Summary Basis of Decision for Emgality
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 Emgality is located below.
Recent Activity for Emgality
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 Emgality
Updated:
The following table describes post-authorization activity for Emgality, a product which contains the medicinal ingredient galcanezumab. 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 that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02491087 - 120 mg/mL, galcanezumab, solution, subcutaneous injection
- DIN 02491060 - 120 mg/mL, galcanezumab, solution, subcutaneous injection
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02491087) market notification | Not applicable | Date of first sale:2019-10-02 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| Drug product (DIN 02491060) market notification | Not applicable | Date of first sale:2019-10-07 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 219521 | 2018-08-21 | Issued NOC2019-07-30 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Emgality
Date SBD issued: 2019-12-20
The following information relates to the new drug submission for Emgality.
Galcanezumab
Drug Identification Number (DIN):
- DIN 02491087 - 120 mg/mL, solution, subcutaneous
- DIN 02491060 - 120 mg/mL, solution, subcutaneous
Eli Lilly Canada Inc.
New Drug Submission Control Number: 219521
On July 30, 2019, Health Canada issued a Notice of Compliance to Eli Lilly Canada Inc. for the drug product Emgality.
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 Emgality is favourable for the prevention of migraine in adults who have at least four migraine days per month.
Emgality should be initiated by physicians experienced in the diagnosis and treatment of migraine.
1 What was approved?
Emgality is a monoclonal antibody designed to bind calcitonin gene-related peptide (CGRP). Emgality was authorized for the prevention of migraine in adults who have at least four migraine days per month.
Emgality should be initiated by physicians experienced in the diagnosis and treatment of migraine.
Data for pediatric patients (<18 years of age) were not available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
The safety and efficacy of Emgality has not been studied in patients 65 years of age or older.
Emgality is contraindicated for patients with known serious hypersensitivity to the active ingredient, galcanezumab, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Emgality 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.
Emgality (120 mg/mL galcanezumab solution) is presented as a solution in a prefilled syringe or a pen device. In addition to the medicinal ingredient, the solution contains L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, sodium chloride, 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 Emgality Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Emgality approved?
Health Canada considers that the benefit-risk profile of Emgality is favourable for the prevention of migraine in adults who have at least four migraine days per month.
Migraine is a disabling primary headache disorder manifesting as recurring severe headaches that are generally associated with nausea and light and/or sound sensitivity. A comprehensive approach to migraine management involves lifestyle modification along with acute and prophylactic treatments as appropriate. The decision to a use a specific medication is based on individual patient history, other comorbid conditions and patient tolerability of adverse events. Currently, erenumab and onabotulinum toxin are biologic products authorized for migraine prophylaxis in Canada.
Emgality has been shown to be efficacious as preventive treatment in patients with episodic and chronic migraine. The market authorization was based on three Phase III randomized, multicentre, double-blind, placebo-controlled studies in adult patients with a history of migraine according to the International Classification of Headache Disorders (ICHD-3). The use of Emgality demonstrated a statistically significant and clinically meaningful difference in the reduction of monthly migraine headache days (MHD) against placebo. A 240 mg loading dose followed by a monthly maintenance of 120 mg is recommended.
The frequency of adverse events was comparable across the active treatment and placebo groups in the clinical studies. The adverse events that were identified as adverse drug reactions were injection site reactions, pruritus, urticaria, constipation, and vertigo. The safety profile of Emgality is acceptable for the specified indication. Some uncertainty remains with regard to the safety and efficacy of Emgality for geriatric patients, pediatric patients, pregnant patients, and patients who are breastfeeding. These limitations of data have been adequately mitigated through labelling.
A Risk Management Plan (RMP) for Emgality was submitted by Eli Lilly 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 Emgality 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 Emgality was accepted.
The overall benefit-risk profile is considered favourable for Emgality when used for the prevention of migraine in adults 18-65 years of age who experience at least four migraine days per month. With the addition of Emgality to the available treatment options for Canadians, patients and healthcare practitioners will have additional choices when considering management strategies for migraine.
