p; Pediatric Use
Safety and effectiveness of Brineura have been established in pediatric patients 3 years of age and older. Pediatric use of Brineura to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency, is supported by a non-randomized single-arm dose escalation clinical study with extension in patients with CLN2 disease and compared to untreated patients with CLN2 disease from an independent natural history cohort [see Clinical Studies (14)]. Safety and effectiveness in patients less than 3 years of age have not been established.
11 DESCRIPTION
Cerliponase alfa is a purified human enzyme produced by recombinant DNA technology in a Chinese hamster ovary cell line. The active substance is a recombinant human tripeptidyl peptidase-1 (rhTPP1), a lysosomal exopeptidase. The primary activity of the mature enzyme is the cleavage of N-terminal tripeptides from a broad range of protein substrates.
Cerliponase alfa contains 544 amino acids with an average molecular mass of 59 kDa. The mature enzyme is 368 amino acids in length. There are 5 consensus N-glycosylation sites on rhTPP1 that contain high mannose, phosphorylated high mannose and complex glycosylation structures.
Brineura (cerliponase alfa) Injection and Intraventricular Electrolytes Injection are administered by intraventricular infusion. The solutions are sterile, nonpyrogenic, and free of foreign particulates. Brineura is a clear to slightly opalescent and colorless to pale yellow solution. Intraventricular Electrolytes is a clear to colorless solution.
Brineura and Intraventricular Electrolytes Injection are packaged in 10 mL clear Type 1 single-dose glass vials [see How Supplied/Storage and Handling (16)]. Each vial of Brineura provides 5 mL of solution containing 150 mg cerliponase alfa. Each vial of Intraventricular Electrolytes Injection provides 5 mL of solution. Both Brineura and Intraventricular Electrolytes Injection are formulated with the following excipients: calcium chloride dihydrate (1.05 mg); magnesium chloride hexahydrate (0.8 mg); potassium chloride (1.1 mg); sodium chloride (43.85 mg); sodium phosphate, dibasic, heptahydrate (0.55 mg); sodium phosphate, monobasic, monohydrate (0.4 mg); and Water for Injection, USP. The pH of the solution is between 6.2 to 6.8 for Brineura, and between 6.0 to 7.0 for Intraventricular Electrolytes Injection.
Each vial contains: sodium: 0.76 mEq, and potassium: 0.015 mEq.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
CLN2 disease is a neurodegenerative disease caused by deficiency of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1), which catabolizes polypeptides in the CNS. TPP1 has no known substrate specificity. Deficiency in TPP1 activity results in the accumulation of lysosomal storage materials normally metabolized by this enzyme in the central nervous system (CNS), leading to progressive decline in motor function.
Cerliponase alfa (rhTTP1), a proenzyme, is taken up by target cells in the CNS and is translocated to the lysosomes through the Cation Independent Mannose-6-Phosphate Receptor (CI-MPR, also known as M6P/IGF2 receptor). Cerliponase alfa is activated in the lysosome and the activated proteolytic form of rh |
