Summary Basis of Decision for Nucala

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 Nucala is located below.

Recent Activity for Nucala

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. ​​​​​​

Post-Authorization Activity Table (PAAT) for Nucala

Updated: 2025-08-15

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

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

Drug Identification Number (DIN):

  • DIN 02449781 - 100 mg/vial, mepolizumab, powder for solution, subcutaneous administration
  • DIN 02492989 - 100 mg/mL, mepolizumab, solution, subcutaneous administration (pre-filled autoinjector)
  • DIN 02492997 - 100 mg/mL, mepolizumab, solution, subcutaneous administration (pre-filled syringe)
  • DIN 02530821 - 40 mg/0.4 mL, mepolizumab, solution, subcutaneous administration (single-use pre-filled syringe)

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 283380 2024-01-31 Issued NOL 2024-03-26 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug substance fermentation process and changes in the control strategy of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 281330 2023-11-21 Issued NOL 2023-12-20 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls (in-process tests and/or acceptance criteria) applied during the drug product manufacturing process or on intermediates. The submission was considered acceptable, and an NOL was issued.
DIN 02449781 cancelled (post market) Not applicable Discontinuation date 2023-12-06 The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DIN(s) pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
SNDS # 270798 2022-12-19 Issued NOC 2023-11-28 Submission filed as a Level I – Supplement to remove the Nucala Pregnancy Exposure Study and replace it with routine pharmacovigilance with enhanced data collection, and to update the PM accordingly. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued.
NC # 276327 2023-06-16 Issued NOL 2023-07-11 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update a testing method for the drug substance. The submission was considered acceptable, and an NOL was issued.
NC # 272976 2023-03-02 Issued NOL 2023-05-10 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add an alternative testing site for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02530821) market notification Not applicable Date of first sale: 2023-02-13 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 257207 2021-10-01 Issued NOC 2022-09-15 Submission filed as a Level I – Supplement for a new presentation, a pre-filled safety syringe for the approved 40 mg/0.4 mL dose for children aged 6 to 11 years. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02530821) was issued for the new presentation.
SNDS # 247542 2020-12-15 Issued NOC 2021-11-05 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as add-on maintenance treatment with intranasal corticosteroids in adult patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) inadequately controlled by intranasal corticosteroids alone. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 244472 2020-10-07 Issued NOC 2021-09-14 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as an add-on to standard therapy for the treatment of adult patients with hypereosinophilic syndrome (HES) for ≥6 months without an identifiable non-hematologic secondary cause. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
Drug Recall Not applicable Posted 2021-07-09 Drug Recall posted on the Healthy Canadians website for the general public, healthcare professionals, hospitals.
Drug Recall Not applicable Posted 2021-07-09 Drug Recall posted on the Healthy Canadians website for the general public, healthcare professionals, hospitals.
NC # 249015 2021-01-29 Issued NOL 2021-03-26 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug substance fermentation and purification processes and a change to a drug substance manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 226197 2019-03-27 Issued NOC 2020-03-12 Submission filed as a Level I – Supplement for a new indication and for the use of the liquid formulation in pre-filled autoinjector and safety syringe formats for adolescents. The indication authorized was: the add-on treatment of adolescents (12 to 17 years of age) and children (6 to 11 years of age) with severe eosinophilic asthma. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
Drug product (DINs 02492989, 02492997) market notification Not applicable Date of first sale: 2019-12-10 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 222929 2018-12-12 Issued NOC 2019-11-21 Submission filed as a Level I – Supplement to update the PM with long-term safety and efficacy data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions, Action and Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 221528 2018-10-30 Issued NOC 2019-10-08 Submission filed as a Level I – Supplement for Nucala liquid formulation (100 mg/mL solution) in a pre-filled autoinjector and safety syringe for the same dose, dosing regimen, and route of administration as currently approved. The submission was reviewed and considered acceptable, and an NOC was issued. New DINs (02492997, 02492989) were issued for the new dosage forms. A Regulatory Decision Summary was published.
SNDS # 212242 2017-12-19 Cancellation Letter Received
2018-10-18		 Submission filed as a Level I - Supplement to propose Nucala (mepolizumab for injection) Lyophilized Powder for Subcutaneous Injection as an add-on maintenance treatment for adult patients with chronic obstructive pulmonary disease (COPD). GlaxoSmithKline Inc. cancelled the submission before a final decision was issued by Health Canada. Regulatory Decision Summary.
SNDS # 208467 2017-08-15 Issued NOC
2018-07-17		 Submission filed as a Level I - Supplement to seek market authorization for Nucala (mepolizumab for injection) as an add-on to corticosteroids for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA). Regulatory Decision Summary published.
NC # 210737 2017-10-27 Issued NOL
2018-01-15		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternate site for quality control testing of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 204339 2017-03-31 Issued NOL
2017-06-15		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to a release test for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 198042 2016-08-26 Issued NOL
2016-10-06		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, additions were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02449781) market notification Not applicable Date of first sale:
2016-03-14		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 179850 2014-11-19 Issued NOC
2015-12-03		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Nucala

Date SBD issued: 2016-03-01

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

Mepolizumab, 144 mg/vial (100 mg/mL, powder for solution, subcutaneous

Drug Identification Number (DIN):

  • 02449781

GlaxoSmithKline Inc.

