An Adapted Clinical Measurement Tool for the Key Symptoms of CLN2 Disease

Abstract

Neuronal ceroid lipofuscinosis type-2 (CLN2) disease is a rare, autosomal recessive, pediatric-onset, neurodegenerative lysosomal storage disease caused by mutations in the TPP1 gene. Cerliponase alfa (Brineura ® ), a recombinant form of human tripeptidyl peptidase-1, was recently developed as a treatment for CLN2 disease. In clinical trials, the primary end point to evaluate treatment effect was the aggregate score for the motor and language (ML) domains of the CLN2 Clinical Rating Scale, an adaptation of the Hamburg scale's component items that include anchor point definitions to allow consistent ratings in multinational, multisite, clinical efficacy studies. Psychometric analyses demonstrated that the ML score of the CLN2 Clinical Rating Scale and individual item scores are well defined and possess adequate measurement properties (reliability, validity, and responsiveness) to demonstrate a clinical benefit over time. Additionally, analyses comparing the CLN2 Clinical Rating Scale ML ratings to the Hamburg scale's ML ratings demonstrated adequate similarity.

Review of Cerliponase Alfa: Recombinant Human Enzyme Replacement Therapy for Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2

“…The CLN2 Clinical Rating Scale was adapted from the Hamburg Scale and Weill Cornell Scale to allow for consistency in multicenter, clinical efficacy studies on patients with neuronal ceroid lipofuscinosis type 2 disease. 11 The motor and language domains are the key disease domains. Each domain rating is scaled from 3 to 0, or normal function to complete loss of function, respectively.…”

Cerliponase Alfa for the Treatment of Atypical Phenotypes of CLN2 Disease: A Retrospective Case Series

“…Disease progression was quantitatively assessed for each patient by their treating physician using reported scores from the motor and language (ML) domains of the CLN2 Clinical Rating Scale, an established method to measure the clinical course of classical CLN2 disease and the clinical impact of cerliponase alfa therapy. 10 , 26 , 27 The CLN2 Clinical Rating Scale is based primarily on natural history data from individuals with classical phenotypes. Because of the dearth of extensive natural history data on individuals with atypical presentations, no comparative tool based on disease progression data from atypical phenotypes currently exists; the CLN2 Clinical Rating Scale, which allows both retrospective and prospective natural history data collection, was therefore implemented to evaluate treatment effect in this subset of patients by monitoring changes in language and motor functions The ML score ranges from 0 to 6, with 0 representing complete loss of function, 1 representing severe abnormality, 2 representing slight abnormality, and 3 representing normal function within each of the 2 domains ( Table 1 ).…”

Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses

“…After a dose-escalation period, they received the drug at a dose of 300 mg every other week for at least 96 weeks (mean 115 ± 15 weeks). The rate of decline in a CLN2 clinical rating scale score for motor and language functions [ 14 ] was used as the primary outcome measure for efficacy. The unadjusted mean rate of decline in this motor-language score per 48-week period was 0.27 ± 0.35 points in the 23 treated patients as compared with 2.12 ± 0.98 in untreated historical controls [ 8 ].…”