Summary Basis of Decision for Kanuma

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Kanuma is located below.

Recent Activity for Kanuma

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.

Post-Authorization Activity Table (PAAT) for Kanuma

Updated: 2023-11-29

The following table describes post-authorization activity for Kanuma, a product which contains the medicinal ingredient sebelipase alfa. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

  • DIN 02469596 - 2 mg/mL, sebelipase alfa, solution, intravenous administration
  •  

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 267618

2022-09-02

Issued NOC 2023-10-11

Submission filed as a Level I – Supplement to update the PM with a change to the recommended starting dose for Kanuma from 1 mg/kg of body weight per week to 1 or 3 mg/kg of body weight per week in the subgroup of patients with rapidly progressive lysosomal acid lipase deficiency (LAL‑D) presenting within the first 6 months of life, and to provide guidance for dose escalation in pediatric and adult LAL‑D patients. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration section of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 267715

2022-09-08

Issued NOC 2023-04-28

Submission filed as a Level I – Supplement for the addition of a drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

PBRER-C # 246097

2020-11-06

Filed 2023-02-15

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C #8, #9, and #10 for the period 2019-08-29 to 2022-08-28. The information was reviewed and found acceptable.

SNDS-C # 244429

2020-09-25

Issued NOC 2021-09-08

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The submission filed data to remove conditions 2) I-III of the NOC/c-QN issued November 07, 2017 for NDS # 204085, with condition 2) I being changed to a post-market commitment. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed and an NOC was issued.

SNDS # 235924

2020-02-07

Issued NOC 2020-09-21

Submission filed as a Level I – Supplement for the addition of a drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

PBRER-C # 233278

2019-11-06

Cleared 2020-06-02

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C #7 for the period 2018-08-29 to 2019-08-28. The information was reviewed and found acceptable.

SNDS-C # 236842

2020-03-05

Cancellation Letter Received 2020-04-24

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The submission filed data to remove conditions 2) II-III of the NOC/c-Qualifying Notice (NOC/c-QN) issued November 07, 2017 for NDS # 204085. The submission also provided an expanded indication and the final study reports for studies LAL-CL01 and LAL-EA01, which was outside the scope of the conditions set out the NOC/c-QN. Thus, Health Canada requested that the sponsor withdraw the SNDS-C and refile with only information requested in the NOC/c-QN and to refile the additional items separately. The submission was cancelled by the sponsor.

NC # 231309

2019-09-05

Issued NOL 2019-12-03

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf-life of a drug substance intermediate. The submission was reviewed and considered acceptable, and an NOL was issued.

PBRER-C # 221725

2018-11-06

Cleared 2019-05-03

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER C #5 and #6 for the period 2017-08-29 to 2018-08-28. The information was reviewed and found acceptable.

Drug product (DIN 02469596) market notification

Not applicable

Date of first sale: 2018-04-05

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 204085

2017-03-23

Issued NOC under NOC/c Guidance 2017-12-15

Notice of Compliance issued under the NOC/c Guidance for New Drug Submission.
 
Summary Basis of Decision (SBD) for Kanuma

Date SBD issued: 2018-02-09

The following information relates to the New Drug Submission for Kanuma.

Sebelipase alfa
2 mg/mL solution, intravenous

Drug Identification Number (DIN):

  • 02469596

Alexion Pharma GmbH

New Drug Submission Control Number: 204085

 

On December 15, 2017, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Alexion Pharma GmbH for the drug product Kanuma. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Kanuma is favourable for the treatment of infants, children, and adults diagnosed with lysosomal acid lipase (LAL) deficiency.

 

1 What was approved?

 

Kanuma (sebelipase alfa) is a recombinant human lysosomal acid lipase. Lysosomal acid lipase catalyzes the hydrolysis of cholesteryl esters to free cholesterol and fatty acids and the hydrolysis of triglycerides to glycerol and free fatty acids.

Lysosomal acid lipase (LAL) deficiency is characterized by the loss of lysosomal acid lipase enzyme activity and leads to the accumulation of cholesteryl esters and triglycerides in various tissues and cell types throughout the body.

