doi: 10.1016/j.toxrep.2023.02.014.
eCollection 2023.
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Toxicol Rep.
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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.
Keywords:
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.
© 2023 The Authors.
Conflict of interest statement
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Emma McCullagh reports a relationship with Allievex Corporation that includes: consulting or advisory. Jami L. Trombley reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Randall P. Reed reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Eric L. Adams reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Robert B. Boyd reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Mark T. Butt reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory. Jason Pinkstaff reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Emma McCullagh reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Anita Grover reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Andrew C. Melton reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Anu Cherukuri reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Jill CM Wait reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Annalisa Nguyen reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Sundeep Chandra reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Joshua Henshaw reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Charles A. O’Neill reports a relationship with BioMarin Pharmaceutical Inc that includes: employment and equity or stocks. Eric Zanelli reports a relationship with Allievex Corporation that includes: employment and equity or stocks. Joseph Kovalchin reports a relationship with Allievex Corporation that includes: employment and equity or stocks.