Cerliponase alfa

Cerliponase alfa is a recombinant form of human tripeptidyl peptidase-1 (rhTPP1). Cerliponase alfa is a proteolytic inactive proenzyme (zymogen) that is activated in the lysosome. Cerliponase alfa is taken up by target cells and translocated to the lysosomes through the Cation Independent Mannose-6-Phosphate Receptor (CI-MPR, also known as M6P/IGF2 receptor). The glycosylation profile of cerliponase alfa results in consistent cellular uptake and lysosomal targeting for activation.

The activated proteolytic enzyme (rhTPP1) cleaves tripeptides from the N-terminus of the target protein with no known substrate specificity. Inadequate levels of TPP1 cause CLN2 disease, resulting in neurodegeneration, loss of neurological function and death during childhood.

The pharmacokinetics of cerliponase alfa were evaluated in patients with CLN2 disease who received intracerebroventricular infusions of 300 mg over approximately 4.5 hours once every other week.

All pharmacokinetic parameters were similar following the initial infusion on Day 1 and following infusions at Week 5 and Week 13, indicating no apparent accumulation or time dependent PK of cerliponase alfa in CSF or plasma when administered at of dose of 300 mg once every other week. The pharmacokinetic parameters in CSF were assessed in 17 patients and are summarized in the table below. Cerliponase alfa plasma pharmacokinetics were assessed in 13 patients, and a median T_max of 12.0 hours (since start of infusion), a mean C_max of 1.39 μg/ml, and mean AUC_0-t of 24.1 μg-hour/ml were characterized. There was no apparent effect of serum or CSF ADA on the plasma or CSF pharmacokinetics, respectively.

Pharmacokinetic properties following first Intracerebroventricular infusion (approximately 4 hours in duration) of 300 mg cerliponase alfa in CSF:

* T_max expressed as time since start of ~4 hour infusion and presented as median [min, max], and occurred at the first sampling timepoint post infusion

Distribution

The estimated volume of distribution of cerliponase alfa following intracerebroventricular infusion of 300 mg (V_z=435 ml) exceeds the typical CSF volume (100 ml), suggesting distribution to tissues outside the CSF. The large CSF to plasma ratios in C_max and AUC_0-t (approximately 1000 and 400, respectively) suggest that the majority of administered cerliponase alfa remains localized within the CNS. Intracerebroventricular administration of cerliponase alfa is not expected to result in therapeutic concentrations in the eye due to the limited access from the CSF to the affected cells of the retina and the presence of the blood-retinal barrier.

Elimination

Cerliponase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of cerliponase alfa. Renal elimination of cerliponase alfa is considered a minor pathway for clearance.

Limited preclinical safety data of cerliponase alfa were generated from single dose toxicity studies in monkeys and repeated-dose studies in a dachshund dog model of classic late infantile neuronal ceroid lipofuscinosis type 2. This disease model primarily served to investigate the pharmacodynamic and pharmacokinetic properties of cerliponase alfa, but also aimed to evaluate the toxicity of the substance. However, the results of these studies in dachshund dogs cannot reliably predict human safety, because the regimen of cerliponase alfa infusions was different and highly variable even within the same study due to difficulties with the indwelling catheter system and prominent hypersensitivity reactions. In addition, these investigations included very small animal numbers, mostly tested single dose groups and lacked appropriate controls. Thus, the non-clinical development is inconclusive with respect to the clinical safety of cerliponase alfa. Genotoxicity, carcinogenicity and reproductive toxicity investigations have not been performed.