Kanuma was authorized for the treatment of infants, children, and adults diagnosed with LAL deficiency.

Kanuma treatment should be supervised by a healthcare professional experienced in the management of patients with LAL deficiency, other metabolic disorders, or chronic liver diseases. Kanuma should be administered by a trained healthcare professional who can manage medical emergencies.

Kanuma is contraindicated in patients who are diagnosed with life-threatening hypersensitivity to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Kanuma 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.

Kanuma (2 mg/mL sebelipase alfa) is presented as solution. In addition to the medicinal ingredient, the solution contains trisodium citrate dihydrate, citric acid monohydrate, human serum albumin, and water for injections.

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 Kanuma Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Kanuma approved?

 

Health Canada considers that the benefit-risk profile of Kanuma is favourable for the treatment of infants, children, and adults diagnosed with lysosomal acid lipase (LAL) deficiency. Kanuma was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further evaluations to confirm the clinical benefit.

Lysosomal acid lipase (LAL) deficiency is a rare, serious, and potentially fatal autosomal recessive monogenic disorder. Deficient LAL enzyme activity results in the lysosomal accumulation of cholesteryl esters and triglycerides. In the liver, this accumulation leads to increased hepatic fat content, and progression to fibrosis, cirrhosis, and complications of end-stage liver disease. Lipid accumulation in the intestinal wall leads to malabsorption and growth failure. Dyslipidemia due to impaired degradation of lysosomal lipid is common with elevated low-density lipoprotein (LDL) and triglycerides and low high-density lipoprotein (HDL). In Canada, there are no currently authorized treatments for LAL deficiency.

The market authorization with conditions was based on two ongoing pivotal studies. Interim data were submitted from Study LAL-CL02, a multicentre, double-blind, placebo-controlled study in 66 children and adults with LAL deficiency; and Study LAL-CL03, a multicentre, open-label, single-arm study in 9 patients with LAL deficiency with growth failure or other evidence of rapidly progressive disease prior to 6 months of age. In order to confirm the effectiveness of the product, final study reports will be submitted for evaluation to Health Canada as part of the post-approval commitments.

The interim results from Study LAL-CL02 showed a significantly greater improvement in lipid parameters including low-density lipoprotein cholesterol (LDL-c) at the completion of the 20-week, double-blind period of the study in patients treated with Kanuma compared to patients treated with placebo. A reduction in LDL-c likely represents a clinical benefit in this patient population since patients with LAL deficiency exhibit dyslipidemia and are at risk for atherosclerosis. Therefore, even though the effects of the observed improvements in lipid parameters on cardiovascular morbidity and mortality have yet to be established, the efficacy results are considered promising. An improvement in liver chemistry was also observed in the patients treated with Kanuma. However, it is unclear how this improvement relates to liver disease progression in patients with LAL deficiency.

In infants, LAL deficiency is also known as Wolman disease and is a rapidly progressive disease especially if the affected infants present with early growth failure (before 6 months of age). These infants rarely survive beyond the first year of life. In Study LAL-CL03, 6 out of 9 Kanuma-treated infants with rapidly progressive LAL deficiency and growth failure within the first 6 months of age survived to 12 months, compared to 0 of 21 infants in the historical cohort from an observational study.

In both studies, the safety profile of Kanuma was found to be acceptable and consistent with other enzyme replacement therapies, with infusion-associated reactions and immunogenicity being the clinically relevant risks. These risks appear manageable and have been addressed through appropriate labelling in the Kanuma Product Monograph.

In view of the promising survival outcome in infants with LAL deficiency which is considered rare and life-threatening, the improvements in lipid parameters observed in children and adults, and the manageable safety profile of Kanuma, the overall benefit-risk profile of Kanuma is considered favourable.

A Risk Management Plan (RMP) for Kanuma was submitted by Alexion Pharma GmbH 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.

To support a favourable long-term benefit-risk profile of Kanuma in patients with LAL deficiency, in addition to the submitted RMP, the results of 5 ongoing studies (LAL-CL02, LAL-CL03, LAL-CL04, LAL-CL06 and LAL-CL08) and reports from the patient registry are required as conditions for market authorization. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Kanuma will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available. See What follow-up measures will the company take?

