Summary Basis of Decision for Aimovig

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 Aimovig is located below.

Recent Activity for Aimovig

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 Aimovig

Updated: 2024-04-05

The following table describes post-authorization activity for Aimovig, a product which contains the medicinal ingredient erenumab. 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 02479605 - 70 mg/mL erenumab solution, prefilled syringe, subcutaneous administration
  • DIN 02479613 - 70 mg/mL erenumab solution, prefilled autoinjector, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 279528

2023-09-29

Issued NOL 2023-12-041

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release or shelf-life specifications .The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 271915

2023-01-30

Issued NOC 2023-10-06

Submission filed as a or Level I – Supplement for a change in the drug product manufacturing process to increase the maximum drug product batch size for the 70 mg/mL and 140 mg/mL strengths. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 276212

2023-06-13

Cancellation Letter Received 2023-08-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release or shelf-life specifications. A number of issues were identified with the submission during review, and the submission was cancelled by the sponsor.

NC # 274659

2023-04-24

Issued NOL 2023-06-29

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug product (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 265234

2022-06-15

Issued NOC 2022-12-12

Submission filed as a Level I – Supplement for updates to the inner and outer labels for the pre-filled syringe presentation. The submission was reviewed and considered acceptable, and an NOC was issued

SNDS # 264464

2022-05-20

Issued NOC 2022-10-27

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 260920

2022-01-28

Issued NOL 2022-04-12

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the shelf life for the drug product and in the labelled storage conditions for the drug product or the diluted or reconstituted product. The submission was considered acceptable, and an NOL was issued.

NC # 258954

2021-11-23

Issued NOL 2022-02-11

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls (in‐process tests and/or acceptance criteria) applied during the drug product manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.

Summary Safety Review

Not applicable

Posted 2021-12-08

Summary Safety Review posted for Aimovig (erenumab) (Assessing the Potential Risks of Non-Fatal Stroke, Non-Fatal Heart Attack and Cardiovascular Death).

NC # 256829

2021-09-24

Issued NOL 2021-11-02

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product release or shelf‐life specifications. The submission was considered acceptable, and an NOL was issued.

SNDS # 246916

2020-11-30

Issued NOC 2021-03-23

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information, and to the package insert. An NOC was issued.

New safety and effectiveness review

Not applicable

Started between 2020-11-01 and 2020-11-30

Health Canada started a new safety and effectiveness review for Aimovig related to cardiac (heart related) events.

SNDS # 238511

2020-04-17

Issued NOC 2020-08-12

Submission filed as a Level I – Supplement to update the inner and outer labels and package inserts for the 70 mg/mL and 140 mg/mL pre-filled auto-injector presentations. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 235623

2020-01-29

Issued NOL 2020-04-22

Submission filed as a Level II (90 day) Notifiable Change to update the PM with safety information. As a result of the NC, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 229875

2019-07-19

Issued NOC 2020-02-27

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

NC # 231041

2019-08-23

Issued NOL

2019-11-18

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions; Adverse Reactions; and Dosage Forms, Strengths, Composition and Packaging sections of the PM. Corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 224431

2019-02-01

Issued NOL

2019-05-23

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 219765

2018-08-31

Issued NOC

2019-04-11

 

Délivrance d’un AC

Submission filed as a Level I - Supplement to seek authorization for a 140 mg/mL strength of Aimovig (erenumab injection) and to update the Aimovig Product Monograph to include information regarding the 140 mg/mL strength. Regulatory Decision Summary published.

