Safety evaluation of chronic intrathecal administration of idursulfase-IT in cynomolgus monkeys.

Felice, B.R., Wright, T.L., Boyd, R.B., Butt, M.T., Pfeifer, R.W., Pan, J., Ruiz, J.A., Heartlein, M.W., Calias, P.
Journal   Toxicol Pathol.
Analytes Measured  
Matrix Tested   Cerebrospinal fluid (CSF), Serum
Year   2011
Volume   39
Page Numbers   879-892
Application   Immunogenicity
Recombinant human idursulfase, an intravenous enzyme replacement therapy indicated for treatment of somatic symptoms of mucopolysaccharidosis II (Hunter syndrome), is anticipated to have minimal benefit for the cognitive impairment associated with the severe phenotype. Because intrathecal (IT) administration of enzyme replacement therapy for other lysosomal enzyme disorders has shown efficacy in animal models, an IT formulation of idursulfase (idursulfase-IT) and a drug-delivery device (subcutaneous port connected to a lumbar IT catheter) were developed for treating central nervous system (CNS) involvement. In this chronic safety study, cynomolgus monkeys were dosed weekly with IV idursulfase (0.5 mg/kg) and every four weeks with idursulfase-IT (3, 30, and 100 mg) for six months, with device and vehicle controls treated similarly (n = 6, all groups). Necropsies were performed twenty-four hours post-final IT dose or after a recovery period (four weeks post-final dose in vehicle-control, 3 mg, and 100 mg IT groups: n = 6). No clinical signs or gross central nervous system lesions were observed. Compared to controls, more pronounced cellular infiltrates in brain and spinal cord meninges were noted, which largely resolved after the recovery period. Central nervous sytem levels of idursulfase-IT were dose dependent, as determined by enzyme activity and immunohistochemistry. The no-observed-adverse-effect level of idursulfase-IT was 100 mg.

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