A Look-alike Sound-alike brand name assessment was performed and the proposed name Kanuma was accepted.

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 Kanuma?

 

The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the new drug submission for Kanuma. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness that the drug has the potential to provide effective treatment of a disease or condition for which no drug is presently marketed in Canada.

 

Submission Milestones: Kanuma

Submission Milestone Date
Pre-submission meeting: 2016-12-06
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: 2017-02-01
Submission filed: 2017-03-23
Screening  
Screening Acceptance Letter issued: 2017-04-21
Review  
Quality Evaluation complete: 2017-11-06
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued: 2017-11-07
Review of Response to NOC/c-QN:  
Response filed (Letter of Undertaking): 2017-11-17
Labelling Review complete: 2017-12-14
Clinical Evaluation complete: 2017-12-15
Notice of Compliance (NOC) issued by Director General, Biologics and Genetic Therapies Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance: 2017-12-15

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Kanuma was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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?

 

In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide the following:

  • A Supplement to a New Drug Submission- Confirmatory (SNDS-C) by December 2019 which will include final clinical study reports for Studies LAL-CL02, LAL-CL03, LAL-CL04, LAL-CL06 and LAL-CL08, including
    • A table showing the completion of the above ongoing studies and whether or not the primary and key secondary endpoints have been met. If the studies were not completed, a rationale for the delay and revised completion date will be provided. If the primary and key secondary endpoints were not achieved, a rationale for failing to meet the endpoints should be included.
    • An evaluation of the benefit-risk profile of Kanuma based on the data from the clinical study reports.
    • A determination of any change to the benefit-risk profile of Kanuma for patients with lysosomal acid lipase (LAL) deficiency. Infants with rapidly progressive LAL deficiency and children/adults with LAL deficiency are to be evaluated separately.
    • The identification of any new safety signals. An assessment will be provided to determine whether the risk mitigation strategies remain adequate for safe use of Kanuma, or if additional risk mitigation strategies are required and the implementation plan for these additional strategies.
  • Annual interim reports and the final report of the ongoing patient registry to Health Canada. The sponsor agrees to submit the results of the registry commitment made to the United States Food and Drug Administration (FDA) as a clinical study report in an SNDS-C submission by April 30, 2030.

Safety Monitoring

The sponsor has agreed to provide Health Canada with the following:

  • Status reports on the progress of the ongoing confirmatory studies on an annual basis, within 60 calendar days of the market authorization anniversary or a date agreed upon at the time of issuance of market authorization. Safety updates for all on-going clinical studies with Kanuma will be included.
  • Reports of serious adverse reactions. Annual Periodic Benefit-Risk Evaluation Reports for NOC/c Products will be submitted.
  • Any updates to the Risk Management Plan when available.
  • Copies of any marketing authorizations or other regulatory activities for Kanuma from other regulatory authorities on a timely basis.
  • Medical educational materials for Kanuma.

The sponsor agrees to revise the Kanuma Product Monograph as updated information becomes available.

 

5 What post-authorization activity has taken place for Kanuma?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (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. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Kanuma is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

The medicinal ingredient of Kanuma, sebelipase alfa, is a recombinant human lysosomal acid lipase (rhLAL). The primary site of action of the lysosomal acid lipase (LAL) enzyme is the lysosome, where the enzyme normally causes the breakdown of lipid particles including low-density lipoprotein cholesterol (LDL-c).

Deficient LAL enzyme activity results in the lysosomal accumulation of cholesteryl esters and triglycerides. In the liver, this accumulation leads to increased hepatic fat content, and progression to fibrosis, cirrhosis, and complications of end stage liver disease. Lipid accumulation in the intestinal wall leads to malabsorption and growth failure. Dyslipidemia due to impaired degradation of lysosomal lipid is common with elevated low-density lipoprotein (LDL), triglycerides, and low high-density lipoprotein (HDL).

