Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2018

Open Access 01-12-2018 | Research

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

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

Published in: Orphanet Journal of Rare Diseases | Issue 1/2018

Login to get access

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.
Literature
1.
Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med. 2001;344(3):182–8.CrossRefPubMed
2.
Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr. 2004;144(5):581–8.CrossRefPubMed
3.
Pastores GM, Arn P, Beck M, Clarke JT, Guffon N, Kaplan P, et al. The MPS I registry: design, methodology, and early findings of a global disease registry for monitoring patients with Mucopolysaccharidosis Type I. Mol Genet Metab. 2007;91(1):37–47.CrossRefPubMed
4.
Wraith JE, Beck M, Lane R, van der Ploeg A, Shapiro E, Xue Y, et al. Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase). Pediatrics. 2007;120(1):e37–46.CrossRefPubMed
5.
Boado RJ, Pardridge WM. Brain and Organ Uptake in the Rhesus Monkey in Vivo of Recombinant Iduronidase Compared to an Insulin Receptor Antibody-Iduronidase Fusion Protein. Mol Pharm. 2017;14(4):1271–7.CrossRefPubMed
6.
Aldenhoven M, Wynn RF, Orchard PJ, O'Meara A, Veys P, Fischer A, et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood. 2015;125(13):2164–72.CrossRefPubMed
7.
Kunin-Batson AS, Shapiro EG, Rudser KD, Lavery CA, Bjoraker KJ, Jones SA, et al. Long-Term Cognitive and Functional Outcomes in Children with Mucopolysaccharidosis (MPS)-IH (Hurler Syndrome) Treated with Hematopoietic Cell Transplantation. JIMD Rep. 2016;29:95–102.CrossRefPubMedPubMedCentral
8.
Boado RJ, Zhang Y, Zhang Y, Xia CF, Wang Y, Pardridge WM. Genetic engineering of a lysosomal enzyme fusion protein for targeted delivery across the human blood-brain barrier. Biotechnol Bioeng. 2008;99(2):475–84.CrossRefPubMed
9.
Boado RJ, Hui EK, Lu JZ, Pardridge WM. AGT-181: expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys. J Biotechnol. 2009;144(2):135–41.CrossRefPubMedPubMedCentral
10.
Boado RJ, Hui EK, Lu JZ, Zhou QH, Pardridge WM. Reversal of lysosomal storage in brain of adult MPS-I mice with intravenous Trojan horse-iduronidase fusion protein. Mol Pharm. 2011;8(4):1342–50.CrossRefPubMed
11.
Pardridge WM, Boado RJ, Giugliani R, Schmidt M. Plasma Pharmacokinetics of Valanafusp Alpha, a Human Insulin Receptor Antibody-Iduronidase Fusion Protein, in Patients with Mucopolysaccharidosis Type I. BioDrugs. 2018;32:169–76.CrossRefPubMed
12.
Boado RJ, Hui EK, Lu JZ, Pardridge WM. IgG-enzyme fusion protein: pharmacokinetics and anti-drug antibody response in rhesus monkeys. Bioconjug Chem. 2013;24(1):97–104.CrossRefPubMed
13.
Dickerman MJ, Jacobs BR, Vinodrao H, Stockwell DC. Recognizing hypoglycemia in children through automated adverse-event detection. Pediatrics. 2011;127(4):e1035–41.CrossRefPubMed
14.
van der Lee JH, Morton J, Adams HR, Clarke L, Ebbink BJ, Escolar ML, et al. Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure. Mol Genet Metab. 2017;121(2):70–9.CrossRefPubMed
15.
Boado RJ, Lu JZ, Hui EK, Pardridge WM. Reduction in Brain Heparan Sulfate with Systemic Administration of an IgG Trojan Horse-Sulfamidase Fusion Protein in the Mucopolysaccharidosis Type IIIA Mouse. Mol Pharm. 2018;15(2):602–8.CrossRefPubMed
16.
Shapiro EG, Whitley CB, Eisengart JB. Beneath the floor: re-analysis of neurodevelopmental outcomes in untreated Hurler syndrome. Orphanet J Rare Dis. 2018;13:76.CrossRefPubMedPubMedCentral
17.