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 Emgality?
Submission Milestones: Emgality
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2018-05-25 |
| Submission filed: | 2018-08-21 |
| Screening | |
| Screening Acceptance Letter issued: | 2018-10-05 |
| Review | |
| Review of Risk Management Plan complete: | 2019-05-21 |
| Clinical/Medical Evaluation complete: | 2019-07-24 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2019-07-25 |
| Quality Evaluation complete: | 2019-07-26 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2019-07-30 |
The Canadian regulatory decision on the review of Emgality 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 Emgality, 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 Periodic Benefit Risk Evaluation Reports including, but not limited to, all serious adverse events for Emgality every six months for the first two years and annually for five years thereafter following market authorization. The reports should include information obtained from monitoring the effect of calcitonin gene-related peptide on bone metabolism.
- Providing Health Canada with the ongoing pregnancy registry data as per the commitment made to the United States Food and Drug Administration.
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
The active ingredient of Emgality, galcanezumab, is a humanized immunoglobulin G4 monoclonal antibody that binds calcitonin gene-related peptide (CGRP) and prevents its biological activity. The relationship of CGRP blood levels in headache detection and induction suggests a role of this interaction in migraine pathophysiology.
The pharmacokinetic (PK) profile of galcanezumab has been adequately characterized by a population PK analysis that pooled data from six clinical studies (two Phase I studies, one Phase II study, and three Phase III studies). Galcanezumab exhibited linear pharmacokinetics and exposure increased proportionally across the dose range of 5-300 mg. The apparent volume of distribution was estimated to be 7.3 L, the apparent clearance was estimated to be 0.008 L/hour, and the half-life was estimated to be 27 days. Following a subcutaneous dose at steady-state, the median time to maximum concentration was predicted to be 5 days (range: 3 to 14 days).
Although lower galcanezumab exposures were observed in subjects with higher body weight, weight-based dose adjustment was considered unnecessary based on clinical response (efficacy) data from the Phase III studies. Overall, the clinical pharmacology data provided support for the Emgality dose regimen of a 240 mg subcutaneous (SC) loading dose followed by monthly 120 mg SC maintenance dosing.
For further details, please refer to the Emgality Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Emgality was evaluated as preventive treatment (a treatment expected to decrease migraine headache frequency) of episodic or chronic migraine in three Phase III randomized, multicentre, double-blind, placebo-controlled studies in adult patients. Studies enrolled patients with a history of migraine according to the International Classification of Headache Disorders. Patients who had myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, stroke, certain electrocardiogram abnormalities or deep vein thrombosis/pulmonary embolism within six months of screening, or had planned cardiovascular surgery or percutaneous coronary angioplasty were excluded. Patients with a persistent daily headache, history of headache other than migraine and body mass index ≥40 kg/m2 were also excluded.
Two studies, EVOLVE-1 (CGAG) and EVOLVE-2 (CGAH), evaluated the use of Emgality in patients between 18 and 65 years of age with a history of episodic migraine. In EVOLVE-1, a total of 858 patients with a history of episodic migraine (4 to 14 migraine days per month) were randomized to receive either Emgality 120 mg (number of patients [n] = 213), Emgality 240 mg (n = 212), or placebo (n = 433) by subcutaneous injection once monthly. In EVOLVE-2, a total of 915 patients with a history of episodic migraine were randomized to receive either Emgality 120 mg (n = 231), Emgality 240 mg (n = 223), or placebo (n = 461) by subcutaneous injection once monthly. All patients in the Emgality 120 mg dose group received an initial loading dose of 240 mg.
The primary efficacy endpoint for EVOLVE-1 and EVOLVE-2 was the mean change in the number of monthly migraine headache days (MHD) over Months 1-6 relative to the baseline measurement. In both studies, the mean change in monthly MHD was greater in patients treated with Emgality (-4.7 days in EVOLVE-1 and -4.3 days in EVOLVE-2) than in patients who received the placebo (-2.8 days in EVOLVE-1 and -2.3 days in EVOLVE-2). The observed difference between Emgality and the placebo is considered statistically significant. Both doses (120 mg and 240 mg) provided a similar change (~1.9 days) in the primary endpoint.
One study, REGAIN (CGAI), evaluated the use of Emgality in patients between 18 and 65 years of age with a history of chronic migraine. REGAIN was a randomized, 3-month, double-blind, placebo-controlled study. A total of 1,113 patients with a history of chronic migraine (≥15 headache days per month with ≥8 migraine days per month) were randomized to receive either Emgality 120 mg (n = 278), Emgality 240 mg (n = 277), or placebo (n = 558) by subcutaneous injection once monthly. All patients in the Emgality 120 mg dose group received an initial loading dose of 240 mg.
The primary efficacy endpoint for REGAIN was the mean change from baseline in the number of monthly migraine headache days over Months 1 to 3. There was a statistically significant reduction in the mean MHD from baseline for Emgality compared to placebo. Although the two doses (120 mg and 240 mg) demonstrated superiority over placebo, the reduction in mean MHD was comparable (-2 days) among the 120 mg dose group and the 240 mg dose group.
Overall, Emgality demonstrated a statistically significant and clinically meaningful difference in the reduction of monthly MHD against placebo. While both doses provided a similar reduction across the three studies, a 240 mg loading dose followed by 120 mg monthly maintenance is recommended.
Indication
The New Drug Submission for Emgality was filed by the sponsor with the following indication:
- Emgality (galcanezumab) is indicated for the preventive treatment of migraine in adults.
To ensure safe and effective use of the product, Health Canada approved the following indication:
- Emgality (galcanezumab) is indicated for prevention of migraine in adults who have at least four migraine days per month.
- Emgality should be initiated by physicians experienced in the diagnosis and treatment of migraine.
For more information, refer to the Emgality Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
A total of 1,647 patients were exposed to Emgality for more than six months (six monthly doses) and 279 patients were exposed for 12 months (12 monthly doses) at the time of submission. There was limited data on exposure beyond 12 months.
The frequency of adverse events was comparable when comparing the active treatment to the placebo arms in the different studies. The adverse events that were identified as adverse drug reactions were injection site reactions, pruritus, urticaria, constipation, and vertigo. These were generally mild in nature and did not lead to the discontinuation of Emgality. The most common adverse reaction was injection site reactions.
In the three integrated pivotal migraine placebo-controlled study periods (EVOLVE-1, EVOLVE-2, and REGAIN) injection site pain was the most frequently (≥10%) reported event. For example, in EVOLVE-1 and EVOLVE-2, injection site pain was reported in 12.5%, 14.5%, and 12.8% of patients in the Emgality 120 mg group, 240 mg group, and in the placebo group, respectively. In most patients, reported injection site pain occurred within one hour of injection and resolved the same day.
The effect of Emgality on cardiac and vascular parameters was a topic of interest. Despite literature and theoretical concerns, no apparent imbalance was observed in the clinical studies. The integrated summary of safety pools demonstrated no evidence to support additional risk for cardiovascular, cerebrovascular, or other vascular events. There was some concern regarding the exacerbation of peripheral vascular disorders; this may be more evident in the post-market setting as the variability in the study population was limited.
Hypersensitivity was also a topic of interest. Although no events of anaphylaxis were observed in the clinical studies, there has been anecdotal post-market data and reports of patients experiencing severe hypersensitivity events. Based on toxicological data, decrease in bone mineral density changes and associated sequelae emerged as possible adverse events of interest. However, despite the biologic plausibility and observation in the pre-clinical setting, no additional signal was detected during the safety review.
The safety of Emgality has not been studied in patients over the age of 65, pregnant women, women who are breastfeeding, pediatric patients and those currently taking other medications for chronic conditions. Patients with severe hepatic and renal impairment were not included in the studies. Despite the uncertainties for the above populations, there is evidence regarding the safety of Emgality as a potential therapy for migraine prophylaxis. The safety profile of Emgality could make this a more tolerable therapy over other prophylactic agents.
