TPP1 cleaves tripeptides from the N-terminus of proteins.
12.3 Pharmacokinetics
The pharmacokinetics of cerliponase alfa were eva luated in patients with CLN2 disease who received intraventricular infusions of 30 mg (0.1 times the approved recommended dosage), 100 mg (approximately 0.3 times the approved recommended dosage), and 300 mg over approximately 4.5 hours once every other week.
Cerliponase alfa CSF exposure following the initial single dose administration of Brineura increased less than proportionally across doses of 30 mg, 100 mg, and 300 mg. There was no apparent accumulation of cerliponase alfa in CSF or plasma when Brineura was administered at a dose of 300 mg once every other week.
Cerliponase alfa pharmacokinetics have high inter-subject and intra-subject variability. Following intraventricular infusions of 300 mg of Brineura at Day 1, Week 5, and Week 13, the pharmacokinetic parameters in CSF and plasma were assessed in 14 patients and are summarized in Table 2.
Table 2: Pharmacokinetic Parameters of Cerliponase Alfa Following Intraventricular Infusion (approximately 4.5 hours in duration) of Brineura 300 mg Every Two Weeks
CSF
Parameter
Median [Min, Max]
Day 1
Week 5
Week 13
N
13
14
13
Tmax*, hr
4.5 [4.3, 5.8]
4.3 [3.8, 4.5]
4.3 [4.0, 4.5]
Cmax, mcg/mL
1260 [359, 4380]
1630 [376, 4670]
1390 [1110, 2340]
AUC0-t, mcg‑hr/mL
9290 [3660, 19000]
12400 [4620, 26200]
10500 [7000, 18200]
Vss, mL
245 [78.4, 909]
196 [85.4, 665]
186 [131, 257]
CL, mL/hr
32.3 [15.8, 81.9]
24.2 [11.4, 64.9]
28.7 [16.5, 42.9]
t1/2, hr
6.2 [5.5, 16.3]
7.4 [3.3, 9.5]
7.7 [5.1, 9.4]
Plasma#
N
12
12
9
Tmax*, hr
12.0 [4.3, 24.5]
12.0 [7.5, 24.2]
12.3 [4.3, 75.9]
Cmax, mcg/mL
1.3 [0.2, 3.9]
1.9 [0.2, 4.3]
1.0 [0.03, 2.6]
AUC0-t, mcg‑hr/mL
16.2 [1.1, 69.9]
40.1 [11.1, 78.9]
9.5 [0.2, 51.6]
CSF/Plasma
Ratio
N
11
12
9
Cmax
1200 [305, 4530]
809 [202, 9370]
1320 [541, 51200]
AUC0-t
393 [115, 1910]
340 [126, 1780]
1330 [167, 38900]
*Tmax expressed as time since start of ~4.5 hour infusion.
#Vss, CL, and t1/2 were not estimated due to insufficient plasma pharmacokinetic data
The estimated CSF volume of distribution of cerliponase alfa following intraventricular infusion of 300 mg of Brineura (median Vss = 245 mL) exceeds the typical CSF volume (100 mL).
Cerliponase alfa is a protein and is expected to be degraded through peptide hydrolysis.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, genotoxicity, and fertility studies have not been performed with cerliponase alfa. Based on the mechanism of action, cerliponase alfa is not expected to be tumorigenic.
14 CLINICAL STUDIES
The efficacy of Brineura was assessed over 96 weeks in a non-randomized single-arm dose escalation clinical study with extension in symptomatic pediatric patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, confirmed by TPP1 deficiency. Brineura-treated patients were compared to untreated patients from a natural hi |
