee3a05f40029c32020-11-25T00:40:30ZengBMCOrphanet Journal of Rare Diseases1750-11722018-07-0113111110.1186/s13023-018-0849-8Neurocognitive 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 trialRoberto Giugliani0Luciana Giugliani1Fabiano de Oliveira Poswar2Karina Carvalho Donis3Amauri Dalla Corte4Mathias Schmidt5Ruben J. Boado6Igor Nestrasil7Carol Nguyen8Steven Chen9William M. Pardridge10Hospital de Clínicas de Porto Alegre and UFRGSHospital de Clínicas de Porto Alegre and UFRGSHospital de Clínicas de Porto Alegre and UFRGSHospital de Clínicas de Porto Alegre and UFRGSHospital de Clínicas de Porto Alegre and UFRGSArmaGen, Inc.ArmaGen, Inc.Department of Pediatrics and Adolescent Health, University of MinnesotaDepartment of Pediatrics and Adolescent Health, University of MinnesotaDepartment of Radiology, Duke UniversityArmaGen, Inc.Abstract Background Mucopolysaccharidosis (MPS) Type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-L-iduronidase (IDUA), and a majority of patients present with severe neurodegeneration and cognitive impairment. Recombinant IDUA does not cross the blood-brain barrier (BBB). To enable BBB transport, IDUA was re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain targets the BBB human insulin receptor to enable transport of the enzyme into the brain. We report the results of a 52-week clinical trial on the safety and efficacy of valanafusp alpha in pediatric MPSI patients with cognitive impairment. In the phase I trial, 6 adults with attenuated MPSI were administered 0.3, 1, and 3 mg/kg doses of valanafusp alpha by intravenous (IV) infusion. In the phase II trial, 11 pediatric subjects, 2-15 years of age, were treated for 52 weeks with weekly IV infusions of valanafusp alpha at 1, 3, or 6 mg/kg. Assessments of adverse events, cognitive stabilization, and somatic stabilization were made. Outcomes at 52 weeks were compared to baseline. Results Drug related adverse events included infusion related reactions, with an incidence of 1.7%, and transient hypoglycemia, with an incidence of 6.4%. The pediatric subjects had CNS involvement with a mean enrollment Development Quotient (DQ) of 36.1±7.1. The DQ, and the cortical grey matter volume of brain, were stabilized by valanafusp alpha treatment. Somatic manifestations were stabilized, or improved, based on urinary glycosaminoglycan levels, hepatic and spleen volumes, and shoulder range of motion. Conclusion Clinical evidence of the cognitive and somatic stabilization indicates that valanafusp alpha is transported into both the CNS and into peripheral organs due to its dual targeting mechanism via the insulin receptor and the mannose 6-phosphate receptor. This novel fusion protein offers a pharmacologic approach to the stabilization of cognitive function in MPSI. Trial registration Clinical Trials.Gov, NCT03053089. Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341. Registered 6 March, 2017.http://link.springer.com/article/10.1186/s13023-018-0849-8Mucopolysaccharidosis Type IIduronidaseBlood-brain barrierInsulin receptorOpen label clinical trialSafety |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Roberto Giugliani Luciana Giugliani Fabiano de Oliveira Poswar Karina Carvalho Donis Amauri Dalla Corte Mathias Schmidt Ruben J. Boado Igor Nestrasil Carol Nguyen Steven Chen William M. Pardridge |
spellingShingle |
Roberto Giugliani Luciana Giugliani Fabiano de Oliveira Poswar Karina Carvalho Donis Amauri Dalla Corte Mathias Schmidt Ruben J. Boado Igor Nestrasil Carol Nguyen Steven Chen William M. Pardridge 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 Journal of Rare Diseases Mucopolysaccharidosis Type I Iduronidase Blood-brain barrier Insulin receptor Open label clinical trial Safety |
author_facet |
Roberto Giugliani Luciana Giugliani Fabiano de Oliveira Poswar Karina Carvalho Donis Amauri Dalla Corte Mathias Schmidt Ruben J. Boado Igor Nestrasil Carol Nguyen Steven Chen William M. Pardridge |
author_sort |
Roberto Giugliani |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
BMC |
series |
Orphanet Journal of Rare Diseases |
issn |
1750-1172 |
publishDate |
2018-07-01 |
description |
Abstract Background Mucopolysaccharidosis (MPS) Type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-L-iduronidase (IDUA), and a majority of patients present with severe neurodegeneration and cognitive impairment. Recombinant IDUA does not cross the blood-brain barrier (BBB). To enable BBB transport, IDUA was re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain targets the BBB human insulin receptor to enable transport of the enzyme into the brain. We report the results of a 52-week clinical trial on the safety and efficacy of valanafusp alpha in pediatric MPSI patients with cognitive impairment. In the phase I trial, 6 adults with attenuated MPSI were administered 0.3, 1, and 3 mg/kg doses of valanafusp alpha by intravenous (IV) infusion. In the phase II trial, 11 pediatric subjects, 2-15 years of age, were treated for 52 weeks with weekly IV infusions of valanafusp alpha at 1, 3, or 6 mg/kg. Assessments of adverse events, cognitive stabilization, and somatic stabilization were made. Outcomes at 52 weeks were compared to baseline. Results Drug related adverse events included infusion related reactions, with an incidence of 1.7%, and transient hypoglycemia, with an incidence of 6.4%. The pediatric subjects had CNS involvement with a mean enrollment Development Quotient (DQ) of 36.1±7.1. The DQ, and the cortical grey matter volume of brain, were stabilized by valanafusp alpha treatment. Somatic manifestations were stabilized, or improved, based on urinary glycosaminoglycan levels, hepatic and spleen volumes, and shoulder range of motion. Conclusion Clinical evidence of the cognitive and somatic stabilization indicates that valanafusp alpha is transported into both the CNS and into peripheral organs due to its dual targeting mechanism via the insulin receptor and the mannose 6-phosphate receptor. This novel fusion protein offers a pharmacologic approach to the stabilization of cognitive function in MPSI. Trial registration Clinical Trials.Gov, NCT03053089. Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341. Registered 6 March, 2017. |
topic |
Mucopolysaccharidosis Type I Iduronidase Blood-brain barrier Insulin receptor Open label clinical trial Safety |
url |
http://link.springer.com/article/10.1186/s13023-018-0849-8 |
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