Safety, pharmacokinetics and CNS distribution of tralesinidase alfa administered via intracerebroventricular infusion to juvenile cynomolgus monkeys.
Toxicol Rep
; 10: 357-366, 2023.
Article
em En
| MEDLINE
| ID: mdl-36923444
ABSTRACT
Mucopolysaccharidosis Type IIIB (MPS IIIB) is an ultrarare, fatal pediatric disease with no approved therapy. It is caused by mutations in the gene encoding for lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). Tralesinidase alfa (TA) is a fusion protein comprised of recombinant NAGLU and a modified human insulin-like growth factor 2 that is being developed as an enzyme replacement therapy for MPS IIIB. Since MPS IIIB is a pediatric disease the safety/toxicity, pharmacokinetics and biodistribution of TA were evaluated in juvenile non-human primates that were administered up to 5 weekly intracerebroventricular (ICV) or single intravenous (IV) infusions of TA. TA administered by ICV slow-, ICV isovolumetric bolus- or IV-infusion was well-tolerated, and no effects were observed on clinical observations, electrocardiographic or ophthalmologic parameters, or respiratory rates. The drug-related changes observed were limited to increased cell infiltrates in the CSF and along the ICV catheter track after ICV administration. These findings were not associated with functional changes and are associated with the use of ICV catheters. The CSF PK profiles were consistent across all conditions tested and TA distributed widely in the CNS after ICV administration. Anti-drug antibodies were observed but did not appear to significantly affect the exposure to TA. Correlations between TA concentrations in plasma and brain regions in direct contact with the cisterna magna suggest glymphatic drainage may be responsible for clearance of TA from the CNS. The data support the administration of TA by isovolumetric bolus ICV infusion to pediatric patients with MPS IIIB.
ADA, anti-drug antibodies; AUC, area under the curve; CLN2, Neuronal Ceroid Lipofuscinosis Type 2; CNS, central nervous system; CSF, cerebrospinal fluid; Cmax, maximal concentration; ERT, enzyme replacement therapy; Enzyme replacement therapy; H&E, Hematoxylin and Eosin; HS, heparan sulfate; ICV, intracerebroventricular; IGF2, insulin-like growth factor 2; IT-L, intrathecal lumbar; IV, intravenous; Intracerebroventricular; LLOQ, lower limit of quantitation; MPS IIIB; MPS IIIB, mucopolysaccharidosis type IIIB; NAGLU; NAGLU, alpha-N-acetylglucosaminidase; NBF, neutral buffered formalin; NHP, non-human primate; PK, pharmacokinetics; QW, once weekly; Sanfilippo syndrome; T1/2, time required for compound concentration to decrease by 50%; TA, tralesinidase alfa; Tmax, time at which maximal concentration is achieved; WBC, white blood cell count; aCSF, artificial cerebrospinal fluid
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Toxicol Rep
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos