Summary Basis of Decision for Ajovy

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 Ajovy is located below.

Recent Activity for Ajovy

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Ajovy, a product which contains the medicinal ingredient fremanezumab. 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.

Updated: 2024-02-01

Drug Identification Number (DIN):

DIN 02497859 - 225 mg fremanezumab in 1.5 mL (150 mg/mL), solution, subcutaneous administration, single-dose prefilled syringe

DIN 02509474 - 225 mg fremanezumab in 1.5 mL (150 mg/mL), solution, subcutaneous administration, single-dose prefilled autoinjector

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 278800

2023-09-01

Issued NOL 2023-11-02

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

NC # 262919

2022-03-30

Issued NOL 2022-06-22

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an extension of the reference standard shelf-life or retest period for the drug substance. The submission was considered acceptable, and an NOL was issued.

NC # 254585

2021-07-06

Issued NOL 2021-08-11

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

SNDS # 245209

2020-10-16

Issued NOC 2021-04-23

Submission filed as a Level I – Supplement to update the PM with efficacy data from the pivotal trail (Study TV48125-CNS-30068 [FOCUS]) in adults with migraine who failed 2 to 4 classes of prior preventive treatment of migraine. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued.

Drug product (DIN 02509474) market notification

Not applicable

Date of first sale: 2021-04-01

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

SNDS # 239000

2020-04-30

Issued NOC 2020-12-15

Submission filed as a Level I – Supplement for the addition of an auto-injector presentation to the already authorized pre-filled syringe presentation. The submission was reviewed and considered acceptable, and an NOC was issued and a new DIN (02509474) was issued for the new presentation.

Drug product (DIN 02497859) market notification

Not applicable

Date of first sale: 2020-08-04

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

NC # 239144

2020-05-05

Issued NOL 2020-05-28

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 239079

2020-05-05

Issued NOL 2020-05-28

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 reviewed and considered acceptable, and an NOL was issued.

NDS # 226828

2019-05-01

Issued NOC 2020-04-09

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Ajovy

Date SBD issued: 2020-06-15

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

Fremanezumab

Drug Identification Number (DIN):

  • DIN 02497859 - 225 mg in 1.5 mL (150 mg/mL), solution, subcutaneous administration

Teva Canada Ltd.

New Drug Submission Control Number: 226828

 

On April 9, 2020, Health Canada issued a Notice of Compliance to Teva Canada Limited for the drug product Ajovy.

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 Ajovy is considered favourable for the prevention of migraine in adults who have at least 4 migraine days per month.

 

1 What was approved?

 

Ajovy (fremanezumab) is a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor. It was authorized for the prevention of migraine in adults who have at least 4 migraine days per month.

Treatment with Ajovy should be initiated by health professionals experienced in the diagnosis and treatment of migraine.

Safety and efficacy of Ajovy in patients younger than 18 years of age have not been studied. Consequently, Health Canada has not authorized Ajovy for pediatric use.

Clinical studies of Ajovy did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently to Ajovy than younger subjects.

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

Ajovy 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.

Ajovy (225 mg in 1.5 mL [150 mg/mL] fremanezumab) is presented as a solution. In addition to the medicinal ingredient, the solution contains disodium ethylenediaminetetraacetic acid dihydrate (EDTA), L-histidine, polysorbate 80, sucrose, and water for injection.

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

 

2 Why was Ajovy approved?

 

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

Migraine is a common neurological disorder that affects more than 10% of adults globally. It is characterized by recurrent episodes of headaches, accompanied by associated symptoms such as nausea, vomiting, photophobia, and phonophobia. The headache is often unilateral, of moderate to severe intensity, throbbing, and aggravated by physical activity. Migraine attacks are often disabling and associated with missed activities at work, school, or at home. The prevalence of migraine is highest during peak productive years (i.e., at around 30 to 50 years of age), which maximizes its impact to the sufferer, family, and society.

