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A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B

Standard

A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B. / Muschol, Nicole; Koehn, Anja; von Cossel, Katharina; Okur, Ilyas; Ezgu, Fatih; Harmatz, Paul; de Castro Lopez, Maria J; Couce, Maria Luz; Lin, Shuan-Pei; Batzios, Spyros; Cleary, Maureen; Solano, Martha; Nestrasil, Igor; Kaufman, Brian; Shaywitz, Adam J; Maricich, Stephen M; Kuca, Bernice; Kovalchin, Joseph; Zanelli, Eric.

in: J CLIN INVEST, Jahrgang 133, Nr. 2, e165076, 17.01.2023.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Muschol, N, Koehn, A, von Cossel, K, Okur, I, Ezgu, F, Harmatz, P, de Castro Lopez, MJ, Couce, ML, Lin, S-P, Batzios, S, Cleary, M, Solano, M, Nestrasil, I, Kaufman, B, Shaywitz, AJ, Maricich, SM, Kuca, B, Kovalchin, J & Zanelli, E 2023, 'A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B', J CLIN INVEST, Jg. 133, Nr. 2, e165076. https://doi.org/10.1172/JCI165076

APA

Muschol, N., Koehn, A., von Cossel, K., Okur, I., Ezgu, F., Harmatz, P., de Castro Lopez, M. J., Couce, M. L., Lin, S-P., Batzios, S., Cleary, M., Solano, M., Nestrasil, I., Kaufman, B., Shaywitz, A. J., Maricich, S. M., Kuca, B., Kovalchin, J., & Zanelli, E. (2023). A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B. J CLIN INVEST, 133(2), [e165076]. https://doi.org/10.1172/JCI165076

Vancouver

Muschol N, Koehn A, von Cossel K, Okur I, Ezgu F, Harmatz P et al. A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B. J CLIN INVEST. 2023 Jan 17;133(2). e165076. https://doi.org/10.1172/JCI165076

Bibtex

@article{8065114754734d3db66b16b6a12ab93c,
title = "A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B",
abstract = "BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.",
keywords = "Humans, Mucopolysaccharidosis III/drug therapy, Heparitin Sulfate, Brain, Liver, Spleen",
author = "Nicole Muschol and Anja Koehn and {von Cossel}, Katharina and Ilyas Okur and Fatih Ezgu and Paul Harmatz and {de Castro Lopez}, {Maria J} and Couce, {Maria Luz} and Shuan-Pei Lin and Spyros Batzios and Maureen Cleary and Martha Solano and Igor Nestrasil and Brian Kaufman and Shaywitz, {Adam J} and Maricich, {Stephen M} and Bernice Kuca and Joseph Kovalchin and Eric Zanelli",
year = "2023",
month = jan,
day = "17",
doi = "10.1172/JCI165076",
language = "English",
volume = "133",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",

}

RIS

TY - JOUR

T1 - A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B

AU - Muschol, Nicole

AU - Koehn, Anja

AU - von Cossel, Katharina

AU - Okur, Ilyas

AU - Ezgu, Fatih

AU - Harmatz, Paul

AU - de Castro Lopez, Maria J

AU - Couce, Maria Luz

AU - Lin, Shuan-Pei

AU - Batzios, Spyros

AU - Cleary, Maureen

AU - Solano, Martha

AU - Nestrasil, Igor

AU - Kaufman, Brian

AU - Shaywitz, Adam J

AU - Maricich, Stephen M

AU - Kuca, Bernice

AU - Kovalchin, Joseph

AU - Zanelli, Eric

PY - 2023/1/17

Y1 - 2023/1/17

N2 - BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.

AB - BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.

KW - Humans

KW - Mucopolysaccharidosis III/drug therapy

KW - Heparitin Sulfate

KW - Brain

KW - Liver

KW - Spleen

U2 - 10.1172/JCI165076

DO - 10.1172/JCI165076

M3 - SCORING: Journal article

C2 - 36413418

VL - 133

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 2

M1 - e165076

ER -