New Drug Submission Control Number: 179850

On December 3, 2015, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product Nucala.

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 Nucala is favourable for use as add-on maintenance treatment of adult patients with severe eosinophilic asthma who:

  • are inadequately controlled with high-dose inhaled corticosteroids and an additional asthma controller(s) (for example, long-acting beta-adrenoceptor agonists [LABA]), and
  • have a blood eosinophil count of ≥150 cells/µL (0.15 GI/L at initiation of treatment with Nucala or ≥300 cells/µL (0.3 GI/L) in the past 12 months.

Nucala is not indicated for other eosinophilic conditions or for relief of acute bronchospasm or status asthmaticus.

1 What was approved?

Nucala, a monoclonal antibody/interleukin-5 (IL-5) inhibitor, was authorized as add-on maintenance treatment of adult patients with severe eosinophilic asthma who:

  • are inadequately controlled with high-dose inhaled corticosteroids and an additional asthma controller(s)) (for example, long-acting beta-adrenoceptor agonists [LABA]), and
  • have a blood eosinophil count of ≥150 cells/µL (0.15 GI/L) at initiation of treatment with Nucala or ≥300 cells/µL (0.3 GI/L) in the past 12 months.

Nucala is not indicated for other eosinophilic conditions or for relief of acute bronchospasm or status asthmaticus.

This is a first-in-class IL-5 inhibitor for the treatment of severe eosinophilic asthma.

Nucala is contraindicated for patients who are hypersensitive to mepolizumab (the active ingredient in Nucala) or to any ingredient in the formulation or component of the container. Nucala was approved for use under the conditions stated in the Nucala Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Nucala should be reconstituted and administered by a qualified healthcare professional who is experienced in the monitoring of signs and symptoms of hypersensitivity after administration of biologic agents and is prepared to manage anaphylaxis that can be life-threatening.

Nucala (144 mg/vial [100 mg/mL] mepolizumab) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains sucrose, sodium phosphate dibasic heptahydrate, and polysorbate 80.

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

2 Why was Nucala approved?

Health Canada considers that the benefit/risk profile of Nucala is favourable as add-on maintenance treatment of adult patients with severe eosinophilic asthma who:

  • are inadequately controlled with high-dose inhaled corticosteroids and an additional asthma controller(s) (for example, long-acting beta-adrenoceptor agonists [LABA]), and
  • have a blood eosinophil count of ≥150 cells/µL (0.15 GI/L) at initiation of treatment with Nucala or ≥300 cells/µL (0.3 GI/L) in the past 12 months.

Nucala is not indicated for other eosinophilic conditions or for relief of acute bronchospasm or status asthmaticus.

Asthma is a chronic heterogeneous lung disease characterized by inflammation, narrowing of the airways, and reversible airway obstruction. Some patients experience uncontrolled asthma despite attempts to control their disease following step-wise treatment recommendations (for example, high-dose inhaled corticosteroids [ICS] plus additional controller medications).

Studies in the severe asthma population have shown that more than half of these patients have persistent eosinophilic (>300 cells/µL) airway inflammation despite corticosteroid therapy. Severe eosinophilic asthma can be reliably characterized by establishing blood eosinophil thresholds in the presence of high-dose ICS in a poorly controlled, exacerbating phenotype. Eosinophilic asthma can be associated with increased asthma severity, atopy, late-onset disease, and steroid insensitivity.

At present, corticosteroids are considered the most effective anti-inflammatory treatments for all levels of severity of persistent asthma. Control should first be attempted through the use of high-dose ICS before adding daily oral corticosteroids (OCS) or omalizumab (for the subgroup of patients with elevated immunoglobulin E [IgE] and who are allergic to a perennial allergen).

The overproduction of interleukin-5 (IL-5) has been specifically reported in patients with a variety of eosinophil-associated disorders including asthma. Nucala (mepolizumab), a humanized monoclonal antibody (mAb) (immunoglobulin G1 [IgG1], kappa, mAb), binds with high specificity and affinity to human IL-5, which results in reduced eosinophil levels. Nucala has been developed as an add-on treatment for a subgroup of patients with severe eosinophilic asthma.

