Summary Basis of Decision for Fasenra

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 Fasenra is located below.

Recent Activity for Fasenra

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 Fasenra

Updated: 2023-09-21

 

The following table describes post-authorization activity for Fasenra, a product which contains the medicinal ingredient benralizumab. 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 and Applications Guidance.

Drug Identification Number (DIN):

  • DIN 02473232 – 30 mg/mL, benralizumab, solution, subcutaneous administration (single-dose prefilled syringe)
  • DIN 02496135 – 30 mg/mL, benralizumab, solution, subcutaneous administration (single-use prefilled autoinjector)
  •  

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities

NC # 273687

2023-03-27

Issued NOL 2023-05-03

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of a drug substance manufacturing facility. The submission was considered acceptable, and an NOL was issued.

SNDS # 267954

2022-09-16

Issued NOC 2023-04-26

Submission filed as a Level I – Supplement for the addition of a drug product manufacturing, testing, labelling, and primary packaging facility. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 246458

2020-11-16

Issued NOC 2021-06-07

Submission filed as a Level I – Supplement for changes to the drug substance manufacturing process and the drug substance and drug product manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02496135) market notification

Not applicable

Date of first sale: 2021-01-13

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

NC # 244558

2020-09-30

Issued NOL 2021-01-05

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of an alternative labelling, assembly, secondary packaging, and release testing facility for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 239884

2020-07-14

Issued NOL 2020-07-27

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to provide data from cell line characterization studies. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 238324

2020-04-09

Issued NOL 2020-07-14

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

NC # 238911

2020-04-24

Cancellation Letter Received 2020-05-13

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to provide data from studies related to the container closure systems and cell line characterization. Elements of the submission were not in scope of an NC and should be reported in Yearly Biologic Product Reports. The submission was therefore cancelled administratively by the sponsor.

NC # 233401

2019-11-12

Issued NOL 2020-02-25

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to include a list of product categories within the Certified Product Information Document for a facility. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 233300

2019-11-07

Issued NOL 2020-02-17

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

SNDS # 225080

2019-02-26

Issued NOC 2020-02-10

Submission filed as a Level I – Supplement for the addition of a new presentation (single-use prefilled autoinjector), to add self-administration, and to update the PM with new safety and efficacy information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Dosage and Administration; Dosage Forms, Strengths, Composition and Packaging; Adverse Reactions; Drug Interactions; Action and Clinical Pharmacology; Storage, Stability and Disposal; Pharmaceutical Information; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued and a new DIN (02496135) was issued for the new presentation.

NC # 224687

2019-02-14

Issued NOL

2019-05-22 -

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

NC # 218170

2018-07-12

Issued NOL

2018-08-13 -

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

Drug product (DIN 02473232) market notification

Not applicable

Date of first sale: 2018-03-28

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

NDS # 204008

2017-03-21

Issued NOC 2018-02-22

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

Date SBD issued: 2018-04-30

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

Benralizumab
30 mg/mL, solution, subcutaneous

Drug Identification Number (DIN):

  • 02473232

AstraZeneca Canada Inc.

New Drug Submission Control Number: 204008

 

On February 22, 2018, Health Canada issued a Notice of Compliance to AstraZeneca Canada Inc. for the drug product Fasenra.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Fasenra is favourable as an add-on maintenance treatment of adult patients with severe eosinophilic asthma.

 

1 What was approved?

 

Fasenra, an anti-interleukin-5 receptor alpha (IL-5Rα) monoclonal antibody, was authorized as an add-on maintenance treatment of adult patients with severe eosinophilic asthma.

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

The efficacy and safety of Fasenra has not been established in patients younger than 18 years of age. Therefore, Fasenra is not indicated in the pediatric population.

There is limited experience with Fasenra in patients 65 years of age and older. Of the total number of patients in clinical trials for Fasenra, 13% were 65 years of age and older, while 0.4% were 75 years of age and older. No overall differences in efficacy or safety of Fasenra were observed between geriatric patients and adult patients, but greater sensitivity of some older individuals cannot be excluded.

Fasenra is contraindicated in patients who are hypersensitive to benralizumab, or to any ingredient in the formulation.

Fasenra 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.

Fasenra (30 mg/mL, benralizumab) is presented as a solution for subcutaneous injection. In addition to the medicinal ingredient, the solution contains L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dehydrate, polysorbate 20, 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 Fasenra Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Fasenra approved?

 

Health Canada considers that the benefit-risk profile of Fasenra is favourable as an add-on maintenance treatment of adult patients with severe eosinophilic asthma.

Asthma is a chronic heterogeneous disease that has been traditionally characterized by variable degrees of reversible airflow obstruction, associated with bronchial hyperresponsiveness, airway inflammation, and airway remodelling. Asthma is clinically defined by the history of respiratory symptoms, such as wheezing, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory flow limitations.

More than 2.4 million (8.4%) Canadians aged 12 years and over have asthma. Asthma attacks resulted in over 70,000 emergency room visits in Canada in 2015. Approximately 250 Canadians die each year from asthma. Asthma often affects quality of life, as it results in time away from school, work, or other activities.

Current Canadian and international recommendations advocate a stepwise approach to asthma management, including inhaled corticosteroids (preventer/controller medication) and short-acting β2-agonists (rescue/reliever medication). Additional controller medications including long-acting β2-agonists, leukotriene receptor antagonists, theophylline, and tiotropium may be introduced to achieve asthma control.

In approximately 5-10% of patients with asthma, despite clinical best practice, their asthma remains difficult-to-treat and may be classified as severe asthma. These individuals are often at greatest risk of morbidity and mortality, and account for a large proportion of asthma-related costs. Severe asthma is defined as asthma that requires treatment with high-dose inhaled corticosteroids plus a second controller (e.g., long-acting β2-agonists) and/or oral corticosteroids to prevent it from becoming uncontrolled or which remains uncontrolled despite this therapy. In individuals with severe asthma, biologic agents may be considered in an effort to reduce exacerbations, improve lung function, and/or relieve symptoms. In Canada, currently authorized biologic agents indicated for the treatment of adults with severe asthma include the anti-immunoglobulin E (anti-IgE) monoclonal antibody Xolair (omalizumab), and the anti-interleukin (IL)-5 monoclonal antibodies Nucala (mepolizumab) and Cinqair (reslizumab).

Fasenra (benralizumab injection) is a targeted, humanized monoclonal antibody (IgG1κ) that selectively binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with a low dissociation constant. The IL-5 receptor is expressed on the surface of eosinophils and basophils. Eosinophilic inflammation can be an important component in the pathogenesis of asthma. In patients with asthma, eosinophils have been associated with greater asthma severity, exacerbations, decreased lung function, and mortality.

Fasenra has been shown to be efficacious as an add-on maintenance treatment in adult patients with severe eosinophilic asthma. The market authorization of Fasenra was primarily based on efficacy and safety data from two pivotal Phase III asthma exacerbations studies (SIROCCO and CALIMA). Additionally, supporting data were derived from a Phase III oral corticosteroid reduction study (ZONDA).

In patients with baseline blood eosinophil counts greater than or equal to 300 cells/µL, Fasenra significantly reduced the rate of clinically relevant annual asthma exacerbations compared with placebo by 51% (rate ratio [RR]: 0.49; 95% confidence interval [CI]: 0.37, 0.64; p<0.001) and 28% (RR: 0.72; 95% CI: 0.54, 0.95; p = 0.019), in the pivotal trials SIROCCO and CALIMA, respectively. Additionally, the risk of having an asthma exacerbation was reduced by 40% (hazard ratio [HR]: 0.60; 95% CI: 0.46, 0.78) and 27% (HR: 0.73; 95% CI: 0.55, 0.95), in SIROCCO and CALIMA, respectively (although not controlled for multiplicity, this finding is clinically meaningful). Compared to placebo, Fasenra also demonstrated robust trends in the improvement of key secondary endpoints, including lung function (forced expiratory volume in 1 second [FEV1], measured by spirometry), asthma symptoms (assessed using the Asthma Control Questionnaire [ACQ-6]), and quality of life (assessed using the Asthma Quality of Life Questionnaire (Standardized) for ages 12 and older [AQLQ(S)+12]).

In patients with baseline blood eosinophil counts fewer than 300 cells/µL (analysis not controlled for multiplicity), Fasenra demonstrated a relatively robust trend towards a clinically meaningful reduction in the asthma exacerbation rate, suggestive of improvements in asthma management for these patients. This finding was supported by key secondary endpoints, which generally demonstrated results consistent with those observed in patients with baseline blood eosinophils greater than or equal to 300 cells/µL.

Additionally, Fasenra reduced the median daily oral corticosteroid dose from baseline by 75% in patients receiving Fasenra (95% CI: 60, 88) compared to 25% in patients receiving placebo (95% CI: 0, 33), in the supporting trial ZONDA.