Boado RJ, Hui EK, Lu JZ, Pardridge WM. Glycemic control and chronic dosing of rhesus monkeys with a fusion protein of iduronidase and a monoclonal antibody against the human insulin receptor. Drug Metab Dispos. 2012;40(10):2021–5.CrossRefPubMedPubMedCentral
18.
Xue Y, Richards SM, Mahmood A, Cox GF. Effect of anti-laronidase antibodies on efficacy and safety of laronidase enzyme replacement therapy for MPS I: A comprehensive meta-analysis of pooled data from multiple studies. Mol Genet Metab. 2016;117(4):419–26.CrossRefPubMed
19.
Shapiro EG, Nestrasil I, Rudser K, Delaney K, Kovac V, Ahmed A, et al. Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment. Mol Genet Metab. 2015;116(1-2):61–8.CrossRefPubMedPubMedCentral
20.
Fan Z, Styner M, Muenzer J, Poe M, Escolar M. Correlation of automated volumetric analysis of brain MR imaging with cognitive impairment in a natural history study of mucopolysaccharidosis II AJNR. Am J Neuroradiol. 2010;31(7):1319–23.CrossRefPubMed
21.
Zhang H, Young SP, Auray-Blais C, Orchard PJ, Tolar J, et al. Analysis of glycosaminoglycans in cerebrospinal fluid from patients with Mucopolysaccharidosis by isotope-dilution ultra-performance liquid chromatography-tandem mass spectrometry. Clin Chem. 2011;57:1005–12.CrossRefPubMed
22.
Tardieu M, Zerah M, Gougeon M-L, Ausseil J, de Bournonville S, et al. Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Lancet Neurol. 2017;16:712–20.CrossRefPubMed
23.
Muenzer J, Hendriksz CJ, Fan Z, Vijayaraghavan S, Perry V, Santra S, et al. A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II. Genet Med. 2016;18(1):73–81.CrossRefPubMed
24.
Jones SA, Breen C, Heap F, Rust S, de Ruijter J, Tump E, et al. A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA. Mol Genet Metab. 2016;118(3):198–205.CrossRefPubMed
25.
Auclair D, Finnie J, Walkley SU, White J, Nielsen T, Fuller M, et al. Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats. Pediatr Res. 2012;71(1):39–45.CrossRefPubMed
26.
Boado RJ, Hui EK, Lu JZ, Pardridge WM. Very High Plasma Concentrations of a Monoclonal Antibody against the Human Insulin Receptor Are Produced by Subcutaneous Injection in the Rhesus Monkey. Mol Pharm. 2016;13(9):3241–6.CrossRefPubMed
27.
Giugliani R, Rojas VM, Martins AM, Valadares ER, Clarke JT, Goes JE, et al. A dose-optimization trial of laronidase (Aldurazyme) in patients with mucopolysaccharidosis I. Mol Genet Metab. 2009;96(1):13–9.CrossRefPubMed
28.
Muenzer J, Beck M, Eng CM, Giugliani R, Harmatz P, Martin R, et al. Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Genet Med. 2011;13(2):95–101.CrossRefPubMed
Metadata
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
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
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2018
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-018-0849-8

Other articles of this Issue 1/2018

Orphanet Journal of Rare Diseases 1/2018 Go to the issue

Research

The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome

Research

Investigating the landscape of US orphan product approvals

Research

Meta-analysis of the clinical and immunopathological characteristics and treatment outcomes in epidermolysis bullosa acquisita patients

Research

The French National Registry of patients with Facioscapulohumeral muscular dystrophy

Research

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

Research

A nomenclature and classification for the congenital myasthenic syndromes: preparing for FAIR data in the genomic era