Nucala has been shown to be efficacious in patients with severe eosinophilic asthma. A clinically meaningful effect in the reduction of blood eosinophil counts and the number of asthma exacerbations was demonstrated in the clinical development program. This effect was observed for both formulations/routes of administration, Nucala (100 mg mepolizumab subcutaneous [SC] and mepolizumab 75 mg intravenous [IV]); however, the Nucala formulation was considered more convenient for patients and healthcare professionals. Only the SC route of administration of Nucala has been submitted for market authorization; the IV route is not recommended.

The safety profiles across all doses of mepolizumab in severe asthma patients were similar in terms of the incidence and type of event, with the most common events being headache, nasopharyngitis, back pain, and injection site reactions/infusion site reactions. Approximately 80% of patients in the placebo and mepolizumab groups reported at least one adverse event (AE) during the trials. Injection-site reactions were more common in the Nucala group (8% versus 3% in placebo) but nasopharyngitis and headache occurred in similar proportions.

The most common serious adverse events were asthma exacerbations, which occurred more frequently in placebo-treated patients across all trials. Mepolizumab was tolerated by patients as there was low withdrawal due to AEs (~3%) and high enrollment in extension phases (~94%). There were no apparent links to demography in the subgroup analyses.

The appearance of an imbalance of cardiovascular events in mepolizumab-treated patients in the DREAM trial triggered an enhanced monitoring programme conducted by the sponsor. Cardiovascular events were not reported commonly in other trials (either placebo-controlled or open label).

A Risk Management Plan (RMP) for Nucala was submitted by GlaxoSmithKline 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.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Nucala has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal studies are promising and the benefits of Nucala therapy are considered to outweigh the potential risks. Nucala has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Nucala 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 Nucala?

Submission Milestones: Nucala

Submission Milestone Date
Pre-submission meetings: 2013-11-14
Pre-submission meetings: 2014-09-25
Submission filed: 2014-11-19
Screening  
Screening Deficiency Notice issued: 2015-01-09
Response filed: 2015-01-22
Screening Acceptance Letter issued: 2015-02-06
Review  
On-Site Evaluation:  
Quality Evaluation complete: 2015-12-03
Clinical Evaluation complete: 2015-12-01
Labelling Review complete: 2015-12-03
Notice of Compliance issued by Director General: 2015-12-03

The Canadian regulatory decision on the non-clinical and clinical review of Nucala was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.

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 Nucala, Health Canada requested 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):

  • To submit to Health Canada a Supplementary New Drug Submission (SNDS) with the final Clinical Study Report (CSR) for ongoing trials conducted with Nucala for the treatment of eosinophilic asthma (for example [e.g.], Study MEA115661, 115666, etc).
  • To submit to Health Canada, in accordance with Canadian Regulations, all serious adverse events (including malignancies, hypersensitivity reactions, etc.) that occurred in all clinical trials with Nucala.
  • To provide Health Canada with Nucala Medical Educational materials for review prior the launch of the product.
  • To provide Health Canada with all reports/correspondence pertaining to post-approval commitments from major Regulatory Authorities (e.g. United States Food and Drug Administration [FDA], European Medicines Agency [EMA], Australia's Therapeutic Goods Administration, etc.).
  • To provide Health Canada with an updated Canadian Risk Management Plan (RMP) to reflect the Canadian labelling and to capture the post-approval commitments to Health Canada and other regulatory agencies.
  • To provide Health Canada with Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRER) for Nucala on a yearly basis. Each PSUR/ PBRER will include an analysis of all Adverse Drug Events as per the Pharmacovigilance Plan and should include safety updates from all ongoing clinical trials with Nucala.
  • To provide Health Canada with regular safety updates from the Pregnancy Registry (post-marketing observational study) committed to the FDA.
5 What post-authorization activity has taken place for Nucala?

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Nucala is found above.

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

6 What other information is available about drugs?

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

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

Clinical Pharmacology

The overproduction of interleukin-5 (IL-5) has been specifically reported in patients with a variety of eosinophil associated disorders including asthma. Nucala (mepolizumab) is a targeted anti-interleukin-5 (IL-5) immunoglobulin G1 (IgG1) kappa monoclonal antibody (mAb). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Mepolizumab binds to IL-5 with high affinity, preventing IL-5 from binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface, thereby reducing the production and survival of eosinophils. As inflammation is an important component in the pathogenesis of asthma,the reduction of eosinophilic inflammation may play an important role in therapeutic effect in severe eosinophilic asthma; however, the precise mechanism of mepolizumab action in asthma has not been definitively established.

