Cerliponase alfa is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients three years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.The efficacy of cerliponase alfa was established in a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort (an independent historical control group) who were at least three years old and had motor or language symptoms. Taking into account age, baseline walking ability and genotype, cerliponase alfa-treated patients demonstrated fewer declines in walking ability compared to untreated patients in the natural history cohort.The safety of cerliponase alfa was evaluated in 24 patients with CLN2 disease aged three to eight years who received at least one dose of cerliponase alfa in clinical studies. The trial was conducted in the United States, United Kingdom, Germany and Italy. The safety and effectiveness of cerliponase alfa has not been established in patients less than three years of age.Brineura-treated patients were compared to untreated patients from a natural history cohort by assessing disease progression through Week 96 of treatment. The investigators measured the loss of ability to walk or crawl using the Motor domain of the CLN2 Clinical Rating Scale.
Once brought into the cell, the receptor-proenzyme complex vesicle is transported to the lysosome where the lower pH promotes both dissociation of the proenzyme from the receptor and activation of the proenzyme to its active catalytic form via cleavage of the proenzyme sequence.Like natural TPP1, cerliponase alfa functions as a serine protease, cleaving N-terminal tripeptides from a broad range of protein substrates. The enzyme uses a catalytic triad active site composed of the three amino acids, aspartic acid, glutamic acid, and serine. Serine functions as the amino acid that performs the nucleophilic attack during the ping pong catalytic activity of a serine protease. The products of this reaction are a tripeptide and the remaining length of the protein substrate with a new N-terminal end that can be cleaved again. In CLN2 disease, TPP1 is deficient or not made at all, meaning that proteins are unable to be degraded in the lysosome and accumulate, leading to damage in nerves. As a protein, cerliponase alfa gets degraded by proteolysis. Therefore, cerliponase alfa is administered repeatedly to maintain sufficient levels of the recombinant TPP1 enzyme in place of the deficient form to degrade proteins and prevent further build up. Cerliponase alfa is a treatment that can potentially slow disease progression but does not cure the disease itself. References
External links
"Cerliponase alfa". Drug Information Portal. U.S. National Library of Medicine.