Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is one of a group of inherited, neurodegenerative, lysosomal storage disorders collectively referred to as Batten disease. It is a rare autosomal recessive disease caused by a deficiency of tripeptidyl peptidase 1 (TPP1) enzyme, due to a mutation in the TPP1 gene. It is characterized by seizures, ataxia, language delays, blindness, and early death. Language delay and seizures are typically the initial symptoms and usually present between the ages of 2 and 4 years of age. Visual impairment may begin as early as 4 years, leading to blindness by age 7 to 10 years. Children generally succumb to the disease by the mid-teenage years.
The tripeptidyl peptidase 1 (TPP1) gene provides instructions for making tripeptidyl peptidase 1 enzyme, which is an inactive enzyme. This enzyme, found in the cells' lysosomes, breaks down peptides into amino acids. A deficiency of this enzyme decreases the breakdown of peptides and thereby causes peptide accumulation in the lysosomes. These accumulations cause cell damage and eventually cell death, particularly in the nerve cells. The progressive death of nerve cells in the brain leads to the signs and symptoms of CLN2 disease.
Cerliponase alfa (Brineura®) was approved April 27, 2017 to slow the loss of ambulation in symptomatic individuals 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). It is a proenzyme, taken up by target cells in the central nervous system (CNS), and translocated to the lysosomes where it is activated. The activated form then cleaves the proteins, preventing the accumulation of lysosomal storage materials.
Cerliponase alfa (Brineura®) is administered to the cerebrospinal fluid by intraventricular infusion at a dose of 300 mg once every other week.
The efficacy of cerliponase alfa (Brineura®) was studied over 96 weeks in a non-randomized, single-arm, dose-escalation study with extension consisting of 24 individuals, aged 3 to 8 years, with symptomatic late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), confirmed by TPP1 deficiency. Results of the Brineura®-treated group were compared to the scores of untreated individuals from an independent natural history cohort, consisting of 42 individuals. The matched efficacy population consisted of 21 treated individuals matched to an untreated individual based on baseline age, genotype, and motor CLN2 score. Assessment for decline in the motor domain of the CLN2 Clinical Rating Scale was done at 48, 72, and 96 weeks. Decline was defined as having an unreversed 2-point decline or an unreversed score of 0 in the motor domain of the CLN2 Clinical Rating Scale. The results showed that when compared to the natural cohort group at 96 weeks, 21/21 (100%) of the matched Brineura®-treated individuals had an absence of 2-point decline in motor language (ML) score compared with 9/21 (43%) of the untreated individuals. Also, the majority (95%) of the Brineura®-treated individuals demonstrated sustained ambulation, as evidenced by less than a 2-point decline in the CLN2 motor domain score.
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