FV 1183. Long-Term Safety and Efficacy of Intraventricular Enzyme Replacement Therapy in CLN2 Disease: 2-Year Results from an Ongoing Multicenter Extension Study

Background: CLN2 disease, a rare, inherited, pediatric, neurodegenerative lysosomal storage disorder caused by TPP1 deficiency, is characterized by seizures, language and motor function loss, blindness, and early death. A phase 1/2 study (NCT01907087) demonstrated that intracerebroventricular (ICV) infusion of 300 mg cerliponase alfa, a recombinant human TPP1 enzyme, every other week for 48 weeks slowed progression in motor and language function. This extension study (NCT02485899) assesses the long-term safety and efficacy of ICV-administered cerliponase alfa in children with CLN2 disease for up to 240 weeks.

Design: Subjects who completed the phase 1/2 study continued receiving 300 mg cerliponase alfa in this open-label extension study. Cumulative data from both studies were used to evaluate long-term safety (assessed by adverse events [AEs] frequency) and efficacy (assessed by changes in the CLN2 clinical rating scale motor and language [ML] domains).

Results: Twenty-four subjects were initially treated with cerliponase alfa in the phase 1/2 study (9 males, 15 females, mean [SD] age 4.3 years [1.24]); 23 subjects enrolled in the extension study (96–161 weeks total exposure, median 116 weeks). All had AEs; most were Grades 1 to 2. Common AEs included pyrexia, vomiting, and convulsion. Twenty (83%) subjects had at least one serious AE, which were mostly consistent with neurodegenerative disease in a pediatric population. Significant attenuation of the rate of decline in ML score (mean [95% confidence interval]: 0.27 [0.12, 0.42] points/48 weeks, p < 0.0001) was observed compared with a rate of decline of 2.0 points/48 weeks in untreated patients. The responder (<2 point loss/48 weeks) rate at 96 weeks (100%, p < 0.0001) was improved compared with that observed at 48 weeks, suggesting a persistent treatment effect.

Conclusion: These data suggest that enzyme replacement therapy with ICV-administered cerliponase alfa has an acceptable safety profile and a sustained effect over time.