Summary Basis of Decision for Brineura
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Brineura is located below.
Recent Activity for Brineura
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Brineura
Date SBD issued: 2019-05-09
The following information relates to the new drug submission for Brineura.
Cerliponase alfa
Drug Identification Number (DIN):
- DIN 02484013 - 150 mg/5mL, solution, intracerebroventricular infusion
BioMarin International Ltd.
New Drug Submission Control Number: 216539
On December 19, 2018, Health Canada issued a Notice of Compliance to BioMarin International Limited for the drug product Brineura.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Brineura is favourable for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease, also known as tripeptidyl peptidase 1 (TPP1) deficiency.
1 What was approved?
Brineura is an enzyme replacement therapy that contains the active substance cerliponase alfa. Brineura was authorized for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease, also known as tripeptidyl peptidase 1 (TPP1) deficiency.
Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of Brineura in pediatric patients have been established; therefore, Health Canada has authorized an indication for pediatric use.
Data for geriatric use were not available to Health Canada. Consequently, Health Canada has not authorized an indication for geriatric use.
Brineura is contraindicated in:
- CLN2 patients with ventriculo-peritoneal shunts.
- Patients with signs of acute intracerebroventricular access device complications e.g., leakage, device failure, or device-related infection.
- Patients who have severe hypersensitivity reactions to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Brineura was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Brineura (150 mg/5mL, cerliponase alfa) is presented as a solution. In addition to the medicinal ingredient, the solution contains calcium chloride dihydrate, magnesium chloride hexahydrate, potassium chloride, sodium chloride, sodium dihydrogen phosphate monohydrate, sodium phosphate dibasic heptahydrate, and water for injection. The Flushing Solution (FS) is a sterile solution composed of the same ingredients, at the same concentrations, as the Brineura drug product, with the exception of the active ingredient.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Brineura Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Brineura approved?
Health Canada considers that the benefit-risk profile of Brineura is favourable for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease, also known as tripeptidyl peptidase 1 (TPP1) deficiency.
Neuronal ceroid lipofuscinosis type 2 is a rare, rapidly progressing, irreversible, neurodegenerative disease caused by mutations of the CLN2/TPP1 gene that result in accumulation of lysosomal storage materials in the central nervous system (CNS) and other tissues. The onset of disease symptoms is approximately at the age of 2 to 4 years. Untreated patients have a rapid, severe neurodegenerative course resulting in progressive and irreversible language decline, ambulation loss, involuntary movements, seizures, bulbar dysfunction, blindness, and death during childhood. The estimated worldwide prevalence of CLN2 disease is less than 1 per million people. The incidence is approximately 0.5 per 100,000 live births worldwide, and 9 per 100,000 live births in Newfoundland.
Brineura (cerliponase alfa) is a recombinant form of human TPP1 administered by intracerebroventricular (ICV) infusion. It is expected to restore TPP1 enzyme activity in the CNS of CLN2 patients and attenuate the progression of the disease. Brineura is administered through an ICV device that is surgically implanted prior to treatment initiation. Devices compatible with Brineura treatment are available for marketing in Canada; a specific device was not included or reviewed as part of this drug submission. There was no treatment in Canada that could cure or halt the symptoms in CLN2 disease patients. Seizures may be controlled or reduced with anti-epileptic drugs. Physical, speech, and occupational therapies may help affected patients to some extent.
Brineura has been shown to be efficacious in patients with CLN2 disease. The market authorization was based on an open-label, dose-escalation clinical study and an ongoing long-term extension study. The primary efficacy endpoint was the proportion of patients with an absence of an unreversed two-point decline on a disease-specific clinical rating scale for the motor and language functions. Efficacy was demonstrated at Week 48 of the open-label study where 87% of the patients met the primary endpoint. The proportion of patients with no decline at both Week 48 and Week 96 was 83% and showed durability of treatment effect.
The major risks associated with Brineura treatment were severe or life-threatening device-related infections and meningitis. The most common adverse events (AEs) were pyrexia (71%), vomiting (63%) and seizure (58%). The most common serious AE was hypersensitivity (29%). There were no deaths during the clinical development program. Given the poor prognosis of this disease, the safety profile of Brineura is considered acceptable with the appropriate labelling and post-market monitoring that has been put in place through the Brineura Risk Management Plan (RMP).
The RMP for Brineura was submitted by BioMarin International Limited to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Brineura Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Brineura was accepted.
Overall, the therapeutic benefits of Brineura therapy seen in the pivotal study are positive and are considered to outweigh the potential risks. The identified safety issues can be managed through labelling, and adequate monitoring. Warnings and precautions are in place in the Brineura Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Brineura?
The drug submission for Brineura was reviewed under the Priority Review Policy. Brineura demonstrated a significant increase in effectiveness with an improved benefit-risk profile compared to existing therapies for neuronal ceroid lipofuscinosis type 2 (CLN2) a condition that is not adequately managed by a drug marketed in Canada.
