| 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
|
|---|---|
| Published in |
Orphanet Journal of Rare Diseases, July 2018
|
| DOI | 10.1186/s13023-018-0849-8 |
| Pubmed ID | |
| Authors |
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 |
| Abstract |
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. 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. 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. Clinical Trials.Gov, NCT03053089 . Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341 . Registered 6 March, 2017. |
X Demographics
The data shown below were collected from the profiles of 8 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 3 | 38% |
| Spain | 1 | 13% |
| Brazil | 1 | 13% |
| Unknown | 3 | 38% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 5 | 63% |
| Scientists | 2 | 25% |
| Practitioners (doctors, other healthcare professionals) | 1 | 13% |
Mendeley readers
The data shown below were compiled from readership statistics for 156 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 156 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 25 | 16% |
| Student > Ph. D. Student | 17 | 11% |
| Student > Bachelor | 15 | 10% |
| Student > Master | 13 | 8% |
| Other | 8 | 5% |
| Other | 17 | 11% |
| Unknown | 61 | 39% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 24 | 15% |
| Medicine and Dentistry | 18 | 12% |
| Agricultural and Biological Sciences | 10 | 6% |
| Nursing and Health Professions | 6 | 4% |
| Chemistry | 5 | 3% |
| Other | 23 | 15% |
| Unknown | 70 | 45% |
Attention Score in Context
This research output has an Altmetric Attention Score of 6. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 November 2021.
All research outputs
#5,736,117
of 23,094,276 outputs
Outputs from Orphanet Journal of Rare Diseases
#718
of 2,648 outputs
Outputs of similar age
#98,040
of 327,553 outputs
Outputs of similar age from Orphanet Journal of Rare Diseases
#24
of 53 outputs
Altmetric has tracked 23,094,276 research outputs across all sources so far. Compared to these this one has done well and is in the 75th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 2,648 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 7.6. This one has gotten more attention than average, scoring higher than 72% of its peers.
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We're also able to compare this research output to 53 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 54% of its contemporaries.