Final results of the phase 1/2, open-label clinical study of intravenous recombinant human N-acetyl-α-d-glucosaminidase (SBC-103) in children with mucopolysaccharidosis IIIB.
Mol Genet Metab
; 126(2): 131-138, 2019 02.
Article
em En
| MEDLINE
| ID: mdl-30635159
Mucopolysaccharidosis IIIB is caused by a marked decrease in N-acetyl-α-d-glucosaminidase (NAGLU) enzyme activity, which leads to the accumulation of heparan sulfate in key organs, progressive brain atrophy, and neurocognitive decline. In this open-label study, 11 eligible patients aged 2 to <12â¯years (developmental ageâ¯≥â¯1â¯year) were sequentially allocated to recombinant human NAGLU enzyme (SBC-103) in 3 staggered- and escalating-dose groups (0.3â¯mg/kg [nâ¯=â¯3], 1.0â¯mg/kg [nâ¯=â¯4], or 3.0â¯mg/kg [nâ¯=â¯4]) by intravenous infusion every 2â¯weeks for 24â¯weeks, followed by a 4-week interruption (Part A), treatment at 1.0 and/or 3.0â¯mg/kg every 2â¯weeks starting at week 28 (Part B), and treatment at 5.0 or 10.0â¯mg/kg every 2â¯weeks (Part C) for approximately 2 total years in the study. The primary objective of the study was safety and tolerability evaluation; secondary objectives included evaluation of SBC-103 effects on total heparan sulfate levels in cerebrospinal fluid (CSF), brain structural magnetic resonance imaging (cortical gray matter volume), and neurocognitive status (age equivalent/developmental quotient). During the study, 13 treatment-emergent serious adverse events (SAEs) occurred in 3 patients; 32 infusion-associated reactions (IARs) occurred in 8 patients. Most AEs were mild and intravenous treatment with SBC-103 was well tolerated. Mean (SD) changes from baseline at 52â¯weeks in Part C for the 5.0 and 10.0â¯mg/kg doses, respectively, were: -4.7% (8.3) andâ¯-â¯4.7% (14.7) for heparan sulfate levels in CSF, -8.1% (3.5) andâ¯-â¯10.3% (9.4) for cortical gray matter volume, +2.3 (6.9) points and +1.0 (9.2) points in cognitive age equivalent and -8.9 (10.2) points and -14.4 (9.2) points in developmental quotient. In summary, SBC-103 was generally well tolerated. Changes in heparan sulfate levels in CSF were small and were not maintained from earlier study time points, there was no clear evidence overall of clinically meaningful improvement in neurocognitive function at the higher doses investigated, and no dose-dependent effects were observed.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acetilglucosaminidase
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Proteínas Recombinantes
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Mucopolissacaridose III
Tipo de estudo:
Clinical_trials
Limite:
Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Mol Genet Metab
Assunto da revista:
BIOLOGIA MOLECULAR
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BIOQUIMICA
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METABOLISMO
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos