Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study

Muenzer, Joseph; Burton, Barbara K.; Harmatz, Paul; Gutiérrez-Solana, Luis González; Ruiz-Garcia, Matilde; Jones, Simon A.; Guffon, Nathalie; Inbar‐Feigenberg, Michal; Bratkovic, Drago; Hale, Michael; Wu, Yanyu; Yee, Karen S.; Whiteman, David A.H.; Alexanderian, David; Aleck, Kyrieckos; Amartino, Hernán; Anadiotis, George; Benke, Paul J.; Cohn, Ronald D.; Erwin, Angelika; Fıçıcıoğlu, Can; Grange, Dorothy K.; Hanna, Rabi; Khan, Aneal; Villareal, Martha Luz Solano; McGill, Jim; Ortiz, Damara; Pedro, Hélio; Raiman, Julian; Rizzo, William B.; Segal, Devorah; Sevin, Caroline; Spiller, Susan; Sun, Angela

doi:10.1016/j.ymgme.2022.07.017

Cited by 20 publications

(41 citation statements)

References 40 publications

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“…For each study, age, cognitive status at the time of enrollment and change over time, and, when available, GAG csf levels were retrieved. Internal data included non‐interventional and placebo data from a total of 73 participants from three Takeda‐sponsored studies (NCT00937794, NCT01822184, NCT02055118) 4–6 . External data included published natural history data from a total of 65 participants, previously reviewed by Shapiro and Eisengart 3 and digitized from data reported in the original publications 7–9 .…”

Section: Methodsmentioning

confidence: 99%

“…Internal data included non‐interventional and placebo data from a total of 73 participants from three Takeda‐sponsored studies (NCT00937794, NCT01822184, NCT02055118). 4 , 5 , 6 External data included published natural history data from a total of 65 participants, previously reviewed by Shapiro and Eisengart 3 and digitized from data reported in the original publications. 7 , 8 , 9 Participants from internal clinical trials were all boys, with a median enrollment age of 4.4 years (range 2.5–8.8 years), and a median enrollment Differential Ability Scales‐II (DAS‐II) general conceptual ability (GCA) score of 73 (range 30–122).…”

Section: Methodsmentioning

confidence: 99%

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Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively‐driven reverse translation framework

Latzman,

Campagne,

Modi

et al. 2024

Clinical Translational Sci

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A quantitatively‐driven evaluation of existing clinical data and associated knowledge to accelerate drug discovery and development is a highly valuable approach across therapeutic areas, but remains underutilized. This is especially the case for rare diseases for which development is particularly challenging. The current work outlines an organizational framework to support a quantitatively‐based reverse translation approach to clinical development. This approach was applied to characterize predictors of the trajectory of cognition in Hunter syndrome (Mucopolysaccharidosis Type II; MPS‐II), a rare X‐linked lysosomal storage disorder, highly heterogeneous in its course. Specifically, we considered ways to refine target populations based on age, cognitive status, and biomarkers, that is, cerebrospinal fluid glycosaminoglycans (GAG), at trial entry. Data from a total of 138 subjects (age range 2.5 to 10.1 years) from Takeda‐sponsored internal studies and external natural history studies in MPS‐II were included. Quantitative analyses using mixed‐effects models were performed to characterize the relationships between neurocognitive outcomes and potential indicators of disease progression. Results revealed a specific trajectory in cognitive development across age with an initial progressive phase, followed by a plateau between 4 and 8 years and then a variable declining phase. Additionally, results suggest a faster decline in cognition among subjects with lower cognitive scores or with higher cerebrospinal fluid GAG at enrollment. These results support differences in the neurocognitive course of MPS‐II between distinct groups of patients based on age, cognitive function, and biomarker status at enrollment. These differences should be considered when designing future clinical trials.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively‐driven reverse translation framework

Latzman,

Campagne,

Modi

et al. 2024

Clinical Translational Sci

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“…Notably, the intrathecal administration of idursulfase to patients with MPS II or recombinant sulfamidase to patients with MPS IIIA decreased GAG/HS concentrations in the CSF but was hardly effective for cognitive function in most cases [ 146 , 147 , 148 , 149 , 150 ], casting doubt on the use of CSF HS as a surrogate biomarker for brain HS deposition and neurological dysfunction. In this regard, the biodistribution of enzymes by direct injection into the lumbar spine may well vary from that via intravenous administration of BBB-penetrating enzymes.…”

Section: Hs As a Biomarker For Mpssmentioning

confidence: 99%

Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses

Minami

Morimoto

Morioka

et al. 2022

IJMS

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Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs.

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“…Unfortunately, these studies have been hampered by severe adverse events and data on efficacy are still inconclusive, although a trend toward neurocognitive improvement was detected in MPS II. 9,10 Alternatively, bioengineered lysosomal enzymes that can cross the blood-brain-barrier have been developed and are they are showing promising results in clinical trials. 11,12 Besides the limited efficacy on some disease manifestations, ERT has other disadvantages, including the need for lifelong (bi-)weekly intravenous infusions that carry the risks of immune reactions, infections, and the development of neutralizing or cell-uptake blocking antibodies to the infused enzyme that decrease the long-term efficacy of ERT.…”

Section: Introductionmentioning

confidence: 99%

“…Intrathecal ERT has been investigated in clinical trials for MPS type I, II, and IIIA to deliver recombinant enzymes to the CNS. Unfortunately, these studies have been hampered by severe adverse events and data on efficacy are still inconclusive, although a trend toward neurocognitive improvement was detected in MPS II 9,10 . Alternatively, bioengineered lysosomal enzymes that can cross the blood–brain‐barrier have been developed and are they are showing promising results in clinical trials 11,12 …”

Section: Introductionmentioning

confidence: 99%

Gene therapies for mucopolysaccharidoses

Rossi

Brunetti‐Pierri

2023

J of Inher Metab Disea

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Current specific treatments for mucopolysaccharidoses (MPSs) include enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). Both treatments are hampered by several limitations, including lack of efficacy on brain and skeletal manifestations, need for lifelong injections, and high costs. Therefore, more effective treatments are needed. Gene therapy in MPSs is aimed at obtaining high levels of the therapeutic enzyme in multiple tissues either by engrafted gene‐modified hematopoietic stem progenitor cells (ex vivo) or by direct infusion of a viral vector expressing the therapeutic gene (in vivo). This review focuses on the most recent clinical progress in gene therapies for MPSs. The various gene therapy approaches with their strengths and limitations are discussed.

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Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study

Cited by 20 publications

References 40 publications

Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively‐driven reverse translation framework

Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively‐driven reverse translation framework

Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses

Gene therapies for mucopolysaccharidoses

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