Drug product (DIN 02479613) market notification

Not applicable

Date of first sale:

2018-12-04

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

NDS # 208607

2017-08-18

Issued NOC

2018-08-01

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Aimovig

Date SBD issued: 2018-12-19

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

Erenumab
70 mg/mL, solution, subcutaneous

Drug Identification Number (DIN):

  • DIN 02479605 - 70 mg/mL solution, prefilled syringe
  • DIN 02479613 - 70 mg/mL solution, prefilled autoinjector

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 208607

 

On August 1, 2018, Health Canada issued a Notice of Compliance (NOC) to Novartis Pharmaceuticals Canada Inc. for the drug product Aimovig. Amgen Canada Inc. originally filed the New Drug Submission (NDS) for Aimovig, and transferred all Canadian rights to Novartis Pharmaceuticals Canada Inc. while the submission was in review.

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 Aimovig is favourable for the prevention of migraine in adults who have at least 4 migraine days per month. Aimovig should be initiated by physicians experienced in the diagnosis and treatment of migraine.

 

1 What was approved?

 

Aimovig, an anti-calcitonin gene-related peptide receptor (anti-CGRPR), was authorized for the prevention of migraine in adults who have at least 4 migraine days per month. Aimovig should be initiated by physicians experienced in the diagnosis and treatment of migraine.

Aimovig is not approved for pediatric use. The safety and efficacy of Aimovig have not been studied in pediatric or geriatric patients (<18 years of age and ≥65 years of age, respectively).

Aimovig is contraindicated in patients who are hypersensitive to erenumab or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Aimovig 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.

Aimovig (70 mg/mL erenumab) is presented as a solution in a prefilled syringe or in a prefilled autoinjector. In addition to the medicinal ingredient, erenumab, the solution contains glacial acetic acid, polysorbate 80, sucrose, water for injection, and sodium hydroxide.

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

 

2 Why was Aimovig approved?

 

Health Canada considers that the benefit-risk profile of Aimovig is favourable for the prevention of migraine in adults who have at least 4 migraine days per month.

Migraine is a common disabling primary headache disorder manifesting as recurring severe headaches that are generally associated with nausea and light and/or sound sensitivity. It is a common disorder that affects up to 12 percent of the population and is a significant cause of morbidity. In Canada, at least 2.6 million women and almost 1 million men experience migraine, making migraine the most common type of headache and one of the most common reasons for patients seeking help from family physicians.

A comprehensive approach to migraine management involves lifestyle modification along with acute and prophylactic treatments, as appropriate. Acute pharmacologic therapies for migraine include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, triptans and ergotamine derivatives. Some patients may be prescribed opioids as acute therapy. Prophylactic treatments include beta blockers, tricyclic antidepressants, antiepileptics, angiotensin converting enzyme inhibitors and angiotensin receptor blockers. The decision to use a specific medication is based on individual patient history, other comorbid conditions, and patient tolerability of adverse events. At present, there is a single biologic product (onabotulinum toxin) authorized for chronic migraine prophylaxis in Canada.

The market authorization for Aimovig was based on two pivotal clinical studies which demonstrated its efficacy and safety for preventing migraine in adults. These two studies were very similarly designed, with the main differences being the frequency of migraine experienced by the patients, and the duration of the study. Study 20120295 was a 12-week-long Phase II trial focused on patients with chronic migraine. This condition was defined as having a history of 15 or more days of headache per month; at least eight of which are migraine days. Study 20120296 was a Phase III trial lasting 24 weeks. Patients enrolled in this study experience episodic migraine, which was defined as four to 14 migraine days per month.

Both studies were randomized, double-blind and placebo-controlled, and enrolled adult patients (18-65 years of age). Patients in each study were randomized to one of three groups: receiving either 140 mg or 70 mg Aimovig subcutaneously once per month or a placebo subcutaneously once per month. The primary endpoint evaluated in both studies was the change in patients' monthly migraine days (MMD) from study initiation to the last four weeks of the treatment period (12 weeks for Study 20120295, and 24 weeks for Study 20120296). These two studies had consistent outcomes, which indicated that patients who received Aimovig experienced a statistically significant decrease in mean MMD versus patients who received the placebo. Additionally, it should be noted that in both studies, the decrease in mean MMD was similar in patients receiving 70 mg or 140 mg per month. This suggests comparable efficacy between the two dosage strengths.