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, 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, three biologic products are authorized for chronic migraine prophylaxis in Canada: onabotulinumtoxinA (Botox) and two calcitonin gene-related peptide (CGRP) antagonists, erenumab (Aimovig) and galcanezumab (Emgality).

Fremanezumab, the medicinal ingredient in Ajovy, is a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks both CGRP isoforms (α- and β-CGRP) from binding to the CGRP receptor.

Ajovy has been shown to be efficacious when used for prevention of migraine in adults 18 to 65 years of age who experience at least 4 migraine days per month. The market authorization of Ajovy was based on efficacy and safety data derived from two pivotal, multicentre, randomized, double-blind, placebo-controlled, Phase III clinical trials.

Study 1 was conducted in patients with episodic migraine. All patients were randomized (1:1:1) to receive subcutaneous injections of either Ajovy 675 mg once every 3 months (quarterly), Ajovy 225 mg once a month, or placebo once a month, over a 3-month treatment period.

Study 2 involved patients with chronic migraine. All patients were randomized (1:1:1) to receive subcutaneous injections of either Ajovy 675 mg starting dose followed by 225 mg once a month, Ajovy 675 mg every 3 months (quarterly), or placebo once a month, over a 3-month treatment period.

In patients with episodic migraine (Study 1), the results for the primary efficacy endpoint, the mean change from baseline in the monthly average number of migraine days, were -3.4, -3.7, and -2.2 days, for the Ajovy 675 mg quarterly group, the Ajovy 225 mg monthly group, and the placebo group, respectively. The adjusted mean treatment difference was -1.2 days between the Ajovy 675 mg quarterly group and the placebo group (p<0.0001) and -1.4 days between Ajovy 225 mg monthly group and the placebo group (p<0.0001).

In patients with chronic migraine (Study 2), the primary efficacy endpoint was the mean change from baseline in the monthly average number of headache days of at least moderate severity. The results for the primary efficacy endpoint were -4.6, -4.3, and -2.5 days for the Ajovy 675/225/225 mg monthly group, Ajovy 675 mg quarterly group, and placebo group, respectively. The adjusted mean treatment difference was -2.1 between Ajovy 675/225/225 mg monthly group and the placebo group (p<0.0001) and -1.8 days between Ajovy 675 mg quarterly group and the placebo group (p<0.0001).

In both studies, results for key secondary endpoints were supportive of the results for the primary efficacy endpoints.

Although the designs of the pivotal episodic and chronic migraine studies were generally acceptable, the 3-month duration of the trials was not considered sufficient to support a claim of preventive treatment of migraine with sustained efficacy. Therefore, Health Canada requested inclusion of the following recommendations in the Dosage and Administration section of the Ajovy Product Monograph: "The treatment benefit should be assessed within 3 months after initiation of the treatment. Any further decision to continue treatment should be taken on an individual patient basis. Evaluation of the need to continue treatment is recommended regularly thereafter."

The clinical trials demonstrated that Ajovy, at the recommended dosing regimen of 225 mg monthly or 675 mg every 3 months (quarterly), was generally safe and well tolerated in the intended patient population.

The most commonly reported adverse drug reactions were local reactions at the injection site: pain, induration, erythema, and pruritus. Most injection site reactions were transient and predominantly mild to moderate in intensity. Injection site reactions were the most commonly reported adverse drug reactions that led to treatment discontinuation.

Hypersensitivity reactions, including rash, pruritus, and urticaria have been reported in less than 1% of patients receiving Ajovy in the clinical trials and in post-marketing experience. Most reactions were of mild to moderate intensity and occurred from within hours to one month after administration of Ajovy. Some of the reactions led to treatment discontinuation and/or required corticosteroid treatment.

The clinical trials excluded pregnant and lactating women, patients with a history of significant cardiovascular disease, vascular ischemia, or thrombotic events, patients with severe renal impairment, and patients with severe hepatic impairment. Therefore, no safety data are available for these populations.