The clinical pharmacology data included reports on the human pharmacodynamic (PD) and pharmacokinetic (PK) studies. The clinical pharmacological data support the use of Nucala for the recommended indication.

The clinical PK and PD properties of the proposed commercial presentation of mepolizumab following intravenous (IV) or subcutaneous (SC) administration in healthy volunteers or patients with severe eosinophilic asthma were investigated in three completed clinical pharmacology studies. In addition, sparse PK samples collected in the three Phase III trials conducted in the target patient population, that is (i.e.) severe eosinophilic asthma, were analyzed by population PK methods with investigation of covariate effect.

Pharmacokinetics

Following a single SC dose of mepolizumab 250 mg in healthy volunteers, individual peak plasma concentrations (Cmax) were attained in 2 to 14 days. Absolute bioavailability was estimated to be 64 to 75% and the estimated elimination half-life was 18 to 20 days. Following a 30-minute IV infusion, mepolizumab plasma concentrations declined in a bi-exponential manner. Over the course of the IV dose range, 10 to750 mg, mepolizumab showed linear and dose-proportional PK.

Following repeat SC dosing at 12.5 mg, 125 mg, or 250 mg once every 4 weeks for 12 weeks in asthmatic patients with mean baseline blood eosinophils >300 cells/µL (range: 150 to 2,420 cells/µL), the time to Cmax (Tmax) was 6 to 8 days post-dosing and the terminal-phase elimination half-life was 22 days with an accumulation ratio of approximately two-fold by Week 12. The estimated absolute bioavailability was 81%, 82%, and 64% for the 12.5 mg, 125 mg, and 250 mg SC cohorts, respectively. Area under the curve (AUC) and Cmax increased in a slightly less than dose proportional manner, in particular between the 125 and 250 mg SC dose.

Based on the population PK analysis of the MENSA Study, the systemic exposure was comparable between mepolizumab 75 mg IV and Nucala (100 mg mepolizumab SC) every 4 weeks. Systemic clearance (CL) for a typical 70 kg individual following mepolizumab 75 mg IV was estimated to be 0.220 L/day (3.1 mL/day/kg). Apparent clearance (CL/F) for a typical 70 kg individual following administration of Nucala was estimated to be 0.280 L/day with predicted individual values ranging from 0.126 to 0.852 L/day. Steady-state was achieved by Week 16 with approximately two-fold accumulation ratio. The absolute bioavailability of the SC route was estimated to be 80% (90% confidence interval [CI]: 76%-84%).

In a population PK analysis on data obtained from thirteen mepolizumab Phase I-III studies that included patients with severe eosinophilic asthma, the covariates, for example (e.g.), sex, age, race, and body weight, had no significant impact on the pharmacokinetics of mepolizumab.

Pharmacodynamics

The PD effects of mepolizumab, measured by reduction in blood eosinophils, were demonstrated in adult asthmatic patients with baseline mean blood eosinophil levels greater than 300 cells/µL (mean value ranged from 348 to 586 cells/µL) following every 4 weeks repeat SC or IV administration of mepolizumab (Study 114092). At Week 12 (Day 84), the geometric mean reduction from baseline in blood eosinophils was 78%, 64%, 84%, and 90% from the baseline for 75 mg IV, 12.5 mg SC, 125 mg SC, and 250 mg SC groups, respectively.

Dose/exposure-response relationship was observed for reduction of blood eosinophil counts following IV or SC administration of mepolizumab. The estimated dose required for 50% and 90% of maximal percentage reduction of blood eosinophil counts was 11 mg and 99 mg, respectively.

There were no dose-response or exposure-response relationships observed for forced expiratory volume in one second (FEV1) response and exacerbation rate.

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

Clinical Efficacy

The clinical development program of Nucala for the proposed indication was based on one Phase II, dose-ranging study and two Phase III pivotal randomized, parallel-group, double-blind clinical trials of between 24-32 weeks duration, in patients 12 years and older. Nucala was initially studied using IV administration (the DREAM trial), which led to the development program for SC administration (MENSA and SIRIUS trials).

All three studies enrolled patients with severe refractory asthma, who were uncontrolled despite high doses of inhaled corticosteroids in addition to a second controller (and systemic corticosteroids in the third trial). Patients in the DREAM and MENSA trials had a history of exacerbations (at least two per year) requiring systemic corticosteroid treatment and/or hospitalization or emergency department visit. All clinical trials enrolled patients who had evidence of eosinophilic inflammation. The DREAM trial investigated predictive markers of efficacy that were used in the two other trials. The following two criteria were selected: a blood eosinophil count of ≥150 cells/µL at initiation of treatment or a blood eosinophil count of ≥300 cells/µL in the prior 12 months.