The most common adverse events observed during the clinical trials were mild injection-site reactions, and constipation, muscle spasms, and pruritus of mild to moderate severity. The frequency of reported adverse events was consistent across the different treatment groups.

The safety and efficacy of Aimovig in special populations (pregnant and breast-feeding women, pediatric and geriatric patients) are unclear due to the lack of clinical data. Non-clinical data showed that erenumab crosses the placental barrier, which is consistent with other immunoglobulin G (IgG) antibodies. Although results of animal studies are not necessarily reflective of those from clinical trials, pregnant women are advised to avoid using Aimovig. As antibodies may also be excreted in human milk, women are recommended not to nurse and take Aimovig concurrently, and to consult with a healthcare professional to determine which activity should be continued. Additionally, Aimovig is not approved for use in pediatric patients, and has not been studied in pediatric or geriatric populations (<18 years of age and ≥65 years of age, respectively).

The use of any therapeutic antibody also presents the risk of immunogenicity. During clinical development, the immunogenicity of Aimovig was monitored by conducting immunoassays on patient sera to test for the presence of ADAs. Positive results were followed by a second assay to specifically detect the ADAs which produced a neutralizing effect. The incidence of ADA development in both pivotal studies was low - it occurred in 6.3% of patients receiving the 70 mg dose, and in 2.6% of patients receiving the 140 mg dose. ADA development did not affect the efficacy or safety of Aimovig during clinical trials.

Aimovig has an acceptable safety profile in the populations in which it was studied, based on the non-clinical and clinical data. The identified safety issues can be managed through labelling. Appropriate warnings and precautions are in place in the Aimovig Product Monograph to address the identified safety concerns.

A Risk Management Plan (RMP) for Aimovig was submitted by Novartis Pharmaceuticals Canada Inc. to Health Canada, and was considered acceptable upon review. The RMP describes known and potential safety issues, presents the monitoring scheme, and when needed, describes 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 Aimovig 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 Aimovig was accepted. The Patient Medication Information leaflet for both the prefilled syringe and the autoinjector will be consistent with the approved Canadian Product Monograph.

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 Aimovig?

 

Submission Milestones: Aimovig

Submission Milestone Date
Pre-submission meeting: 2017-03-30
Submission filed: 2017-08-18
Screening  
Screening Acceptance Letter issued: 2017-10-06
Review  
Quality Evaluation complete: 2018-08-01
Clinical Evaluation complete: 2018-07-26
Biostatistics Evaluation complete: 2018-07-26
Review of Risk Management Plan complete: 2018-05-11
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-07-31
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2018-08-01

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Aimovig was based on a critical assessment of the data package submitted to Health Canada. Review reports from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were consulted for relevant supplementary information.

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?

 

As part of the marketing authorization for Aimovig, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) providing Health Canada with the following:

  • Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRERs), including but not limited to all serious adverse events for Aimovig every six months for the first three years, and annually thereafter. Each PSUR/PBRER should include an analysis of all Adverse Drug Events as per the Pharmacovigilance Plan.
  • Pregnancy registry data as per the commitment made to the United States Food and Drug Administration (FDA).

 

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

 

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 life cycle.

The PAAT for Aimovig 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

Erenumab, the medicinal ingredient in Aimovig, is a recombinant human monoclonal antibody. It competes with the calcitonin gene-related peptide (CGRP) for binding to the CGRP receptor and antagonizes CGRP receptor function. Erenumab has no significant activity at adrenomedullin, calcitonin, or amylin receptors.

In pharmacokinetic studies, erenumab displayed dose proportionality over a dose range from 70 mg to 140 mg. Peak serum concentrations occur four to six days after subcutaneous administration of erenumab, at each of these doses. Experimental data also suggest that erenumab remains primarily in the blood stream, with a limited amount distributed to other tissues of the body. Higher exposure levels were observed with the 140 mg dose than with the 70 mg dose. However, similar efficacy was observed between these two doses.

