Intracerebroventricular repeat dose CPI-601 recombinant human palmitoyl-protein thioesterase-1 in cynomolgus monkey: safety, pharmacokinetics, and dose selection.

CLN1 Batten Disease is caused by mutations in the CLN1 gene resulting in a reduction or absence of enzyme activity. It is characterized by progressive cognitive, language and motor regression, seizures, loss of vision, and early death. There is currently no approved treatment for this rare disease apart from palliative care. Recombinant human palmitoyl-protein thioesterase-1 (rhPPT1, CPI-601) can be used as an enzyme replacement therapy (ERT) for CLN1. A good laboratory practice (GLP) repeat-dose toxicology and pharmacokinetic study was conducted in juvenile cynomolgus monkeys following intracerebroventricular (ICV) administration of CPI-601 to support clinical translation based on efficacy data seen in the CLN1-/- mouse preclinical efficacy model. Safety assessments included clinical observations, neurologic evaluations, clinical pathology, electrocardiography, ophthalmology, anti-drug antibody (ADA) analysis, pharmacokinetics, and comprehensive neuropathology. CPI-601 demonstrated rapid cerebrospinal fluid (CSF) exposure with peak concentrations observed approximately 0.5 h following administration. Exposure increased with dose, while systemic exposure remained limited. In CLN1 patient fibroblasts, CPI-601 exhibited a half-life of 21.38 h. No anti-drug antibodies (ADAs) were detected during the study. No treatment-related changes were observed in body weight, electrocardiography, ophthalmology, respiratory parameters, or clinical pathology. No comparable adverse findings were observed at lower dose levels. There were microscopic findings only at the highest dose tested, that were minor to moderate in nature and progressed from minimal microgliosis at the end of dosing to moderate neurodegenerative changes during recovery. This study now supports dosing of CPI-601 ICV in a pediatric clinical trial for which allometric scaling was used to enable dose selection. ONE SENTENCE SUMMARY: Safety evaluation and pharmacokinetics of CPI-601 as an enzyme replacement therapy for CLN1 Batten disease in non-human primates.