Dose-Ranging Efficacy and Safety with Mepolizumab (DREAM) Trial

The DREAM trial was a 52-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging clinical trial to determine the effect of mepolizumab on exacerbation rates in patients with severe uncontrolled refractory asthma.

The objectives of the trial were to evaluate the dose-response of three doses of mepolizumab (75 mg IV, 250 mg IV, and 750 mg IV) administered monthly in addition to existing maintenance asthma treatment in patients with severe uncontrolled asthma on pharmacodynamic and efficacy outcomes. A total of 616 patients were enrolled.

The primary efficacy endpoint was the frequency of clinically significant exacerbations of asthma as defined by the worsening of asthma which, in the investigator's opinion, required use of oral/systemic corticosteroids and/or hospitalisation and/or emergency department visits. For patients on maintenance oral corticosteroids (OCS), an exacerbation requiring OCS was defined as the use of oral/systemic corticosteroids at least double the existing maintenance dose for at least 3 days. For patients who completed the study, exacerbations from the start of treatment until 4 weeks after the last dose of investigational product were used in the analysis (Week 52). For patients who withdrew prematurely from the study, all data up to the time of discontinuation were included.

Reductions in exacerbation rates in the mepolizumab groups as compared to placebo were as follows: for the 75 mg group, a 48% reduction; for the 250 mg group, a 39% reduction; and for the 750 mg group, a 52% reduction.

No dose-response relationship was observed.

Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA) Trial

The MENSA trial was a 32-week Phase III, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre clinical trial evaluating the efficacy and safety of mepolizumab adjunctive therapy in patients with with severe eosinophilic asthma. The trial enrolled 576 patients. The MENSA trial was the only pivotal exacerbation study to evaluate the direct effect of SC dosing on the exacerbation rate. Considering that the proposed route of administration is SC, the efficacy labelling is based mainly on the results of this study.

The primary objective of the trial was to evaluate the efficacy of mepolizumab 75 mg IV and Nucala (100 mg mepolizumab SC), every 4 weeks, as compared to placebo, in terms of the frequency of clinically significant exacerbations in adult and adolescent patients.

The primary efficacy endpoint was the frequency of clinically significant exacerbations of asthma (as defined by worsening of asthma which required use of systemic corticosteroids and/or hospitalisation and/or Emergency Department visits) over the 32-week treatment period expressed as exacerbation rate per year. Use of systemic corticosteroids was defined as IV or oral steroid for at least 3 days or a single intramuscular dose. For patients on maintenance systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required.

The primary endpoint, the frequency of clinically significant exacerbations of asthma, was reduced for both mepolizumab treatment groups (exacerbation rate/year: 0.93 for mepolizumab 75 mg IV and 0.83 for Nucala) as compared to placebo (exacerbation rate/year: 1.74). These results were statistically significant (p< 0.001). (Type 1 error was controlled using a closed-testing procedure).

Compared to placebo, the reduction in the rate of exacerbations that required hospitalization or emergency room visits was statistically significant for Nucala, but not for mepolizumab 75 mg IV (61% and 32% reduction versus placebo, respectively). Additionally, the rate of clinically significant exacerbations requiring hospitalization per year in the Nucala 100 mg SC, mepolizumab 75 mg IV, and placebo treatment groups were 0.03, 0.06 and 0.10, respectively.

Steroid Reduction with Mepolizumab Study (SIRIUS)

The SIRIUS trial was a 24-week, Phase IIIA, randomized, double-blind, placebo-controlled, parallel-group, multicentre, clinical trial evaluating the effect of Nucala adjunctive therapy to reduce steroid use in patients with severe refractory asthma.

The primary objective of the trial was to compare the effects of Nucala (100 mg mepolizumab SC) to placebo on reducing the requirement for maintenance OCS in systemic corticosteroid-dependent patients with severe asthma with elevated eosinophils. The trial enrolled 135 patients who were randomized to receive Nucala or placebo every 4 weeks for 20 weeks (i.e., 6 doses), providing 24 weeks of treatment. All patients remained on their existing maintenance asthma therapy throughout this study, in addition to the study treatment, while reducing OCS.

The study consisted of four phases: 1) OCS Optimization (entry to the trial with the lowest dose of OCS that would manage the symptoms); 2) Induction (OCS optimized dose + mepolizumab for 4 weeks, to achieve eosinophil reduction prior to reduction of OCS); 3) OCS Reduction; and 4) Maintenance phase (from Week 20 to 24, no further OCS dose adjustment).

The primary efficacy endpoint was the percent reduction of OCS dose during Weeks 20 to 24 compared with the baseline dose, while maintaining asthma control. The primary efficacy endpoint was met. Patients treated with Nucala were able to achieve greater reductions in daily OCS dose, while maintaining asthma control, compared to patients treated with placebo.