Appropriate warnings and precautions are in place in the approved Emgality Product Monograph to address the identified safety concerns.
For more information, refer to the Emgality Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The active ingredient of Emgality, galcanezumab, was shown to bind to human calcitonin gene-related peptide (CGRP) and inhibit CGRP-mediated signaling in vitro.
Toxicology studies were conducted in pharmacologically relevant species using the subcutaneous route of administration. In six-month repeat-dose toxicity studies, no adverse effects were observed in rats and cynomolgus monkeys at exposures up to 8- and 156-fold greater than the estimated human exposure, respectively. However, two deaths in rats were observed at an exposure 19-fold greater than the estimated human exposure.
No adverse effects on male or female fertility in rats or development in rats and rabbits were observed up to the highest doses tested in dedicated reproductive and developmental toxicity studies. Paternal or maternal exposures at the no-observed-adverse-effect levels (NOAEL) for effects on male fertility in rats, female fertility and embryo-fetal development in rats, embryo-fetal development in rabbits, and pre- and post-natal development in rats were 8-, 38-, 64-, and 34-fold greater than the estimated human exposure, respectively. While galcanezumab-related increases in the fetal and litter incidences of skeletal variations were observed in rats at the highest dose tested in the female fertility and embryo-fetal developmental toxicity study, these changes are considered non-adverse in nature. Other galcanezumab-related non-adverse findings included increased incidences of local injection site findings consistent with inflammation in both rats and cynomolgus monkeys. Carcinogenicity and genotoxicity studies were not conducted, which was considered acceptable.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Emgality Product Monograph. In view of the intended use of Emgality, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Emgality 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 the active ingredient, galcanezumab, consistently exhibits the desired characteristic structure and biological activity.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Drug Substance
The drug substance, galcanezumab, is produced in a mammalian cell line (Chinese Hamster Ovary) using recombinant deoxyribonucleic acid (DNA) technology. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.
The manufacturing process of the drug substance consists of a series of stages which include thaw of a working cell bank vial, flask and seed bioreactor cell expansion, bioreactor production, harvesting, clarification, viral inactivation, chromatography, viral filtration, ultrafiltration, purification, and formulation. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.
Process validation results have demonstrated the effectiveness, consistency, and product and process control of the galcanezumab manufacturing process. Process control was demonstrated by maintaining process parameters (inputs) within suitable defined limits as specified by the process validation protocols. The effectiveness of the process was demonstrated by meeting suitable pre-determined acceptance criteria for product quality (outputs) as specified by the protocols. Process consistency was demonstrated by the above inputs and outputs repeatedly meeting their requirements.
The sponsor provided suitable data to demonstrate that drug substance manufactured using the commercial process at the commercial site is comparable to material used during the clinical studies.
Drug Product
Emgality is supplied as a 120 mg/mL solution and is clear to opalescent, colourless to slightly yellow or slightly brown, free of visible particles, sterile, and a non-pyrogenic parenteral solution for subcutaneous administration.
The validation of the manufacturing process for Emgality consisted of the manufacture of three drug product batches. All batches met suitable pre-determined acceptance criteria and the release specifications. To ensure that the manufacturing process remains in a state of control, a monitoring plan was established and will be maintained for routine production. The sponsor provided satisfactory data from aseptic process simulations to demonstrate their ongoing ability to fill aseptically.
The sponsor provided suitable data to demonstrate that drug product manufactured using the commercial process at the commercial site is comparable to material used during the clinical studies.
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 are in compliance with ICH guidelines.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product 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. The proposed 24-month shelf life at 2°C-8°C for Emgality is considered acceptable.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.
On-Site Evaluations of the facilities involved in the manufacture and testing of the Emgality drug substance and drug product were not warranted since the facilities were recently evaluated and are considered to be in good standing.
Both sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.
The excipients used in the drug product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| EMGALITY | 02491060 | ELI LILLY CANADA INC | GALCANEZUMAB 120 MG / ML |
| EMGALITY | 02491087 | ELI LILLY CANADA INC | GALCANEZUMAB 120 MG / ML |