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

Clinical Efficacy

The clinical efficacy and safety of Aimovig were established in two pivotal trials - one in chronic migraine patients, and the other in episodic migraine patients.

Study 20120295 examined the effects of Aimovig on chronic migraine, which was defined as a history of 15 or more days of headache per month; at least eight of which are migraine days. This was a phase II, randomized, double-blind, placebo-controlled trial conducted in adult patients (18-65 years of age) over a 12-week period. The primary efficacy endpoint was the change in monthly migraine days (MMD), from study initiation to the last four weeks of the treatment period. Patients were randomized to one of three treatment groups: to receive 140 mg Aimovig, 70 mg Aimovig, or a placebo subcutaneously once per month. Results showed a statistically significant decrease in mean MMD in Aimovig-treated patients, compared to those receiving the placebo. Both dosage strengths reduced mean MMD by approximately 2.5 days.

Study 20120296 assessed the ability of Aimovig to treat episodic migraine. Participants in this study were adult patients (18-65 years of age) who experience migraines four to 14 days per month. This phase III, randomized, double-blind, placebo-controlled study was conducted over a 24-week period. Similarly to the trial with chronic migraine patients, patients in this study received 140 mg Aimovig, 70 mg Aimovig, or a placebo subcutaneously once per month. The primary efficacy endpoint was the change in MMD from study initiation to the last three months of the treatment period. The conclusions of this study were consistent with those of the study in chronic migraine patients (Study 20120295). There was a statistically significant reduction in mean MMD in Aimovig-treated patients versus placebo-treated patients. Both dosage strengths appeared to have similar efficacy in this patient population as well; reducing mean MMD by approximately 1.5 days.

Collectively, the study outcomes demonstrate the efficacy of Aimovig in treating both chronic and episodic migraine.

Recommended Dose

The New Drug Submission for Aimovig was filed by the sponsor with a recommended dose of 140 mg, administered once per month. This would require two consecutive injections of 70 mg each, using the single dose prefilled autoinjectors or single dose prefilled syringes.

It was determined during the clinical review that when assessed across the two studies, the 70 mg and 140 mg doses elicited comparable therapeutic effects when administered at the same frequency and by the same route of administration. To ensure safe and effective use of Aimovig, Health Canada approved a dose of 70 mg once per month. Although some patients may benefit from a starting dose of 140 mg once per month, the clinical trial results indicated that the 70 mg dose is most appropriate for the vast majority of patients. This decision is further discussed in the Clinical Safety section.

Indication

Sponsor's proposed indication Health Canada-approved indication
Aimovig (erenumab) is indicated for prevention of migraine in adults. Aimovig (erenumab) is indicated for prevention of migraine in adults who have at least 4 migraine days per month.

Aimovig should be initiated by physicians experienced in the diagnosis and treatment of migraine.

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

Clinical Safety

The outcomes of studies 20120295 and 20120296 have established both the clinical efficacy and safety of Aimovig in adults with chronic or episodic migraine, and are described in the Clinical Efficacy section.

The efficacy of Aimovig relative to the placebo was successfully established in the pivotal studies. However, it was not evident that the 140 mg dose had improved efficacy over the 70 mg dose. Serum concentrations of erenumab in patients receiving 140 mg Aimovig were 2.2- to 2.5-fold higher than those of patients receiving 70 mg Aimovig, but the increased exposure did not lead to increased efficacy. In each pivotal study, the reduction in mean monthly migraine days (MMD) was similar between patients receiving the 70 mg dose and those receiving the 140 mg dose. There is also a significantly greater amount of safety data available for the 70 mg dose than for the 140 mg dose. Collectively, these results provide strong evidence that the 70 mg dose is sufficient to achieve the intended therapeutic effect, and that the 140 mg dose would not provide further benefit for the vast majority of patients. Certain patients may experience improved efficacy with the 140 mg dose; particularly those with a history of chronic migraine and who have failed several prophylactic treatments. However, this is not applicable to the general population of migraine patients, for whom the 70 mg dose is adequate.