Percent Reduction (%) in Oral Corticosteroids (OCS) from Baseline at Weeks 20-24:
Percent Reduction (%) Nucala - 100 mg -
subcutaneous
Number of patients (n) = 69		 Placebo
n = 66
90% - 100% 16 (23%) 7 (11%)
75% - <90% 12 (17%) 5 (8%)
50% - <75% 9 (13%) 10 (15%)
>0% - <50% 7 (10%) 7 (11%)
No decrease in oral
corticosteroids OCS/lack of
asthma control/withdrawal from
treatment		 25 (36%) 37 (56%)
 

For Weeks 20 to 24, 37 (54%) patients in the Nucala group versus 22 (33%) patients in the placebo group achieved ≥50% reduction in the daily OCS dose; 37 (54%) patients in the Nucala group versus 21 (32%) patients in the placebo group achieved a reduction in the daily OCS dose to ≤5.0 mg; and 10 (14%) patients in the Nucala group achieved a total (100%) reduction in OCS dose to 0 mg compared with 5 (8%) subjects in the placebo group.

Indication

The indication sought by the sponsor was as follows:

Nucala (mepolizumab) is indicated as add-on maintenance treatment for severe eosinophilic asthma in patients 18 years of age and older.

  • Nucala has been shown to significantly reduce asthma exacerbations in patients with a history of exacerbations, and to significantly reduce the use of oral corticosteroids in patients requiring systemic corticosteroids.
  • Nucala should be used in patients who have blood eosinophil counts ≥150 cells/µL (0.15 GI/L) at initiation of treatment with Nucala or ≥300 cells/µL (0.3 GI/L) in the past 12 months.

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

Nucala (mepolizumab) is indicated as add-on maintenance treatment of adult patients with severe eosinophilic asthma who:

  • are inadequately controlled with high-dose inhaled corticosteroids and an additional asthma controller(s) (e.g., long acting beta-adrenoreceptor agonist [LABA]), and
  • have a blood eosinophil count of ≥150 cells/µL (0.15 GI/L) at initiation of treatment with Nucala or ≥300 cells/µL (0.3 GI/L) in the past 12 months.

Nucala is not indicated for other eosinophilic conditions or for relief of acute bronchospasm or status asthmaticus.

Overall Analysis of Efficacy

Based on the data provided, Nucala has demonstrated a clinically relevant effect on reducing the number of exacerbations in patients with severe eosinophilic asthma, who are inadequately controlled despite a high dose of inhaled corticosteroids. The clinical development program with mepolizumab indicated that the patients who benefit the most were those who experienced the highest frequency of exacerbations and had the highest levels of blood eosinophils at study entry, which is fully consistent with the mechanism of action of mepolizumab.

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

Clinical Safety

The clinical safety of mepolizumab administered at doses of 100 mg SC (Nucala) or 75 mg to 750 mg IV was evaluated in the three randomized control trials described in the Clinical Efficacy section as well as in two open-label extension phases. These studies formed the basis for the integrated safety summary.

Dose-Ranging Efficacy and Safety with Mepolizumab (DREAM) Trial

The number of patients reporting on-treatment adverse events (AEs) was similar in all four treatment groups: 119 (77%), 126 (82%), 124 (82%), and 122 (78%) in the placebo and mepolizumab 75 mg, 250 mg, and 750 mg groups, respectively. In addition, 6 (4%), 5 (3%), 8 (5%), and 9 (6%) patients in the above groups, respectively, experienced AEs that led to permanent treatment discontinuation or withdrawal from the study.

The most frequently reported AEs in all four groups were headache and nasopharyngitis, with 17% of patients in the placebo group and 21% of patients in each mepolizumab dose group reporting headaches and 15% of patients in the placebo group and 19 to 22% of patients in the mepolizumab dose groups reporting nasopharyngitis.

Comparable numbers of patients experienced AEs assessed as possibly related to the investigational product in each group: 26 (17%); 28 (18%); 29 (19%) and 33 (21%) for placebo, mepolizumab 75 mg, 250 mg, and 750 mg, respectively. The most frequently reported AE assessed as possibly related to investigational product was infusion-related reaction, which was reported in each of the above groups. No more than 2% of patients in any group had an event of hypersensitivity assessed as possibly related to investigational product (2% for placebo, 0 for 75 mg, <1% for 250 mg, and 1% for 750 mg).

