Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial.
Mol Genet Metab
; 126(2): 121-130, 2019 02.
Article
em En
| MEDLINE
| ID: mdl-30528227
ABSTRACT
BACKGROUND:
Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial.METHODS:
Twenty-one patients, randomized 111 to rhHNS IT 45â¯mg administered every 2â¯weeks (Q2W), every 4â¯weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. The primary efficacy goal was defined as ≤10-point decline (responder) in at least three patients in a dosing cohort after 48â¯weeks. Other efficacy assessments included adaptive behavioral function, assessments of cortical gray matter volume, and glycosaminoglycan (GAG) levels in urine.RESULTS:
A clinical response to rhHNS IT was observed in three treated patients (two in the Q2W group, one in the Q4W group). Cerebrospinal fluid heparan sulfate and urine GAG levels were reduced in all treated patients. However, most secondary efficacy assessments were similar between treated patients (nâ¯=â¯14; age, 17.8-47.8â¯months) and untreated controls (nâ¯=â¯7; age, 12.6-45.0â¯months). Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths.CONCLUSION:
rhHNS IT treatment reduced heparan sulfate and GAG levels in treated patients. Though the primary neurocognitive endpoint was not met, important lessons in the design and endpoints for evaluation of cognitive and behavioral diseases resulted. TRIAL REGISTRATION ClinicalTrials.govNCT02060526; EudraCT 2013-003450-24.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfatases
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Injeções Espinhais
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Mucopolissacaridose III
Tipo de estudo:
Clinical_trials
Limite:
Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article