A Risk Management Plan (RMP) for Ajovy was submitted by Teva Canada Limited to Health Canada. Upon revisions, 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 Ajovy 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 Ajovy was accepted.

Based on the non-clinical data and clinical studies, Ajovy has an acceptable safety profile for the intended patient population. Appropriate warnings and precautions are in place in the Ajovy 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 Ajovy?

 

Submission Milestones: Ajovy

Submission Milestone Date
Pre-submission meetings: 2016-02-16 - 2018-10-23
Submission filed: 2019-05-01
Screening  
Screening Acceptance Letter issued: 2019-06-17
Review  
Review of Risk Management Plan complete: 2020-03-31
Quality Evaluation complete: 2020-04-06
Clinical/Medical Evaluation complete: 2020-04-06
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2020-04-07
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate: 2020-04-09

 

The Canadian regulatory decision on the review of Ajovy 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?

 

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

  • Periodic Benefit Risk Evaluation Reports (PBRERs) for Ajovy should be submitted to Health Canada every 6 months for the first 2 years following authorization.
  • The following adverse events of special interest should be monitored and discussed in the PBRERs: liver toxicity, myocardial infarction, stroke, retinal detachment, and retinal vascular occlusion.
  • The following safety concerns should be monitored for Ajovy: medication errors, Stevens-Johnson syndrome, constipation/serious constipation, hypersensitivity, alopecia, lack of efficacy/effectiveness, and risk of suicidal ideation/behaviour.
  • Any updates to the Risk Management Plan regarding safety concerns, pharmacovigilance activities, and risk minimization measures should be submitted to Health Canada, as soon as they become available.

 

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

 

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 Ajovy 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

Fremanezumab, the medicinal ingredient in Ajovy, is a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor. The relationship between the pharmacodynamic activity and the mechanism(s) by which fremanezumab exerts its clinical effects is unknown.

Fremanezumab exhibited linear pharmacokinetics with exposures proportional to doses following single subcutaneous administrations of 225 mg, 675 mg, or 900 mg. The median time to maximum concentrations (Tmax) was 5 to 7 days.

Following subcutaneous administration of fremanezumab, the estimated apparent clearance was 0.14 L/day (23% coefficient of variation [CV]), the estimated half-life was 30 days (21% CV), and the apparent volume of distribution was approximately 6 L, based on a population pharmacokinetic analysis.

The exposure-response relationship analysis demonstrated similar clinical responses in reduction of migraine and headache days over 3 months for the monthly and quarterly dosing regimens. No relationship was observed between fremanezumab exposure and selected adverse events, including abnormal blood pressure and abnormal heart rate, following the proposed subcutaneous dose regimens.

Pharmacokinetic studies in special populations have not been conducted. Based on the population pharmacokinetic and exposure-response relationship analyses, no dose adjustments are required for fremanezumab.

The clinical pharmacology data support the use of Ajovy for the recommended indication.

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

Clinical Efficacy

The efficacy of Ajovy for the preventive treatment of migraine was evaluated in two multicentre, randomized, double-blind, placebo-controlled, pivotal trials, each with a 3-month treatment period (Study 1 in episodic migraine and Study 2 in chronic migraine).

In both trials, patients were allowed to use acute headache treatments. Randomization was stratified based on sex, country, and baseline preventive migraine medication use (yes, no). The total number of patients who received a concomitant migraine preventive medication during each pivotal trial was pre-specified not to exceed 30% of the total sample size of the study. Overall, 21% of the randomized patients in each pivotal trial received a concomitant migraine preventive medication.

Both pivotal trials excluded patients with a history of significant cardiovascular disease, vascular ischemia, or thrombotic events, such as cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or pulmonary embolism.

Throughout both trials, headache information was captured daily using an electronic headache diary device.

Study 1 (Episodic Migraine)

Study 1 included adults with a history of episodic migraine, i.e., patients who had fewer than 15 headache days per month. In total, 875 patients were randomized in a ratio of 1:1:1 to receive subcutaneous injections of either Ajovy 675 mg every 3 months (quarterly), Ajovy 225 mg monthly, or placebo monthly, over a 3-month treatment period. Of these, 791 (90.4%) patients completed the 3-month double-blind phase.

The primary efficacy endpoint was the mean change from baseline in the monthly average number of migraine days during the 3-month treatment period.

Secondary efficacy endpoints included:

  • the proportion of patients reaching at least a 50% reduction in the monthly average number of migraine days during the 3-month treatment period,
  • the mean change from baseline in the monthly average number of days of use of any acute headache medication during the 3-month treatment period, and
  • the mean change from baseline in the number of migraine days during the first month of the treatment period.

The mean change from baseline in the monthly average number of migraine days was -3.4, -3.7, and -2.2 days, for the Ajovy 675 mg quarterly group, the Ajovy 225 mg monthly group, and the placebo group, respectively. The adjusted mean treatment difference was -1.2 days between the Ajovy 675 mg quarterly group and the placebo group (p<0.0001) and -1.4 days between Ajovy 225 mg monthly group and the placebo group (p<0.0001).

There was also a statistically significant increase in the proportion of patients with a 50% reduction in mean monthly number of migraine days in Ajovy treatment groups, as compared to placebo. During the 12-week treatment period, 44.4% of patients in the Ajovy 675 mg quarterly group and 47.7% of patients in the Ajovy 225 mg monthly group had at least a 50% reduction in the monthly average number of migraine days, compared to 27.9% of patients in the placebo group (p<0.0001).

Significantly greater reductions from baseline in the mean number of days (per month) of use of acute migraine-specific drugs were observed in patients treated with Ajovy than in placebo-treated patients. The reductions were 2.9 days and 3.0 days in the Ajovy quarterly and monthly dosing groups, respectively, compared to 1.6 days in the placebo group (p<0.0001).

Study 2 (Chronic Migraine)

Study 2 enrolled 1,130 adults with a history of chronic migraine, i.e., patients who had 15 or more headache days per month. All patients were randomized in a ratio of 1:1:1 to receive subcutaneous injections of either Ajovy 675 mg starting dose followed by 225 mg monthly (675/225/225 mg), Ajovy 675 mg every 3 months (quarterly), or placebo monthly, over a 3-month treatment period. Of the randomized patients, 1,034 (91.5%) completed the 3-month double-blind phase.

The primary efficacy endpoint was the mean change from baseline in the monthly average number of headache days of at least moderate severity during the 3-month treatment period.

Secondary endpoints included:

  • the mean change from baseline in the monthly average number of migraine days,
  • the proportion of patients reaching at least a 50% reduction in the monthly average number of headache days of at least moderate severity, and
  • the mean change from baseline in the monthly average number of days of use of any acute headache medication.

The mean changes from baseline in the monthly average number of headache days of at least moderate severity were -4.6, -4.3, and -2.5 days for the Ajovy 675/225/225 mg monthly group, Ajovy 675 mg quarterly group, and placebo group, respectively. The adjusted mean treatment difference was -2.1 between Ajovy 675/225/225 mg monthly group and the placebo group (p<0.0001) and -1.8 days between Ajovy 675 mg quarterly group and the placebo group (p<0.0001).

A statistically significant increase in the proportion of patients who had at least a 50% reduction in the monthly average number of headache days of at least moderate severity during the 12-week treatment period was observed in the Ajovy treatment groups relative to placebo. The proportions of these patients were 40.8% in the Ajovy 675/225/225 mg monthly group and 37.6% in the Ajovy 675 mg quarterly group, as compared to 18.1% in the placebo group (p<0.0001).

There were also significantly greater reductions from baseline in the mean number of days per month of acute headache medication use in both groups of Ajovy-treated patients in comparison to placebo-treated patients. The reduction equaled 3.7 days and 4.2 days in the Ajovy quarterly and monthly dosing groups, respectively, as compared to 1.9 days in the placebo group (p<0.0001).

Conclusion

The pivotal clinical studies demonstrated statistically significant improvements in the key efficacy outcomes for both monthly and quarterly dosing regimens of Ajovy as compared to placebo over the 3-month treatment period. However, although the designs of the pivotal episodic and chronic migraine studies were generally acceptable, the treatment duration of 3 months was not considered sufficient to support a claim of preventive treatment of migraine with sustained efficacy. For that reason, Health Canada requested inclusion of the following recommendations in the Dosage and Administration section of the Ajovy Product Monograph: "The treatment benefit should be assessed within 3 months after initiation of the treatment. Any further decision to continue treatment should be taken on an individual patient basis. Evaluation of the need to continue treatment is recommended regularly thereafter."

Indication

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

  • Ajovy (fremanezumab) is indicated for preventive treatment of migraine in adults.

Health Canada revised the proposed indication to reflect the study population in the pivotal studies. In addition, to ensure safe and effective use of the product, a caveat statement related to the initiation of treatment with Ajovy has also been included (as implemented for the other CGRP antagonists authorized in Canada). Accordingly, Health Canada approved the following indication:

  • Ajovy (fremanezumab) is indicated for the prevention of migraine in adults who have at least 4 migraine days per month.
  • Ajovy should be initiated by health professionals experienced in the diagnosis and treatment of migraine.

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

Clinical Safety

The safety of Ajovy was evaluated in 2,512 patients with migraine who received at least one dose of Ajovy. Of these, 1,730 patients were exposed to Ajovy 225 mg monthly or Ajovy 675 mg quarterly for at least 6 months, 775 patients for at least 12 months, and 138 patients for at least 15 months. In Study 1 and 2 (described in the Clinical Efficacy section), 662 patients received Ajovy 225 mg monthly for 12 weeks (with or without a loading dose of 675 mg), and 663 patients received Ajovy 675 mg quarterly for 12 weeks.

The clinical trials excluded pregnant and lactating women, patients with a history of significant cardiovascular disease, vascular ischemia, or thrombotic events, patients with severe renal impairment, and patients with severe hepatic impairment. Therefore, no safety data are available for these populations. However, due to the potent vasodilator properties of the calcitonin gene-related peptide, a risk to patients with cardiovascular risk factors who receive long-term treatment with fremanezumab cannot be excluded.

The most commonly reported adverse drug reactions were local reactions at the injection site: pain, induration, erythema, and pruritus. Most of the injection site reactions were transient and predominantly mild to moderate in intensity. Injection site reactions were the most commonly reported adverse drug reactions that led to treatment discontinuation.

Hypersensitivity reactions, including rash, pruritus, and urticaria have been reported in less than 1% of patients receiving Ajovy in the clinical trials and in post-marketing experience. Most reactions were of mild to moderate intensity and occurred from within hours to one month after administration of Ajovy. Some of the reactions led to treatment discontinuation and/or required corticosteroid treatment.

No deaths were related to Ajovy in patients who participated in Phase II and III clinical trials.

There were no laboratory findings suggestive of a safety risk in patients receiving Ajovy.

The clinical trials demonstrated that Ajovy, at the recommended dosing regimen of 225 mg (one subcutaneous injection) once a month (monthly dosing) or 675 mg every 3 months (quarterly dosing) administered as three consecutive subcutaneous injections of 225 mg, was generally safe and well tolerated in the intended patient population.

Appropriate warnings and precautions are in place in the approved Ajovy Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical data support the use of fremanezumab (the medicinal ingredient in Ajovy) for the specified indication.

The safety of fremanezumab was evaluated in repeat-dose toxicity studies of up to 3-month duration, conducted in rats and cynomolgus monkeys, and in chronic toxicity studies in cynomolgus monkeys treated for up to 6 months. The studies tested once weekly dosing of fremanezumab via intravenous or subcutaneous routes.

When fremanezumab was administered at doses of 50, 100, or 200 mg/kg by weekly subcutaneous injections to male and female rats prior to and during mating, and to pregnant females throughout the period of organogenesis, no adverse effects on male or female fertility and embryo-fetal development were observed. The highest dose tested was associated with plasma exposures approximately 2 times the human exposure at a dose of 675 mg.

Carcinogenicity and genetic toxicology studies were not conducted with fremanezumab. In accordance with relevant guidelines, a carcinogenicity risk assessment was provided in this submission.

The non-clinical studies did not identify any pronounced safety risks associated with exposure to fremanezumab.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Ajovy Product Monograph. In view of the intended use of Ajovy, no pharmacological or toxicological issues were identified within this submission to preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

Fremanezumab, the medicinal ingredient in Ajovy, is a fully humanized IgG2Δa/kappa monoclonal antibody specific for the α- and β-isoforms of calcitonin gene-related peptide (α-CGRP and β-CGRP). The antibody has a molecular weight of approximately 148 kDa. It is comprised of two identical heavy and two identical light chains. Amino acid mutations have been introduced into the constant region of the heavy chain to limit the Fc region effector function.

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

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 drug substance, fremanezumab, is produced by recombinant deoxyribonucleic (DNA) technology in Chinese hamster ovary (CHO) cells. During development, the manufacturing process of the drug substance underwent changes in the manufacturing facility, scale, and formulation. Comparability has been adequately demonstrated between batches of the drug substance manufactured using each of the developmental processes.

The manufacturing process begins with the thaw of a vial from the working cell bank. It continues with a series of stages, which include inoculum expansion, seed expansion, production, harvest, clarification steps, viral inactivation, virus reduction filtration, ultrafiltration/diafiltration, formulation, and final filtration. The drug substance is dispensed into drug substance containers and stored frozen.

Process validation studies demonstrated that a drug substance of acceptable quality is consistently manufactured at the proposed manufacturing site.

During development, the manufacturing process of the drug product underwent changes in the manufacturing facility, protein concentration, dosage presentation, and scale. Comparability has been adequately demonstrated between batches of the drug product manufactured using each manufacturing process.

The drug product manufacturing begins with thawing of the drug substance, followed by pooling and mixing, and bioburden reduction filtration. Subsequent steps include sterile filtration and aseptic filling of the drug product into sterile type 1 glass syringes with staked-in needles. The filled syringes are then stoppered, visually inspected, and accepted units are stored until further processing. The prefilled syringes of Ajovy are assembled with functional secondary packaging. Each prefilled syringe delivers 1.5 mL of solution containing 225 mg fremanezumab, disodium ethylenediaminetetraacetic acid dihydrate (EDTA) (0.204 mg), L-histidine (0.815 mg), L-histidine hydrochloride monohydrate (3.93 mg), polysorbate-80 (0.3 mg), sucrose (99 mg), and water for injection. The solution has a pH of 5.5.

Process validation studies demonstrated that a drug product of acceptable quality is consistently manufactured at the proposed manufacturing site.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of fremanezumab with the excipients is supported by the stability data provided.

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. Analytical procedures are validated and in compliance with International Council for Harmonisation guidelines.

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 stability data support the proposed shelf life of 24 months for the Ajovy drug product when stored at a temperature of 2°C to 8°C, protected from light. The data also support a short in-use storage period of up to 24 hours when stored at room temperature (up to 25°C).

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

While initially planned, an on-site evaluation of the drug substance manufacturing facility had to be cancelled due to the coronavirus disease (COVID-19) pandemic. An evaluation of the suitability of the drug substance manufacturing facility was conducted based on a review of additional documentation provided upon Health Canada's request and was considered sufficient to support the final quality review recommendation.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.

Both sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The manufacturing process of fremanezumab incorporates adequate control measures to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate any potential viral contamination from the cell culture process are adequately validated. Endotoxin and bioburden testing are integrated in the control strategy and meet relevant guidelines and requirements.

The fremanezumab drug substance is manufactured without any materials of human or animal origin. In addition, the excipients used in the drug product formulation are not of animal or human origin.

 

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