Numbers of patients with on-treatment serious adverse events (SAEs) were comparable across the four groups: 25 (16%), 20 (13%), 24 (16%), and 19 (12%)  patients in the placebo, mepolizumab 75mg, 250 mg, and 750 mg groups, respectively. Two SAEs, one occurring in the mepolizumab 250 mg (decreased reticulocyte count) and one occurring in the 750 mg (supraventricular tachycardia) groups, were judged to be possibly related to investigational product by the Investigator.

There were no major safety concern with regards to the increased risks of cardiac disorders, neoplasms, systemic reactions, local site reactions, and infections (including opportunistic infections).

The appearance of an imbalance of cardiovascular events in mepolizumab-treated patients in the DREAM trial triggered an enhanced monitoring programme conducted by the sponsor; however, cardiovascular events have not occurred commonly in other trials (either placebo-controlled or open label).

Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA) Trial

Mepolizumab was well tolerated with a safety profile similar to placebo. The most frequently reported AEs included nasopharyngitis (17-24% across treatment groups), headache (17-24%), and upper respiratory tract infection (12-14%). Asthma worsening was reported as an AE that occurred more frequently in placebo patients (15%) than with active treatment (9% and 7% in IV and SC groups).

There was no evidence of increased risk of SAEs with mepolizumab when administered either via IV infusion or SC injection. More SAEs of asthma worsening were reported for patients treated with placebo (17%) than patients treated with either dose of mepolizumab (5% and 3% with 75 mg IV and Nucala 100 mg mepolizumab SC, respectively).

Steroid Reduction with Mepolizumab Study (SIRIUS) Trial

The overall incidence of AEs during treatment was higher in the placebo group (92%) compared with the Nucala group (83%). The most frequently reported AEs were headache and nasopharyngitis which occurred with a similar incidence between the treatment groups. The incidence of other frequent AEs was also similar between the treatment groups with the exception of asthma (exacerbation) which occurred with a higher incidence in the placebo group (12%) compared to the Nucala group (3%).

Thirteen patients (12 in the placebo group and 1 in the Nucala group) experienced non-fatal SAEs during the study. Asthma (exacerbation) (7 patients in the placebo group) and pneumonia (3 patients in the placebo group) were the most frequently reported SAEs.

No serious cardiac, vascular, thromboembolic, or ischemic events were reported during the conduct of this study.

Six patients (3 in the placebo group and 3 in the Nucala group) prematurely withdrew due to AEs. Two of these patients (placebo group) withdrew due to SAEs (fatal gastrointestinal hemorrhage and prostate cancer). The other withdrawals were due to angioedema (placebo group), injection-site reaction, and urticaria (both in the Nucala group - all considered drug-related). In addition, one patient in the Nucala group withdrew due to left bundle branch block (a pre-existing condition).

No treatment-related trends or clinically significant findings were observed in laboratory tests, vital sign assessments, or electrocardiograms (ECGs).

Immunogenicity

Across the trials, few trial participants developed anti-drug antibodies (ADA), with 6% of Nucala-treated patients and 2% of placebo patients exhibiting at least one post-baseline positive sample. Less than 1% of patients developed neutralizing antibodies. There were no apparent associations between safety or efficacy and the development of ADAs. There were no clear associations between the development of ADAs with two formulations of the drug used in trials, and no specific concerns were raised with immunogenicity of the current drug formulation to be marketed.

Special Populations

As limited safety data was provided for elderly patients (over 65 years of age), it was difficult to draw any conclusion on whether the safety profile in this population was comparable to younger patients.

Animal studies did not indicate reproductive toxicity; however, limited data is available demonstrating the use of Nucala in pregnant women. At the time of market authorization, a pregnancy registry was open and is outlined in the Risk Management Plan.

Overall Analysis of Safety

The long-term safety of treatment with Nucala, especially with the SC route, is limited and will be further assessed and characterized with the final results from the on-going open label extension studies.

Based on data provided, there was no apparent increased risk of malignancy, infections, or serious cardiac, vascular, and ischemic events.

The overall risk of systemic allergic and non-allergic reactions with Nucala and the immunogenic potential of Nucala appear to be low.

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

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

7.2 Non-Clinical Basis for Decision

Mepolizumab has been evaluated in the only available pharmacologically responsive species, cynomolgus monkeys, in repeat-dose toxicity studies up to 6 months duration, using IV and SC routes. An enhanced pre- and post-natal development study with mepolizumab was conducted in pregnant cynomolgus monkeys. A male and female fertility and embryo-fetal, development study and a defense model using Mesocestoides corti infection were conducted in mice using a homologous rat anti-IL-5 monoclonal antibody.