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Kanuma for the specified indication.

The pharmacokinetic profile of sebelipase alfa was nonlinear with a greater than dose-proportional increase in exposure between 1 and 3 mg/kg based on non-compartmental analysis of data from 9 adults. No accumulation was observed following once-weekly or once every other week dosing.

After multiple-dose, once-weekly administration of sebelipase alfa in 9 adult subjects with LAL deficiency, the median apparent volume of distribution (Vz) parameter decreased as the dose increased. The lower Vz at higher doses indicates that more sebelipase alfa was in the systemic circulation at the higher doses. The plasma elimination of sebelipase alfa was rapid at all doses with no consistent changes over time.

There was limited information on the impact of anti-drug antibodies on sebelipase alfa pharmacokinetics.

The pharmacokinetic profile in infants (<6 months of age) could not be characterized due to limited pharmacokinetic data.

Overall, the data from the submitted clinical pharmacology studies are considered sufficient and there are no major concerns to prevent the market authorization of Kanuma for the specified indication.

For further details, please refer to the Kanuma Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Kanuma was based on interim data from two ongoing pivotal studies (LAL-CL02 and LAL-CL03) in patients with LAL deficiency. The study results were submitted to support the use of this drug under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further evaluations to confirm the clinical benefit. The drug submission also included two observational studies (LAL-1-NH01 and LAL-2-NH01) to provide historical control and background data for this rare disease.

Study LAL-CL02 in children and adults

Study LAL-CL02 was a multicentre, double-blind, placebo-controlled study in 66 children and adults with LAL deficiency. Patients were randomized to receive Kanuma at a dose of 1 mg/kg (number of patients [n] = 36) or placebo (n = 30) once every other week for 20 weeks in the double-blind period. Patients were stratified for potential confounders (age, alanine aminotransferase [ALT] levels and use of lipid-lowering medications). After completing the double-blind period, each patient had open-label treatment with Kanuma at a dose of 1 mg/kg during the extension period. The age range at randomization was 4-58 years old (71% were <18 years old). For study entry, patients were required to have ALT levels of ≥1.5 times the upper limit based on age and gender specific normal ranges of the central lab performing the assay, on two consecutive measurements at least 1 week apart. The majority of patients (58%) had LDL-c >4.9 mmol/L (>190 mg/dL) at study entry, and 24% of the patients with LDL-c >4.9 mmol/L (>190 mg/dL) were on lipid-lowering medicinal products.

The results showed a significantly greater improvement in lipid parameters including LDL-c at the completion of the 20-week double-blind period of the study in patients treated with Kanuma compared to patients treated with placebo.

A reduction in LDL-c likely represents a clinical benefit in this patient population since patients with LAL deficiency exhibit dyslipidemia and are at risk for atherosclerosis. Therefore, even though the effects of the observed improvements in lipid parameters on cardiovascular morbidity and mortality have yet to be established, the efficacy results based on the lipid parameters are considered promising.

An improvement in liver chemistry and liver fat content (as measured by MRI) was also observed in Kanuma-treated patients in comparison to patients treated with placebo. However, the significance of these findings as they relate to liver disease progression in patients with LAL deficiency has not been established.

Study LAL-CL03 in infants

Study LAL-CL03 was a multicentre, open-label, single-arm study of Kanuma in 9 patients with LAL deficiency with growth failure or other evidence of rapidly progressive disease prior to 6 months of age. The age range at study entry was 1-6 months. Patients received Kanuma 0.35 mg/kg once weekly for the first 2 weeks and then 1 mg/kg once weekly. Due to suboptimal clinical response, all 6 surviving patients received a dose escalation to 3 mg/kg once weekly which occurred between 4 and 88 weeks (median 11 weeks) after starting treatment at 1 mg/kg. One patient, who had a suboptimal growth response at 3 mg/kg in association with the presence of neutralising antibodies, received a dose increase to 5 mg/kg once weekly.