The most commonly reported adverse reactions during treatment with Fasenra in clinical trials were headache, pharyngitis, pyrexia and hypersensitivity reactions (including urticaria, angioedema and rash). There were no increased incidences of events of interest such as anaphylaxis, opportunistic infections, or malignancy that would merit a specific warning/precaution.

An incidence of anti-drug antibodies to benralizumab (the medicinal ingredient of Fasenra) ranging from approximately 7% to 14% was observed in Fasenra-treated patients. Neutralizing antibodies were detected in 12% of the patients. Anti-benralizumab antibodies were associated with increased clearance of benralizumab and increased blood eosinophil levels in patients with high anti-drug antibody titres compared to anti-drug antibody negative patients. There was no indication of a consequential effect of an anti-drug antibody positive status on efficacy or safety of Fasenra in these studies.

The risk of hypersensitivity reactions, the immunogenicity, and commonly reported adverse reactions are addressed through appropriate labelling in the Fasenra Product Monograph and routine pharmacovigilance. As highlighted in the Warnings and Precautions section of the Fasenra Product Monograph, Fasenra should not be used to treat acute bronchospasm or status asthmaticus.

As part of the marketing authorization for Fasenra, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments encompass (but are not limited to) including Canadian patients in the planned Pregnancy Registry Program for Fasenra, and providing Health Canada, as appropriate, with regular safety updates from this program (see What follow-up measures will the company take?).

A Risk Management Plan (RMP) for Fasenra was submitted by AstraZeneca 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 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 Fasenra was accepted.

Based on the non-clinical data and clinical studies, Fasenra has an acceptable safety profile as an add-on maintenance treatment for adult patients with severe eosinophilic asthma. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Fasenra 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; 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 Fasenra?

 

Submission Milestones: Fasenra

Submission Milestone Date
Pre-submission meeting: 2016-12-06
Submission filed: 2017-03-21
Screening  
Screening Acceptance Letter issued: 2017-04-28
Review  
On-Site Evaluation: 2017-06-12 - 2017-06-16
On-Site Evaluation: 2018-01-14 - 2018-01-19
Review of Risk Management Plan complete: 2017-12-22
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-02-20
Quality Evaluation complete: 2018-02-22
Clinical Evaluation complete: 2018-02-22
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2018-02-22

 

The Canadian regulatory decision on the non-clinical and clinical review of Fasenra was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was 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 Fasenra, 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:

 

  • Submitting to Health Canada, in accordance with Canadian regulations, all serious adverse events (including immunogenicity) that occur in all ongoing and planned clinical trials with Fasenra.
  • Providing Health Canada with Fasenra medical educational materials.
  • Providing Health Canada with all reports/correspondence pertaining to Fasenra post-approval commitments agreed upon with other major regulatory authorities (e.g., Food and Drug Administration [FDA], European Medicines Agency [EMA], Australia's Therapeutic Goods Administration [TGA], etc.).
  • Providing Health Canada with Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRER) for Fasenra on a yearly basis. Each PSUR/PBRER will include an analysis of all adverse drug events as per the pharmacovigilance plan, and safety updates from all ongoing clinical trials with Fasenra.
  • Including the adverse event of immunogenicity as a potential risk in the Risk Management Plan (RMP) for Fasenra to allow for further characterization of this risk
  • Providing Health Canada with information related to the design, implementation, and conduct of the planned Pregnancy Registry Program for Fasenra
  • Including Canadian patients in the planned Pregnancy Registry Program for Fasenra, and providing Health Canada, as appropriate, with regular safety updates from this study.
5 What post-authorization activity has taken place for Fasenra?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Fasenra 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

Benralizumab, the medicinal ingredient in Fasenra, is a recombinant humanized afucosylated immunoglobulin G1, kappa (IgG1κ) monoclonal antibody that binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with a dissociation constant of 16 pM. The IL-5 receptor is expressed on the surface of eosinophils and basophils. The results of in vitro studies have shown that the absence of fucose in the Fc domain of benralizumab results in higher affinity (45.5 nM) for FcγRIII receptors, which are expressed on immune effector cells such as natural killer cells. In vitro, benralizumab induces apoptosis of eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). The exact mechanism of benralizumab action in asthma has not been definitively established.

The clinical pharmacological data support the use of Fasenra for the specified indication.