Mepolizumab was well tolerated in pharmacologically responsive monkeys up to 6 months duration, using IV and SC routes. Administrations of mepolizumab to monkeys resulted in anticipated reductions in peripheral and lung eosinophil counts, with no toxicological findings. There is a theoretical risk of increased parasitic infection associated with ultra-low peripheral and lung eosinophil levels. This risk was mitigated by studies conducted in a murine host defense model using anti-IL-5 and cited reports of mice genetically deficient in IL-5 or eosinophils, which have not demonstrated an impaired ability to clear parasitic infections.

The carcinogenic and mutagenic potential of mepolizumab has not been evaluated. However, there is no evidence of defective tumor surveillance in IL-5-deficient or eosinophil-deficient mice. There was no effect of an anti-IL-5 antibody in male and female mice on mating, fertility, and gonadal function or on embryo-fetal development in pregnant females. In pregnant monkeys, mepolizumab administration was not associated with maternal toxicity, effects on pregnancy outcome, delivery or fetal effects. There were no effects on general health and immunologic development of the monkey offspring evaluated for 9 months post-partum.

Overall, mepolizumab or the murine surrogate were well tolerated, demonstrating the intended pharmacological activity, and were reassuring regarding acute, repeat dose, fertility and developmental effects, and theoretical concerns of increased risk of parasitic infections. Although no embryo-fetal or postnatal toxicity was observed, placental transfer and transfer through breast milk should still be considered when assessing the safety of Nucala in pregnant women and lactating women.

In view of the intended use of Nucala, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Nucala Product Monograph to address the identified safety concerns.

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

7.3 Quality Basis for Decision

Nucala (mepolizumab) lyophilized powder for subcutaneous injection, 100 mg/vial is a humanized immunoglobulin G1 (IgG1) kappa monoclonal antibody which binds with high affinity and specificity to interleukin-5 (IL-5), a soluble cytokine that is key to the regulation of blood and tissue eosinophils.

Characterization of the Drug Substance

Extensive characterization of the physicochemical, biological, and immunological properties of mepolizumab and confirmation of its purity were performed using methods selected in accordance with International Council for Harmonisation (ICH) Q6B. The data demonstrate that mepolizumab has the structure expected of a recombinant humanized monoclonal antibody expressed in Chinese Hamster Ovary (CHO) cells. Product variants and process-related impurities were quantified and were consistent with those described for several other monoclonal antibody products.

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

Mepolizumab is produced in a recombinant suspension-adapted CHO cell line. The manufacturing process consists of a series of steps which include cell culture, harvest, purification stages, including viral inactivation/removal steps, and formulation. Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable. Data from product quality assessments, non-clinical studies, and clinical studies demonstrate that mepolizumab produced by different manufacturing process versions during development is comparable and that there has been no significant impact on quality observed due to the associated process changes. The manufacturing process has been successfully validated with full-scale drug substance batches used to assess the removal of process-related impurities, product quality and process performance attributes, and to support the demonstration of process consistency.

The production of Nucala drug product consists of thawing, pooling, and mixing the contents of the drug substance containers followed by sterile filtration and aseptic filling into sterile glass vials. After lyophilization, the vials are stoppered with sterile rubber closures, and sealed with aluminum seals.

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable.

In-process control tests for the drug substance and drug product were established, corresponding analytical methods validated, and acceptance criteria justified. The manufacturing process is considered to be adequately controlled within justified limits.

Materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered to be suitable and/or meet standards appropriate for their intended use.

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 the mepolizumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The purified bulk drug substance and drug product are tested against suitable reference standards to demonstrate strength, purity, potency, and identity. Analytical procedures have been carefully selected according to their ability to confirm the safety, efficacy, and activity of the mepolizumab drug substance and drug product. The methods were validated in full accordance with the ICH guidelines for method validation.

During the review, issues were identified with the potency assay. These issues were initially identified during review of the method validation and transfer. Subsequently, these concerns were confirmed during detailed analysis of provided test data performed during consistency lot assessment. Following a risk assessment of the issue, Nucala was recommended for approval with commitments from the sponsor to improve the bioassay.

Stability of the Drug Substance and Drug Product

The proposed packaging and components are considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through testing and stability studies.

The proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported by the provided stability data, and are considered to be satisfactory. The shelf-life of 24 months when stored at ≤25°C while protected from light and freezing, proposed for Nucala drug product, is acceptable.

Facilities and Equipment

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

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the drug substance (mepolizumab) and the drug product (Nucala) were not conducted due to limited resources and time. The suitability of the facility was supported by the combination of routine GMP inspections by the local regulatory authorities and the submission review.

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

Adventitious Agents Safety Evaluation

Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious agents (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

Raw materials of animal origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. In addition, raw materials of animal origin are assessed to minimize transmission of transmissible spongiform encephalopathy (TSE). The excipients used in the drug product formulation are not of animal or human origin.

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