Efficacy was assessed by comparing the survival experience of 9 patients treated with Kanuma who survived past 12 months of age with a historical cohort of 21 untreated infants with similar ages presented with LAL deficiency with similar clinical characteristics. In Study LAL-CL03, 6 of 9 infants treated with Kanuma survived beyond 12 months (67% with a 12-month survival, 95% confidence interval [CI]: 30% to 93%) compared to the historical cohort in which none of the 21 patients survived beyond 8 months of age (0% with a 12-month survival, 95% CI: 0% to 16%). With continued treatment beyond 12 months of age, 1 additional patient died at 15 months of age. The median age of the 5 surviving Kanuma-treated patients was 20.4 months (range 15.7 to 42.2 months), based on a data cutoff date of June 10, 2014.

Although this pivotal study was an open-label study involving only 9 infants with LAL deficiency with a historical comparator, the effects of Kanuma in prolonging the survival beyond 12 months were considered both clinically significant and relevant given the rarity of the disease and the early mortality in these infants.

Indication

The New Drug Submission for Kanuma was filed by the sponsor with the following indication:

  • Kanuma (sebelipase alfa), is indicated for long-term enzyme replacement therapy (ERT) in patients with lysosomal acid lipase (LAL) deficiency.

To ensure safe and effective use of the product, Health Canada approved the following indication:

  • Kanuma (sebelipase alfa), is indicated for the treatment of infants, children and adults diagnosed with lysosomal acid lipase (LAL) deficiency.

Approval was based on survival outcome in infants with LAL deficiency which is considered rare and life-threatening, and on the improvements in lipid parameters observed in children and adults with LAL deficiency.

Kanuma has been issued marketing authorization with conditions, pending the results of trials to verify its clinical benefit. Further evaluation will take place upon the submission of the requested studies after they become available. See What follow-up measures will the company take?

For more information, refer to the Kanuma Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety assessment of Kanuma was mainly based on interim data from two ongoing pivotal studies (LAL-CL02 and LAL-CL03) in patients with LAL deficiency. Both studies are discussed in the Clinical Efficacy section.

In Study LAL-CL02, 66 children and adult patients with LAL deficiency aged 4 to 58 years (33 males, 33 females) received Kanuma 1 mg/kg every other week up to 36 weeks. The most common adverse reactions that occurred in ≥8% of children and adult patients with LAL deficiency who received Kanuma at a dosage of 1 mg/kg once every other week during the 20-week double-blind treatment period were headache (number of patients[ n] = 10), fever (n = 9), oropharyngeal pain (n = 6), nasopharyngitis (n = 4), asthenia (n = 3), constipation (n = 3), and nausea (n = 3). Five (14%) Kanuma-treated patients developed anti-drug antibodies (ADA) to Kanuma.

In Study LAL-CL03, 9 infants (5 males, 4 females) who had growth failure or other evidence of rapidly progressive LAL deficiency presented within the first 6 months of life received Kanuma for up to 165 weeks (median 60 weeks) at escalating doses ranging between 0.35 mg/kg and 5 mg/kg once weekly. The most common adverse reactions that occurred in ≥30% of the patients were diarrhea (n = 6), vomiting (n = 6), fever (n = 5), rhinitis (n = 5), anemia (n = 4), cough (n = 3), nasopharyngitis (n = 3), and urticarial (n = 3). Four (57%) of 7 infants developed ADA to Kanuma. Hypersensitivity reactions occurred in all 4 of the ADA-positive infants. In 1 infant, decreased growth velocity in a setting of neutralizing antibodies to Kanuma was observed.

There were 6 clinical studies of Kanuma, including 1 completed study (LAL-CL01) and 5 ongoing studies (LAL-CL02, LAL-CL03, LAL-CL04, LAL-CL06, and LAL-CL08). To date, 1 of 14 infants (7%) and 2 of 92 children/adults (2%) treated with Kanuma experienced signs and symptoms consistent with anaphylaxis. Signs and symptoms consistent with or that may be related to a hypersensitivity reaction were reported in 9 of 14 infants (64%) and 12 of 92 children/adults (13%).