Erenumab, the medicinal ingredient in Aimovig, achieves its therapeutic effect by binding to calcitonin gene-related peptide (CGRP) receptors. This inhibits CGRP from binding to these receptors and effectively blocks an interaction which contributes to migraine pathophysiology. CGRP is a potent vasodilator, and may cause cardiovascular and other vascular adverse events. It is theoretically possible that these adverse events may be experienced during treatment with Aimovig. To address this concern, a supportive study was conducted to examine the safety of Aimovig used concurrently with sumatriptan, another vasoactive substance. No differences were detected in resting blood pressure when both drugs were taken together, or when sumatriptan was administered alone. Additionally, observations of cardiovascular and other vascular adverse events were evenly distributed among Aimovig-treated and placebo-treated patients.

Two deaths were reported across all clinical trials; one in the pivotal trial with episodic migraine patients, and the other in a supportive open-label study. Both deaths were related to cardiac issues, and were further investigated due to the ability of CGRP to produce cardiovascular adverse events. Further investigation revealed that neither of these deaths was caused by treatment with Aimovig. One patient had taken cardiac stimulants, and the other patient had an underlying genetic condition that led to complications.

Treatment with any therapeutic antibody is associated with the inherent risk of immunogenicity. This refers to the development of anti-drug antibodies (ADAs), which have the potential to neutralize the therapeutic protein and compromise its efficacy. During the clinical trials, the development of ADAs was monitored by conducting immunoassays on patient sera. For positive results, a second assay was performed specifically to detect neutralizing ADAs. A low incidence of ADAs was observed in the clinical trials. In the pivotal studies, ADAs were detected in 6.3% of patients (56/884) receiving the 70 mg dose, and in 2.6% of patients (13/504) receiving the 140 mg dose. The three patients who tested positive for neutralizing ADAs received the 70 mg dose. ADA development was not associated with any negative effects on the safety or efficacy of erenumab during clinical trials.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor is believed to contribute to migraine pathophysiology. Erenumab, the medicinal ingredient in Aimovig, blocks this interaction by competitively binding to the CGRP receptors and inhibiting their function. This was initially demonstrated in non-clinical studies. Additionally, erenumab did not display a similar activity at adrenomedullin, calcitonin, or amylin receptors, suggesting selective binding to the CGRP receptor.

In vivo studies were carried out in cynomolgus monkeys, as they are a relevant species for measuring pharmacological parameters. Following a single 225 mg/kg dose, neurobehavioural, respiratory, and cardiovascular endpoints were assessed, and no adverse events were observed. A repeat-dose toxicology study was conducted with sexually mature cynomolgus monkeys, at exposures up to 123-fold greater than the anticipated exposure in humans. No adverse effects were observed that could be attributed to erenumab.

Results of an enhanced pre- and postnatal developmental study revealed that erenumab crosses the placental barrier. Gestating animals were monitored from gestation day 20 to 22 to parturition, and infants were monitored for up to six months after birth. Following maternal exposure 17-fold higher than the anticipated exposure in humans, no adverse effects were observed on pregnancy, embryo-fetal development, or postnatal development. However, erenumab was detected in infant monkeys at birth and during the postnatal period, indicating that it travelled through the placental barrier. Even though no adverse effect was seen in animal studies, based on this observation, pregnant women are advised not to use Aimovig as a precautionary measure.

No carcinogenicity or genotoxicity studies were performed.

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

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

Erenumab is a recombinant human immunoglobulin G2 (IgG2) monoclonal antibody directed against calcitonin gene-related peptide (CGRP) receptors, and it competes with CGRP to bind to these sites.