Submission Milestones: Brineura
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2017-11-22 |
| Request for priority status | |
| Filed: | 2018-02-28 |
| Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics: | 2018-03-23 |
| Submission filed: | 2018-05-25 |
| Screening | |
| Screening Acceptance Letter issued: | 2018-06-22 |
| Review | |
| Review of Risk Management Plan complete: | 2018-10-12 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-12-14 |
| Quality Evaluation complete: | 2018-12-18 |
| Clinical Evaluation complete: | 2018-12-19 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2018-12-19 |
The Canadian regulatory decision on the non-clinical and clinical review of Brineura was based on a critical assessment of the data package submitted to Health Canada. The foreign review documentation from the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) was used as an added reference for the quality evaluation.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Neuronal ceroid lipofuscinosis type 2 (CLN2) disease, also known as tripeptidyl peptidase 1 (TPP1) deficiency, is a neurodegenerative disease caused by deficiency of the lysosomal enzyme TPP1, which catabolizes polypeptides in the central nervous system (CNS). The enzyme 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 CNS, leading to progressive decline in motor function.
The active ingredient of Brineura, cerliponase alfa (recombinant human [rh] TPP1, 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 mannose-6-phosphate/ insulin-like growth factor type 2 [M6P/IGF2] receptor). Cerliponase alfa is activated in the lysosome and the activated proteolytic form of rhTPP1 cleaves tripeptides from the N-terminus of proteins.
The pharmacokinetics (PK) of cerliponase alfa was assessed following intracerebroventricular administration of 30, 100, or 300 mg over 4 hours once every 2 weeks (Q2W). Cerebrospinal fluid (CSF) drug concentrations reached maximum values (Cmax) 15 minutes post-infusion (Tmax) and subsequently declined with a mean half-life of approximately 7 hours. The plasma cerliponase alfa concentration was approximately 1000-fold lower than in the CSF and Cmax was reached at approximately 12 hours post-infusion. Dose proportionality in plasma could not be assessed. At the proposed dose regimen of 300 mg Q2W, the exposure data showed no accumulation of cerliponase alfa in the CSF and plasma. Across the three study visits over 13 weeks, cerliponase alfa PK parameters exhibited high inter- and intra-subject variability.
Anti-drug antibodies (ADA) were detected in 8/24 subjects (33%) in the CSF and 19/24 (79%) in the serum following cerliponase alfa treatment for 97-157 weeks. There was no apparent effect of serum or CSF ADA on the plasma or CSF pharmacokinetics, respectively. However, a conclusive assessment of the impact of immunogenicity on the PK of cerliponase alfa could not be conducted due to the limited number of patients and the high variability in PK parameters.
Overall, the clinical pharmacology data support the use of Brineura for the specified indication.
For further details, please refer to the Brineura Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Brineura was assessed over 96 weeks in an open-label, dose-escalation clinical study (Study 190-201; 48 weeks) and an ongoing long-term extension study (Study 190-202; 48 weeks) in patients with CLN2 disease compared to untreated patients with CLN2 disease, confirmed by TPP1 deficiency, from a natural history database (natural history control group).
Twenty-three patients, aged 3 to 8 years were treated in the Brineura single-arm clinical study and continued treatment during the ongoing extension period (Study 190-202) at the maximum amount of 300 mg Q2W to a maximum of 145 weeks. Sixty-three percent of patients were female and 37% were male.
The primary efficacy endpoint of Study 190-201 and Study 190-202 was the proportion of patients with an absence of an unreversed two-point decline, or score of zero in the CLN2 rating scale. This scale is an adaptation of the Hamburg and the Weill Cornell Medical College CLN2 scales and it only considers the motor and language domains which ranges from 0 to 6 when combined (Motor plus Language score). A score of 0 represents no function and a score of 6 represents normal function (3 for each of the two domains).
Findings from Study 190-201 and Study 190-202 were compared with an expected rate of decline based on a natural history control group that included patients that satisfied the inclusion criteria for those studies. Results from the natural history control group demonstrated an estimated mean rate of decline in the CLN2 score of 2 points per 48 weeks. There were differences in the manner in which the CLN2 clinical rating scales were implemented between the natural history database and both studies (Study 190-201 and Study 190-202). The clinical review team considered these limitations acceptable for the primary efficacy analysis.
In Study 190-201, 20 of the 23 (87%) patients who received Brineura for 48 weeks did not have an unreversed two-point decline (p = 0.0002), demonstrating the efficacy of the treatment. The proportion of patients with no decline at both Week 48 (Study 190-201) and Week 96 (Week 48 of extension Study 190-202) was 83% and showed durability of treatment effect. These results have been included in the Brineura Product Monograph.
Indication
The New Drug Submission for Brineura was filed by the sponsor with the following indication:
- Brineura (cerliponase alfa) is indicated for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease, also known as tripeptidyl peptidase 1 (TPP1) deficiency.
Health Canada recommended the following indication:
- Brineura (cerliponase alfa injection) is indicated for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease, also known as tripeptidyl peptidase 1 (TPP1) deficiency.