Overall, Kanuma appeared to be tolerated by infants, children, and adults with LAL deficiency. No drug-related deaths were reported. Three deaths (hepatic failure, cardiac arrest and peritoneal hemorrhage following abdominal paracentesis) which occurred during the study were not considered to be associated with Kanuma by the investigators. The risks (hypersensitivity and immunogenicity) associated with Kanuma were manageable.

In Canada, there is currently no market authorized therapy for patients diagnosed with LAL deficiency which is considered rare and life-threatening. In view of the promising survival outcome in infants with LAL deficiency, the improvements in lipid parameters observed in children and adults, and the manageable safety profile of Kanuma, it is considered that the overall benefits of Kanuma outweigh the risks.

In order to verify the clinical benefit of Kanuma, study results from five ongoing studies (LAL-CL02, LAL-CL03, LAL-CL04, LAL-CL06 and LAL-CL08) and data from the patient registry are required as conditions for authorization.

To help mitigate the risk, appropriate warnings and precautions are in place in the approved Kanuma Product Monograph to address the identified safety concerns.

For more information, refer to the Kanuma Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical toxicology and pharmacology studies support the use of sebelipase alfa, the medicinal ingredient of Kanuma, for the specified indication.

In repeat-dose toxicity studies conducted in rats and monkeys, no sebelipase alfa-related adverse effects were observed following once-weekly intravenous administration of sebelipase alfa. In 4-week studies, the no-observed-adverse-effect level (NOAEL) was 50 mg/kg body weight in both rats and monkeys, equivalent to area under the curve (AUC) values of 267- and 310-fold greater than the human AUC value of 1,387 ng•h/mL (at 1 mg/kg body weight once every other week), respectively. In a 6-month study conducted in monkeys, the NOAEL was 30 mg/kg body weight, equivalent to an AUC value 766-fold greater than the human AUC value. In all studies, the NOAEL was the highest dose tested.

In safety pharmacology studies, no respiratory adverse effects in rats or cardiovascular adverse effects in monkeys were observed following single intravenous doses of sebelipase alfa of up to 50 mg/kg body weight. In addition, no central nervous system adverse effects were observed in rats following once-weekly intravenous administration for 4 weeks at doses up to 50 mg/kg body weight.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Kanuma Product Monograph. In view of the intended use of Kanuma there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Kanuma Product Monograph to address the identified safety concerns.

For more information, refer to the Kanuma Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The medicinal ingredient of Kanuma, sebelipase alfa, is a recombinant human lysosomal acid lipase (rhLAL) produced in a transgenic chicken system with the protein secreted into egg whites.

Lysosomal acid lipase is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of cholesteryl esters to free cholesterol and fatty acids and the hydrolysis of triglycerides to glycerol and free fatty acids. It is supplied as a sterile, preservative-free, non-pyrogenic aqueous solution in single-use vials for intravenous infusion.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that sebelipase alfa consistently exhibits the desired characteristic structure and biological activity.

The drug substance manufacturing process has been optimized and 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.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

The drug substance, sebelipase alfa, is produced in the egg white of transgenic Gallus by recombinant deoxyribonucleic acid (rDNA) technology.

A comprehensive system for managing and maintaining transgenic chickens has been developed. The management system includes state-of-the art production facilities and biosecurity measures, general husbandry practices (including reproductive management), animal health management, control of adventitious agents and specific pathogens, and confirmation of transgenic animal genetic stability.

Sebelipase alfa is purified from egg whites using conventional chromatographic, nanofiltration, and ultrafiltration/diafiltration methods used in recombinant protein purification to produce a formulated drug substance.

The drug product, Kanuma, is sterile filtered and aseptically filled using conventional aseptic filling equipment and facilities.

In-process controls and lot release tests for the drug substance and drug product were established, and release methods were suitably validated.

The materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered suitable and meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Through Health Canada's lot release testing and evaluation program, representative final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

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 2°C to 8°C for the drug product is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance was waived as other biologics are manufactured there and additional satisfactory batch data was provided.

OSEs of the facilities involved in the manufacture and testing of the drug product were not warranted as other biologics are manufactured there and there have been no reported issues.

The production sites are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The sebelipase 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.

 

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