Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: BioMarin International Limited, Shanbally, Ringaskiddy, County Cork, Ireland
Pharmacotherapeutic group: other alimentary tract and metabolism products, enzymes
ATC code: A16AB17
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 safety and efficacy of Brineura were assessed in an open label, dose escalation clinical study (190-201) and an ongoing long term extension study (190-202) in patients with CLN2 disease compared to untreated patients with CLN2 disease from a natural history database (natural history control group). These studies used the aggregate of the motor and language domains of a disease-specific clinical rating scale (see Table 3) to assess disease progression. Each domain encompasses scores of 3 (grossly normal) to 0 (profoundly impaired), for a total possible score of 6, with unit decrements representing milestone events in the loss of previously attained functions of ambulation and speech.
Table 3. CLN2 Clinical Rating Scale:
| Domain | Score | Rating |
|---|---|---|
| Motor | 3 | Grossly normal gait. No prominent ataxia, no pathologic falls. |
| 2 | Independent gait, as defined by ability to walk without support for 10 steps. Will have obvious instability, and may have intermittent falls. | |
| 1 | Requires external assistance to walk, or can crawl only. | |
| 0 | Can no longer walk or crawl. | |
| Language | 3 | Apparently normal language. Intelligible and grossly age-appropriate. No decline noted yet. |
| 2 | Language has become recognizably abnormal: some intelligible words, may form short sentences to convey concepts, requests, or needs. This score signifies a decline from a previous level of ability (from the individual maximum reached by the child). | |
| 1 | Hardly understandable. Few intelligible words. | |
| 0 | No intelligible words or vocalizations. |
A total of 24 patients, aged 3 to 8 years, were treated with Brineura 300 mg every other week. In study 190-201, 23 patients were treated for 48 weeks (1 patient withdrew after week 1 due to the inability to continue with study procedures). The mean baseline CLN2 score was 3.5 (standard deviation (SD) 1.20) with a range from 1 to 6; no patients with advanced disease progression were studied (inclusion criteria: mild to moderate progression of CLN2 disease). All 23 patients completed study 190-201 and continued to the ongoing extension study 190-202 treated with Brineura at 300 mg every other week to a maximum of 124 weeks.
Findings from studies 190-201 and 190-202 were compared with a natural history control group that included patients that satisfied the inclusion criteria for studies 190-201 and 190-202. Results from the natural history control group demonstrate CLN2 disease is a rapidly progressive neurodegenerative disease with predictable decline in motor and language function with an estimated mean rate of decline in the CLN2 score of 2 points per 48 weeks.
Treatment effect in patients receiving Brineura was assessed using the CLN2 clinical rating scale, and results were compared to the 2 points per 48 weeks predicted decline in the natural history control group. In study 190-201, 20 out of 23 (87%) patients receiving Brineura for 48 weeks did not have an unreversed 2 point decline as observed in the untreated patient population (p=0.0002, binomial test assuming p0=0.50). A total of 15 patients out of 23 (65%) had no overall decline in CLN2 score, irrespective of baseline score, and 2 of these 15 patients increased their score by one point during the treatment period. Five patients experienced a single point decrease, and 3 patients experienced a 2 point decrease.
In study 190-201, the mean rate of decline in patients treated with Brineura at 300 mg every other week was 0.40 points per 48 weeks. When compared to the expected rate of decline based on natural history, the study results are statistically significant (p<0.0001) (see Table 4). The observed treatment effect was considered clinically meaningful in light of the natural history of untreated CLN2 disease.
Table 4. 0 to 6 Point Motor-Language CLN2 Clinical Rating Scale: Rate of Decline over 48 weeks (Intent to Treat (ITT) population):
| Rate of Decline (points/48 weeks)a | Overall (n=23) | p-valueb |
|---|---|---|
| Mean (SD) | 0.40 (0.809)c | <0.0001 |
| Median | 0.00 | |
| Min, Max | -0.88, 2.02 | |
| 95% CI Limits | 0.05, 0.75 |
a Patient rate of decline per 48 weeks: (baseline CLN2 score – last CLN2 score) / (time elapsed in units of 48 weeks)
b p-value based on 1-sample T-test comparing rate of decline to the value 2
c Positive estimates indicate clinical decline; negative estimates indicate clinical improvement
In the ongoing study 190-202 (as of 03 June 2016), the rate of decline in patients treated with Brineura compared to the natural history control group (N=42 patients) continues to show durability of the treatment effect (see Figure 2).
Figure 2. CLN2 Score Mean Change from Baseline (Natural History Control Group vs Brineura treated patients, 300 mg every other week):
Vision and seizure scores when combined with CLN2 score (motor and language domains) remain stable. MRI volumetry measurements show attenuated rate of loss.
It is important to initiate treatment in children as young as possible, although patients less than 3 years of age were not included in the pivotal study.
Study 190-203 is an ongoing open label clinical study evaluating the safety and efficacy in patients from birth to 18 years of age. Posology was based upon analysis of differences in brain mass values for children less than 3 years of age. So far safety results in younger patients appears consistent with the safety profile observed in older children. Currently no clinical experience of Brineura in children below 2 years of age is available (see section 4.8).
The European Medicines Agency has deferred the obligation to submit the results of studies with Brineura in one or more subsets of the paediatric population in CLN2 (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
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 Table 5 below. Cerliponase alfa plasma pharmacokinetics were assessed in 13 patients, and a median Tmax of 12.0 hours (since start of infusion), a mean Cmax of 1.39 μg/ml, and mean AUC0-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.
Table 5. Pharmacokinetic properties following first Intracerebroventricular infusion (approximately 4 hours in duration) of 300 mg cerliponase alfa in CSF:
| Parameter | CSF (N=17) Mean (SD) |
|---|---|
| Tmax*, hr | 4.50 [4.25, 5.75] |
| Cmax, µg/ml | 1490 (942) |
| AUC0-t, µg-hr/ml | 9510 (4130) |
| Vz, ml | 435 (412) |
| CL, ml/hr | 38,7 (19.8) |
| t1/2, hr | 7.35 (2.90) |
* Tmax expressed as time since start of ~4 hour infusion and presented as median [min, max], and occurred at the first sampling timepoint post infusion
The estimated volume of distribution of cerliponase alfa following intracerebroventricular infusion of 300 mg (Vz=435 ml) exceeds the typical CSF volume (100 ml), suggesting distribution to tissues outside the CSF. The large CSF to plasma ratios in Cmax and AUC0-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.
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.
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