Comprehensive characterization studies were carried out to verify that erenumab consistently exhibits the expected structure and biological activity essential to its function. The physicochemical, biological and immunological properties of erenumab, including confirmation of its purity and stability, were all examined using appropriate analytical procedures and found to be satisfactory.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The characterized impurities were found to be within acceptable limits.

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

The drug substance, erenumab, is produced in Chinese hamster ovary (CHO) cells using recombinant deoxyribonucleic acid (DNA) technology. The recombinant DNA from which erenumab is expressed is introduced into CHO cells from well-characterized master and working cell banks. These cells were found to be genetically stable, and have been tested for adventitious contaminants and endogenous viruses according to International Council for Harmonisation (ICH) guidelines.

The drug substance manufacturing process consists of a series of steps: cell culture, harvest, purification, formulation and sterile filtration. The materials used in the manufacture of the drug substance are considered to meet standards appropriate for their intended use.

The drug product manufacturing process involves thawing and pooling of the drug substance, and adjustment of the concentration to 70 mg/mL. This is followed by bioburden reduction, sterile filtration, and aseptic filling into glass syringes. The prefilled syringes are then transported at 2-8ºC to a third facility for assembly, labelling and packaging. The materials used in the manufacture of the drug product are considered to meet standards appropriate for their intended use.

Changes to the manufacturing process and formulation made throughout pharmaceutical development were examined during review and found to be acceptable. Analytical comparability studies accompanied each major change, to verify that it would not compromise product quality, safety, or efficacy.

The manufacturing processes were validated through examination of consecutively manufactured lots of both the drug substance and the drug product. Each drug product lot was divided into separate prefilled syringe and autoinjector fills and release tested for quality. The outcomes of the process validation and batch analyses provided strong evidence that each manufacturing site is capable of consistently producing the drug substance or drug product to an acceptable standard. All analytical methods used for in-process, stability, and release testing of the drug substance and drug product were validated and qualified.

Aimovig is a clear to opalescent and colourless to light yellow solution for subcutaneous administration. The pH of the solution is 5.2. One single-use prefilled syringe or prefilled autoinjector contains 70 mg of erenumab. In addition, each prefilled syringe or autoinjector contains the following excipients: glacial acetic acid, polysorbate 80, sucrose, water for injection, and sodium hydroxide.

Control of the Drug Substance and Drug Product

The erenumab manufacturing process includes an appropriate control strategy that adequately ensures the quality of the drug substance and drug product. All analytical procedures used for in-process, stability, and release testing of the drug substance and drug product were validated and qualified, in compliance with International Council for Harmonisation (ICH) guidelines. The drug substance and drug product were tested against suitable reference standards to verify that they meet approved specifications.

Aimovig 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. Through this program, consecutively manufactured final drug product lots were tested and evaluated. They were found to meet the drug product release specifications and demonstrate consistency in manufacturing.

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.

Aimovig remains stable for 24 months at 5ºC ± 3ºC. If the product is in use, it may be stored at room temperature (up to 25ºC) for up to 14 days, and it must be protected from light. The container closure systems used for both presentations of Aimovig (1 mL prefilled glass syringe and autoinjector) were found to be capable of preserving the integrity and quality of the drug product in these storage conditions.

Facilities and Equipment

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

Satisfactory On-Site Evaluations (OSEs) were recently conducted at both the drug substance and drug product manufacturing facilities in connection with other submissions to Health Canada. Based on the risk evaluation performed and compliance with Good Manufacturing Practices at both manufacturing sites, OSEs were waived during the review of Aimovig.

Adventitious Agents Safety Evaluation

The erenumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate viruses are validated and highly effective for their intended purpose.

Dialyzed fetal bovine serum (dFBS), which is of animal origin, was used during early cell line development. A Certificate of Suitability was included in the New Drug Submission, confirming that dFBS used in connection with the manufacturing of Aimovig does not pose a risk for bovine spongiform encephalopathy or transmissible spongiform encephalopathy (BSE or TSE).

 

Report a problem or mistake on this page
Please select all that apply:
Date modified: