Summary Basis of Decision for Vyepti
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Vyepti is located below.
Recent Activity for Vyepti
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 Vyepti, a product which contains the medicinal ingredient eptinezumab. 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: 2024-08-19
Drug Identification Number (DIN):
- DIN 02510839 - 100 mg/1 mL, eptinezumab, solution, intravenous administration
- DIN 02542269 - 300 mg/3 mL, eptinezumab, solution, intravenous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
Drug product (DIN 02542269) market notification |
Not applicable |
Date of first sale: 2024-07-01 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
SNDS # 272966 |
2023-03-01 |
Issued NOC 2023-10-18 |
Submission filed as a Level I – Supplement to for the introduction of a single-use vial containing 300 mg/3mL (100mg/mL) as an additional fill volume to the 100mg/1mL single-use vial presentation. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02542269) was issued for the new presentation. |
|
SNDS # 268320 |
2022-10-03 |
Issued NOC 2023-09-19 |
Submission filed as a Level I – Supplement to update the PM to include efficacy results from Study 18898A (DELIVER). 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. |
|
SNDS # 270305 |
2022-12-02 |
Issued NOC 2023-04-19 |
Submission filed as a Level I – Supplement to revise the outer carton label that contains 1 vial. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 264535 |
2022-05-25 |
Issued NOC 2022-11-15 |
Submission filed as a Level I – Supplement to update the outer labels and package insert. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
Drug product (DIN 02510839) market notification |
Not applicable |
Date of first sale: 2022-08-17 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
SNDS # 263203 |
2022-04-13 |
Issued NOC 2022-08-11 |
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 and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued. |
|
NC # 261525 |
2022-02-15 |
Issued NOL 2022-03-24 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug substance (release and stability) and changes in the drug substance and drug product release or shelf‐life specifications. The submission was considered acceptable, and an NOL was issued. |
|
SNDS # 251463 |
2021-04-12 |
Issued NOC 2021-08-19 |
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. |
|
NDS # 233288 |
2020-02-03 |
Issued NOC 2021-01-11 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Vyepti
Date SBD issued: 2021-05-17
The following information relates to the New Drug Submission for Vyepti.
Eptinezumab
Drug Identification Number (DIN):
- DIN 02510839 ‑ 100 mg/mL eptinezumab, solution, intravenous administration
Lundbeck Canada Inc.
New Drug Submission Control Number: 233288
On January 11, 2021, Health Canada issued a Notice of Compliance to Lundbeck Canada Inc. for the drug product Vyepti.
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 Vyepti is favourable for the prevention of migraine in adults who have at least 4 migraine days per month.
Vyepti should be prescribed by healthcare professionals experienced in the diagnosis and treatment of migraine.
1 What was approved?
Vyepti (eptinezumab) is a monoclonal antibody that binds to the calcitonin gene‑related peptide (CGRP) ligand and blocks its binding to the receptors. It was authorized for the prevention of migraine in adults who have at least 4 migraine days per month.
Vyepti should be prescribed by healthcare professionals experienced in the diagnosis and treatment of migraine.
Vyepti is not authorized for use in pediatric patients (younger than 18 years of age), as no clinical safety or efficacy data are available for this population.
The safety and efficacy of Vyepti in patients 65 years of age or older have not been established. The clinical study program of Vyepti did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients.
Vyepti is contraindicated in patients who are hypersensitive to eptinezumab or to any ingredient in the formulation, including any non‑medicinal ingredient, or component of the container.
Vyepti 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.
Vyepti (100 mg/mL eptinezumab) is presented as a solution. In addition to the medicinal ingredient, the solution contains L‑histidine, L‑histidine monohydrochloride, polysorbate 80, sorbitol, 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 Vyepti Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Vyepti approved?
Health Canada considers that the benefit‑risk profile of Vyepti is favourable for the prevention of migraine in adults who have at least 4 migraine days per month.
Vyepti should be prescribed by healthcare professionals experienced in the diagnosis and treatment of migraine.
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. In Canada, an estimated 4.7% of men and 11.8% of women are affected by migraines. The 2016 global burden of disease studies identified migraine as the second highest cause of disability worldwide, and the leading cause in men and women aged 15‑49 years.
Current migraine management can be classified as acute treatment, in which the objective is to terminate a migraine attack, or prophylactic treatment, in which the objective is to reduce the frequency of attacks or days on which the patient is affected by migraine. Prophylactic treatments include beta‑blockers, tricyclic antidepressants, antiepileptic drugs, angiotensin‑converting enzyme, and angiotensin receptor blockers. At the time of authorization of Vyepti, four biologic products were authorized in Canada for chronic migraine prophylaxis: onabotulinumtoxinA, and three calcitonin gene‑related peptide (CGRP) antagonists (erenumab, galcanezumab, and fremanezumab). All three CGRP antagonists are administered subcutaneously.
Vyepti (eptinezumab) is another CGRP antagonist for the prevention of migraine, and as of the time of its authorization, it is the only one administered intravenously. Calcitonin gene‑related peptide antagonists bind to the CGRP receptor and inhibit the CGRP‑related cascade of physiological events that is theorized to lead to migraine attacks.
Evidence of the clinical efficacy of Vyepti was provided through the results of two pivotal studies: PROMISE 1 in patients with episodic migraine, and PROMISE 2 in patients with chronic migraine. Both studies were parallel group, double‑blind, and placebo‑controlled.
Episodic migraine was defined as ≤14 headache days of which at least 4 days had to be migraine days, during the 28‑day screening period and the 3 months prior to screening. In the PROMISE 1 study, 888 patients were randomized in a ratio of 1:1:1:1 to receive either placebo, 30 mg Vyepti, 100 mg Vyepti, or 300 mg Vyepti every 12 weeks over a period of 48 weeks (for a total of four infusions).
The primary efficacy endpoint was the change from baseline in mean monthly migraine days (MMD) over Weeks 1‑12. After the first dose, the mean reduction in MMD was 3.9 days for the Vyepti 100 mg group, 4.3 days for the Vyepti 300 mg group, and 3.2 days for the placebo group. The differences from placebo were ‑0.7 in the 100 mg group and ‑1.1 in the 300 mg group, which were statistically significant.
Chronic migraine was defined as ≥15 to ≤26 headache days, of which ≥8 days were assessed as migraine days. In the PROMISE 2 study, 1,072 patients were randomized in a ratio of 1:1:1 to receive either placebo, 100 mg Vyepti, or 300 mg Vyepti every 12 weeks over a period of 24 weeks (for a total of two infusions). Patients with a dual diagnosis of chronic migraine and medication overuse headache attributable to acute medication overuse (triptans, ergotamine, or combination analgesics greater than 10 days per month) were included in the study population (40%).
The primary efficacy endpoint was the change from baseline in MMD over Weeks 1‑12. The mean reduction in MMD was 7.7 days in the Vyepti 100 mg group, 8.2 days in the Vyepti 300 mg group, and 5.6 days in the placebo group. The differences from placebo were ‑2.0 in the 100 mg group and ‑2.6 in the 300 mg group, which were statistically significant.
The clinical safety of Vyepti was evaluated in 2,076 patients with migraine, representing 1,615 patient‑years of exposure. Nasopharyngitis was the most frequently reported adverse event, and occurred in at least 2% of patients in the Vyepti treatment groups (300 mg or 100 mg). A large majority of treatment‑emergent adverse events (TEAEs) were graded by investigators as mild to moderate in severity.
Serious hypersensitivity adverse events, including angioedema and swelling of the face and lips, were reported in fewer than 2% of all patients treated with Vyepti. Hypersensitivity adverse events were observed in the 300 mg group but not the 100 mg group, and occurred at comparable frequencies after the first and the second dose. Most hypersensitivity adverse events occurred during the 30 minutes of infusion, but some were observed up to 4 hours after infusion. All were mild to moderate in severity and resolved by stopping the infusion, with or without standard of care. No deaths or life‑threatening adverse events occurred during the clinical studies.
A Risk Management Plan (RMP) for Vyepti was submitted by Lundbeck Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Vyepti Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look‑alike sound‑alike attributes, was conducted and the proposed name Vyepti was accepted.
Vyepti has an acceptable safety profile based on the non‑clinical and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Vyepti 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 Vyepti?
Submission Milestones: Vyepti
| Submission Milestone | Date |
|---|---|
| Submission filed | 2020-02-03 |
| Screening | |
| Screening Acceptance Letter issued | 2020-03-18 |
| Review | |
| Review of Risk Management Plan complete | 2020-10-22 |
| Quality Evaluation complete | 2021-01-04 |
| Clinical/Medical Evaluation complete | 2021-01-08 |
| Biostatistics Evaluation complete | 2021-01-08 |
| Labelling Review complete | 2021-01-11 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2021-01-11 |
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
4 What follow-up measures will the company take?
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
Eptinezumab, the medicinal ingredient in Vyepti, is a humanized immunoglobulin G1 (IgG1) antibody which binds to the human calcitonin gene‑related peptide (CGRP) ligand with picomolar affinity and blocks its binding to CGRP receptors. As a CGRP antagonist, eptinezumab inhibits the CGRP‑related cascade of physiological events that is theorized to lead to migraine in adults. Eptinezumab is highly selective and does not bind to any of the related neuropeptides amylin, calcitonin, adrenomedullin, or intermedin.
The pharmacokinetics of Vyepti following intravenous administration was characterized based on a study in healthy subjects, two studies conducted in migraine patients, and a population pharmacokinetic modelling analysis using pharmacokinetic data from four Phase I, one Phase II, and three Phase III studies. An exposure‑response modelling analysis was conducted using pooled data from Phase II and III studies, which provided support for the proposed dosage regimens for Vyepti (either a 100 mg or 300 mg intravenous infusion every 12 weeks).
Vyepti exhibited linear pharmacokinetics following a single intravenous dose, with exposure levels increasing in a dose‑proportional manner over a dose range of 100 mg to 300 mg. In repeated dose regimens of 100 mg or 300 mg every 12 weeks, steady state was reached within 24 weeks. The pharmacokinetic parameters examined included the maximum concentration (Cmax) and the area under the concentration‑time curve during a dosing interval (12 weeks) following 30‑ to 60‑minute intravenous infusion (AUC0‑tau). Based on the population pharmacokinetic analysis, the mean accumulation ratios were 1.08 for the Cmax and 1.15 for the AUC0‑tau.
The mean (standard deviation) steady‑state Cmax and AUC0‑tau were 40.9 (10.9) µg/mL and 867 (278) day µg/mL for the 100 mg dose regimen, and 125 (36.5) µg/mL and 2,629 (791) day µg/mL for the 300 mg dose regimen. Results of the population pharmacokinetic analysis indicated that the steady‑state volume of distribution of Vyepti was 4.8 L following intravenous administration in patients with episodic migraine and chronic migraine. The clearance was 0.12 L/day, and the terminal elimination half‑life was approximately 29 days.
Analyses of the dose‑response and exposure‑response relationships revealed similar clinical responses (a decrease in monthly migraine days [MMD]) in patients receiving repeated dose regimens of 100 mg and 300 mg Vyepti every 12 weeks. The efficacy responses elicited by both the 100 mg and 300 mg regimens were close to the maximum response in patients with episodic migraine or chronic migraine. Pharmacokinetic studies have not been conducted in special populations. Based on observations from the population pharmacokinetic and exposure‑response analyses, no dose adjustments are required for Vyepti.
Pharmacokinetic comparability was demonstrated between the eptinezumab commercial drug product and the clinical drug product. The geometric mean ratio for Cmax and the 90% confidence intervals for the total exposure as measured by the area under the concentration‑time curve (AUC0-∞) were within the comparability margins of 80.0% to 125.0%.
For further details, please refer to the Vyepti Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Vyepti was evaluated in two pivotal studies: PROMISE 1 in patients with episodic migraine (EM) and PROMISE 2 in patients with chronic migraine (CM). Both studies were parallel‑group, double‑blind, and placebo‑controlled. Additionally, both studies excluded patients with a known history of cardiovascular disease (hypertension, ischemic heart disease), neurological disease, cerebrovascular disease, autoimmune disease, diabetes, Raynaud's disease, and life‑threatening allergy (e.g., anaphylaxis).
PROMISE 1 evaluated the efficacy and safety of Vyepti for the preventive treatment of episodic migraine in adults. Episodic migraine was defined as ≤14 headache days, at least 4 days of which were migraine days, during the 28‑day screening period and the 3 months prior to screening. A total of 888 patients were randomized to receive 30 mg Vyepti (number of patients [n] = 223), 100 mg Vyepti (n = 221), 300 mg Vyepti (n = 222), or placebo (n = 222), every 12 weeks, as four infusions over a period of 48 weeks.
Concurrent acute migraine or headache medications, including migraine‑specific medications, were permitted during the study with some restrictions. Regular use (more than 7 days per month) of other treatments for the prevention of migraine was not allowed. There were 856 patients (96.4%) with at least one acute concomitant headache medication and 41 patients (4.6%) with at least one prophylactic headache medication. Headache information was captured daily using the electronic headache diary device. The mean migraine frequency at baseline was 8.6 migraine days per month and was similar across treatment groups.
The primary efficacy endpoint was the change from baseline in mean monthly migraine days (MMD) over Weeks 1‑12. After the first dose, the mean reduction in MMD was 3.9 days for the Vyepti 100 mg group, 4.3 days for the Vyepti 300 mg group, and 3.2 days for the placebo group. The differences from placebo were ‑0.7 in the 100 mg group and ‑1.1 in the 300 mg group, and were statistically significant.
The key secondary endpoints included the ≥75% migraine responder rates, defined as the proportion of patients who achieved at least 75% reduction in migraine days over Weeks 1‑4 and Weeks 1‑12. Only the Vyepti 300 mg group met both of these endpoints. Although not part of the primary or key secondary endpoints, the results of the analyses of reduction in MMD following the second dose were comparable to the primary endpoint.
PROMISE 2 evaluated the efficacy of Vyepti for the preventive treatment of chronic migraine in adults. Chronic migraine was defined as ≥15 to ≤26 headache days, at least 8 days of which were assessed as migraine days. A total of 1,072 patients were randomized to receive 100 mg Vypeti (n = 356), 300 mg Vyepti (n = 350), or placebo (n = 350) every 12 weeks, as two infusions over a period of 24 weeks.
During the study, patients were permitted to use an established stable regimen (except for onabotulinumtoxinA) of acute or preventive medication for migraine or headache. Patients using opioids or products containing butalbital for more than 4 days per month were excluded from the study. Forty‑one percent (41%) of patients were taking concomitant preventive medication for migraine. The mean migraine frequency at baseline was 16.1 migraine days per month and was similar across treatment groups.
The primary efficacy endpoint was the change from baseline in MMD over Weeks 1‑12. The mean reduction in MMD was 7.7 days in the Vyepti 100 mg group, 8.2 days in the Vyepti 300 mg group, and 5.6 days in the placebo group. The differences from placebo were ‑2.0 in the 100 mg group and ‑2.6 in the 300 mg group, and were statistically significant. A total of 431 patients (40%) with a dual diagnosis of chronic migraine and medication overuse headache were included in the study (Vyepti 100 mg, n = 139; Vyepti 300 mg, n = 147; and placebo, n = 145). The treatment difference observed between Vyepti 100 mg and placebo and between Vyepti 300 mg and placebo for the reduction of MMD in these patients were ‑3.0 days and ‑3.2 days, respectively.
The key secondary endpoints included the proportion of patients with 50% or greater and 75% or greater reductions in MMD over Weeks 1‑12, compared to baseline levels, and the percentage of patients with migraine on day 1 after dosing. Results for the key secondary endpoints were supportive of the primary endpoint.
Indication
The New Drug Submission for Vyepti was filed by the sponsor with the following indication, which Health Canada subsequently approved:
- Vyepti (eptinezumab for injection) is indicated for the prevention of migraine in adults who have at least 4 migraine days per month.
- Vyepti should be prescribed by healthcare professionals experienced in the diagnosis and treatment of migraine.
For more information, refer to the Vyepti Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Vyepti was evaluated in 2,076 patients with migraine, representing 1,615 patient‑years of exposure. Of these, 1,334 patients had at least 6 months of exposure to Vyepti, including 637 patients who received 300 mg and 511 patients who received 100 mg. A total of 490 patients had one year of exposure to Vyepti, including 167 patients who received 300 mg and 171 patients who received 100 mg.
Nasopharyngitis was the most frequently reported adverse event, and occurred in at least 2% of patients in the Vyepti treatment groups (300 mg or 100 mg). A large majority of treatment‑emergent adverse events (TEAEs) were graded by investigators as mild to moderate in severity.
Serious hypersensitivity adverse events, including angioedema and swelling of the face and lips, were reported in fewer than 2% of all patients treated with Vyepti. Hypersensitivity adverse events were observed in the 300 mg group but not the 100 mg group, and occurred at comparable frequencies after the first and the second dose. Most hypersensitivity adverse events occurred during the 30 minutes of infusion, but some were observed up to 4 hours after infusion. All were mild to moderate in severity and resolved by stopping the infusion, with or without standard of care. No deaths or life‑threatening adverse events occurred during the clinical studies.
Appropriate warnings and precautions are in place in the approved Vyepti Product Monograph to address the identified safety concerns.
For more information, refer to the Vyepti Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Eptinezumab, the medicinal ingredient in Vyepti, binds to the human calcitonin gene‑related peptide (CGRP) and inhibits CGRP‑mediated signalling in vitro.
In a six‑month repeat‑dose toxicity study, male and female cynomolgus monkeys were administered an intravenous bolus injection every two weeks. Animals did not develop any toxicologically significant effects at doses up to 150 mg/kg body weight (123 times greater than the maximum recommended human dose [MRHD] based on exposure as measured by the area under the concentration‑time curve [AUC]). One female monkey in a low‑dose group died shortly after administration of the sixth dose, which was attributed to an anti‑drug antibody‑mediated anaphylactic response. The highest dose tested, 150 mg/kg/dose, was identified as the no‑observed‑adverse‑effect level (NOAEL).
In the fertility study conducted in rats, eptinezumab did not affect male or female fertility or when administered intravenously at doses of 0 (vehicle only), 75, or 150 mg/kg body weight once per week during the pre‑mating, mating, and gestation periods (up to gestation day 4). One female receiving the 150 mg/kg dose died from undetermined causes. The NOAEL was determined to be 150 mg/kg/dose (60 times greater than the human exposure based on body surface area).
In two embryo‑fetal development studies, no signs of maternal or fetal toxicity or teratogenicity were observed in rats or rabbits that received intravenous injections of 0 (vehicle only), 75, or 150 mg/kg body weight during the period of organogenesis. No maternal toxicity was reported. No embryolethality or fetal teratogenicity was observed. The NOAEL was determined to be 150 mg/kg/dose (36 and 33 times greater than the human exposure based on the maximum concentration [Cmax] for the rat and rabbit studies, respectively).
A pre‑ and postnatal development study was also conducted, in which pregnant rats received intravenous injections of eptinezumab at doses of 0 (vehicle only), 75, and 150 mg/kg body weight, once every six days from gestational day 6 to lactation day 20. No overt maternal toxicity was observed. However, one F0 generation female rat died from undetermined causes. In utero exposure to eptinezumab did not affect F1 generation male and female development, sexual maturation, fertility, or reproductive performance. The NOAEL was determined to be 150 mg/kg/dose (60 times greater than the human exposure based on body surface area).
Non‑clinical studies have not been conducted to evaluate the carcinogenic or genotoxic potential of eptinezumab.
The results of the non‑clinical studies as well as the potential risks to humans have been included in the Vyepti Product Monograph. Considering the intended use of Vyepti, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Vyepti Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
Detailed characterization studies were performed to provide assurance that eptinezumab consistently exhibits the desired characteristic structure and biological activity. Primary and higher order structure, product‑related variants, and biological activity were all evaluated, and test results confirmed the expected structure and characteristics of the molecule.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Eptinezumab, the drug substance, is produced in the yeast Pichia pastoris expression system. Manufacturing of the drug substance begins with the thawing of vials from a working cell bank of P. pastoris cells which have been genetically engineered to express eptinezumab. The cell culture is transferred to progressively larger vessels as it expands, and eptinezumab is secreted into the culture medium.
The downstream process involves a series of isolation and purification steps. The process stream is cleared of cells, debris, and impurities, and purified through multiple chromatography steps. The final bulk drug substance is filled into polycarbonate bottles, flash frozen, placed into aluminum bags, and stored at ≤‑60°C.
Manufacturing of the drug product, Vyepti, involves thawing and pooling of the drug substance and the addition of the final excipients. The solution undergoes bioburden reduction filtration and sterile filtration, after which it is filled into vials under aseptic conditions.
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 eptinezumab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
Vyepti 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.
The control strategy for eptinezumab consists of multiple elements including, but not limited to, the control of materials, the control of critical steps within the manufacturing processes and the control of the product through release and stability testing using analytical methods that are suitable for their intended purpose. The data obtained through validation studies reflect consistency in the manufacturing processes of both the drug substance and the drug product. Process validation lots were examined and met all predefined acceptance criteria and release specifications and were comparable to material used in development. Acceptance criteria for the bulk drug substance and drug product align with International Council for Harmonisation (ICH) recommendations and regulatory requirements.
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 Vyepti is considered acceptable. The vial should be stored in the outer carton to protect it from light, and must not be frozen or shaken.
Additional storage and special handling instructions are addressed in greater detail in the Vyepti Product Monograph.
Facilities and Equipment
Based on risk assessment scores determined by Health Canada, on‑site evaluations were not recommended for the drug substance and drug product manufacturing sites.
Adventitious Agents Safety Evaluation
The eptinezumab bulk drug substance is produced through a microbial fermentation process in Pichia pastoris (a species of yeast), which does not support the growth of mammalian viruses. The master and working cell banks used in the manufacture of Vyepti were found to be free of bacterial and fungal contamination.
Other than the yeast cells, there are no materials of biologic origin used in the process.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VYEPTI | 02542269 | LUNDBECK CANADA INC | EPTINEZUMAB 300 MG / 3 ML |
| VYEPTI | 02510839 | LUNDBECK CANADA INC | EPTINEZUMAB 100 MG / ML |