Cerliponase alfa is recombinant human TPP1 delivered by intracerebroventricular (ICV) infusion for CLN2, a pediatric neurodegenerative disease caused by deficiency in lysosomal enzyme TPP1. We report the PK and PD of cerliponase alfa, the first ICV enzyme replacement therapy, characterized in a Phase 1/2 study. Escalating doses (30-300 mg every two weeks, Q2W) followed by 300 mg Q2W for ≥48 weeks were administered in 24 patients aged ≥3 years. Concentrations peaked in CSF at the end of ~4-hour ICV infusion and 8 hours thereafter in plasma. Plasma exposure was 300-1000 fold lower than in CSF, with no correlation in the magnitude of C or AUC between body sites. There was no apparent accumulation in CSF or plasma exposure with Q2W dosing. Inter- and intra-patient variability of AUC, respectively, were 31-49% and 24% in CSF versus 59-103% and 80% in plasma. PK variability was not explained by baseline demographics, as gender, age, weight, and CLN2 disease severity score did not appear to impact CSF or plasma PK. No apparent correlation was noted between CSF or plasma PK and incidence of adverse events (pyrexia, hypersensitivity, seizure, and epilepsy) or presence of antidrug antibodies in CSF and serum. There was no relationship between magnitude of CSF exposure and efficacy (change in CLN2 score from baseline), indicating maximum benefit was obtained across the range of exposures with 300 mg Q2W. Data from this small trial of ultra-rare disease were leveraged to adequately profile cerliponase alfa and support 300 mg ICV Q2W for CLN2 treatment.
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