For more information, refer to the Brineura Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Brineura was evaluated in 24 patients with CLN2 disease who received at least one dose of 300 mg of Brineura, in a non-randomized, single-arm, dose-escalation clinical study with an extension, up to 161 weeks (Study 190-201 and Study 190-202). As of the cut-off date of November 1, 2016, 24 patients (2-8 years of age) who had mild to moderate CLN2 were exposed to Brineura 300 mg dose for a mean duration of 115 weeks.
The most common adverse events (AEs) were pyrexia (71%), vomiting (63%), and seizure (58%). The most common serious AE was hypersensitivity (29%). One patient, with a serious AE of postoperative intracranial hemorrhage, discontinued treatment due to an inability to comply with the investigation protocol. No patients discontinued Brineura due to an AE and no patients died during the clinical development program. Other relevant AEs were device-related (infections, device leakage, failure, etc.), meningitis (1 case of grade 4 meningitis post-marketing), electrocardiogram (ECG) abnormalities, and immunogenicity.
Device-related infections and meningitis were severe or life-threatening and required immediate medical attention. Hypersensitivity reactions, convulsions, and ECG abnormalities were manageable with appropriate medical management and/or monitoring.
Given the poor prognosis of this disease (vegetative state and death), the safety profile of Brineura is considered acceptable with the appropriate labelling and post-market monitoring that has been put in place through the Brineura Risk Management Plan. Warnings and precautions are in place in the approved Brineura Product Monograph to address the identified safety concerns.
For more information, refer to the Brineura Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The results of the non-clinical studies as well as the potential risks to humans have been included in the Brineura Product Monograph. In view of the intended use of Brineura, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
In disease animal models, the active ingredient of Brineura, cerliponase alfa, was shown to significantly delay signs of CLN2 disease progression in both rodent (TPP1-KO mice) and non-rodent (TPP1-null dachshund dogs) models. Improvements in various clinically translatable pharmacological endpoints, including motor function, gait, cognitive function, brain morphology, and overall lifespan were observed.
Following repeat-dose administration, adverse effects related to the delivery device, the development of anti-drug antibodies, and an increasing frequency and severity of hypersensitivity reactions were observed. In the main repeat-dose toxicity study, the lowest-observed-adverse-effect level (LOAEL) was equivalent to a human dose greater than the recommended dose of 300 mg.
Warnings and precautions are in place in the Brineura Product Monograph to address the identified safety concerns.
For more information, refer to the Brineura Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Brineura (cerliponase alfa) is an enzyme replacement therapy indicated for the treatment of neuronal CLN2 disease, also known as TPP1 deficiency. Brineura is a recombinant form of human tripeptidyl peptidase-1 (rhTPP1). Brineura (rhTPP1) is produced as an enzymatically inactive pro-enzyme (a 544 amino acid long zymogen) that is activated in vivo following uptake into the lysosome. Activated rhTPP1 can metabolize the accumulated lysosomal proteinaceous storage materials and reduce disease-related inflammation.
The drug product is a sterile, preservative-free, solution for intracerebroventricular infusion with a cerliponase alfa concentration of 30 mg/mL in a 10 mL glass vial (containing 150 mg/5 mL).
Characterization of the Drug Substance
Detailed characterization studies were performed to provide assurance that the drug substance, cerliponase alfa, consistently exhibits the desired characteristic structure and biological activity.
The drug substance manufacturing process has been scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.
Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The manufacturing process of the drug substance consists of a series of stages which include cell culture, harvest, recovery, and purification. The purification process includes viral inactivation/removal steps and a combination of chromatographic steps. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use. In-process controls and lot release tests for the drug substance were established and validated.
The manufacturing process of the drug product includes thawing of the drug substance, pooling of bottles from the same drug substance lot, sterile filtration, filling, stoppering/capping, 100% visual inspection, freezing, labelling and packaging. The drug product manufacturing process was validated using consecutive commercial scale batches. All process parameters, in process controls, and release testing results for the drug product were consistent between the validation batches and within specification limits, demonstrating that the proposed drug product commercial scale manufacturing process is capable of consistently manufacturing a drug product which meets pre-established specifications.
The Flushing Solution manufacturing process was appropriately validated, with all IPC and release results for the validation batches meeting the pre-established acceptance criteria and specifications, respectively.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against a suitable reference standard to verify that they meet approved specifications. Analytical procedures are validated in accordance with International Council for Harmonisation (ICH) guidelines.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were assessed using a subset of release methods. These methods are acceptable for their intended purposes.
Brineura is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf life at -25°C to -15°C for the drug product is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through stability studies. The container closure system met all validation test acceptance criteria.
Facilities and Equipment
The designs, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.
On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of cerliponase alfa was deferred.
An OSE of the facility involved in the manufacture and testing of the drug product Brineura was not warranted.
Both sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The cerliponase alfa manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.
All raw materials used in the manufacturing process of the drug product are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BRINEURA | 02484013 | BIOMARIN INTERNATIONAL LIMITED | CERLIPONASE ALFA 150 MG / 5 ML |