Evidence map›Paper›PMID 29976218›Full record

Trial reportOrphanet journal of rare diseases2018

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.

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 and 1 more

2 registry-linked trialsOpen access · goldAbstract readClinical Trial, Phase IClinical Trial, Phase II
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Orphanet journal of rare diseases, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 79 papers.

0numbers the graph read from it
0cells of the map it votes in
79citing papers in PubMed
7.6field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03053089 phase1 / phase2completednot on this map

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)

TypeinterventionalSponsorArmaGen, IncRan2015 to 2018Enrolled21ConditionsMucopolysaccharidosis IArmsAGT-181
NCT03071341 phase1 / phase2completednot on this map

An Extension Study Evaluating Long Term Safety and Activity of AGT-181 in Patients With Mucopolysaccharidosis I Who Were Previously Enrolled in Studies With AGT-181

TypeinterventionalSponsorArmaGen, IncRan2016 to 2018Enrolled19ConditionsMucopolysaccharidosis IArmsAGT-181
3 · Its place in the literature

Who cites it

79 citing papers in PubMed, 138 citations in OpenAlex.

  1. Trial
  2. Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil.Molecular therapy : the journal of the American Society of Gene Therapy · 2021
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  6. Antibody-Based Biologics for CNS Disorders.Antibodies (Basel, Switzerland) · 2026
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19 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 4 institutions in 2 countries.

Roberto GiuglianiHospital de Clínicas de Porto Alegre and UFRGS, Porto Alegre, Brazil.
Luciana GiuglianiHospital de Clínicas de Porto Alegre and UFRGS, Porto Alegre, Brazil.
Fabiano de Oliveira PoswarHospital de Clínicas de Porto Alegre and UFRGS, Porto Alegre, Brazil.
Karina Carvalho DonisHospital de Clínicas de Porto Alegre and UFRGS, Porto Alegre, Brazil.
Amauri Dalla CorteHospital de Clínicas de Porto Alegre and UFRGS, Porto Alegre, Brazil.
Mathias SchmidtArmaGen, Inc., 26679 Agoura Road, Calabasas, CA, USA.
Ruben J BoadoArmaGen, Inc., 26679 Agoura Road, Calabasas, CA, USA.
Igor NestrasilDepartment of Pediatrics and Adolescent Health, University of Minnesota, 717 Delaware St. SE, Minneapolis, MN, 55414, USA.
Carol NguyenDepartment of Pediatrics and Adolescent Health, University of Minnesota, 717 Delaware St. SE, Minneapolis, MN, 55414, USA.
Steven ChenDepartment of Radiology, Duke University, Durham, NC, 27710, USA.
William M PardridgeArmaGen, Inc., 26679 Agoura Road, Calabasas, CA, USA. wpardrid@ucla.edu.ORCID 0000-0002-2664-1338
Universidade Federal do Rio Grande do Sul · BRArmaGen (United States) · USUniversity of Minnesota · USDuke University · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundMucopolysaccharidosis (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.

resultsDrug 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.

conclusionClinical 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 registrationClinical Trials.Gov, NCT03053089 . Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341 . Registered 6 March, 2017.

Indexed as

AdolescentAntibodies, MonoclonalBlood-Brain BarrierChildFemaleHumansIduronidaseInfusions, IntravenousMaleMucopolysaccharidosis IReceptor, InsulinRecombinant Fusion ProteinsAntibodies, MonoclonalIduronidaseReceptor, InsulinRecombinant Fusion Proteinsvalanafusp alphaBlood-brain barrierEfficacyIduronidaseInsulin receptorMucopolysaccharidosis Type IOpen label clinical trialSafety

Identifiers

PMID29976218
PMCPMC6034233
OpenAlexW2830135676

What OpenQuestion holds

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LicenceCC BY
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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.