Subcutaneous administration of benralizumab at doses ranging from 2 mg to 200 mg rapidly depleted peripheral blood eosinophils. Mean peripheral blood eosinophil counts were typically reduced by ≥95% within 24 hours of dosing. The depletion was reversible, and the majority of eosinophil counts returned to approximately baseline levels within 6 months after cessation of repeated subcutaneous administration of benralizumab. Peripheral blood basophils were also reduced following benralizumab treatment but at a lesser magnitude than eosinophils.

The pharmacokinetics of benralizumab showed dose linearity and approximate dose proportionality following subcutaneous administration at doses ranging from 20 mg to 200 mg. In the subcutaneous administration regimen of 30 mg benralizumab once every 4 weeks for the first 3 doses, and once every 8 weeks (Q8W) thereafter, the pharmacokinetic steady-state was reached at the third Q8W dose (i.e., at Week 24). According to a population pharmacokinetic analysis, the estimated systemic clearance (CL) for benralizumab was 0.29 L/day. The half-life of elimination (t1/2) was approximately 15.5 days following subcutaneous administration. Benralizumab CL increased with body weight and the formation of anti-drug antibodies. The estimated absolute bioavailability was 59% and the relative bioavailability among the administration sites (abdomen, thigh, or upper arm) was similar. The pharmacokinetics of benralizumab was not significantly impacted by race, ethnicity, age, or gender.

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

Clinical Efficacy

The efficacy of Fasenra as an add-on maintenance treatment of adults with severe eosinophilic asthma was demonstrated in two pivotal, long-term, Phase III asthma exacerbation studies of a replicate design (SIROCCO and CALIMA). Supporting data were derived from a Phase III oral corticosteroid reduction study (ZONDA).

Although the use of peripheral blood eosinophils as a biomarker shows promise for the identification of asthmatic subjects that may respond to anti-eosinophil interventions, it remains a relatively novel and empirically derived diagnostic approach - without established biological rationale - that serves mainly the purpose of clinical trials rather than asthma management. Clinical practice guidelines recommend sputum induction as the gold standard for assessing airway inflammation and guiding asthma management. Although modest correlations have been reported between blood and sputum eosinophils, the correlation becomes weaker as asthma becomes more severe and patients are exposed to higher doses of corticosteroids. At this time, it remains unclear if blood eosinophils are the most appropriate biomarker for determining treatment strategies (treatment initiation and/or monitoring) of patients with severe eosinophilic asthma. For these reasons, in the consideration of efficacy of Fasenra in different populations, more emphasis was placed on the clinical meaning of the results, rather than on reaching statistical significance in some of the endpoints.

Pivotal studies

The pivotal Phase III asthma exacerbation studies, SIROCCO and CALIMA, were randomized, double-blind, parallel-group, placebo-controlled clinical trials of 48-week and 56-week duration, respectively. A total of 2,510 patients were enrolled in both studies, irrespective of their baseline blood eosinophil counts. The patients were stratified in a 2:1 ratio by baseline blood eosinophil counts into a high- (greater than or equal to 300 cells/µL) and low- (fewer than 300 cells/µL) eosinophil stratum. The stratification was intended as a means of enriching the patient population with those most likely to respond to Fasenra, while including patients with baseline blood eosinophil counts below the threshold of 300 cells/µL in order to assess efficacy across a full range of baseline blood eosinophil levels. The primary efficacy population was the high-eosinophil stratum that consisted of 1,537 patients who were taking high-dose inhaled corticosteroids and long-acting β2-agonists.

The primary endpoint for SIROCCO and CALIMA was the annual asthma exacerbation rate, which was defined in accordance with international guidelines. Clinically significant asthma exacerbation was defined as worsening of asthma requiring use of oral/systemic corticosteroids for at least three days, and/or emergency department visits requiring use of oral/systemic corticosteroids and/or hospitalization. For patients on maintenance oral corticosteroids, a clinically significant asthma exacerbation requiring oral corticosteroids was defined as a temporary increase in stable oral/systemic corticosteroids for at least three days or a single depo-injectable dose of corticosteroids.

Secondary endpoints included pulmonary function, i.e., forced expiratory volume in 1 second (FEV1), and asthma symptoms and quality of life, i.e., Asthma Control Questionnaire (ACQ)-6 score; and Asthma Quality of Life Questionnaire (Standardized) for ages 12 and older (AQLQ(S)+12) score.

High-eosinophil stratum (patients with blood eosinophil counts greater than or equal to 300 cells/µL)

Exacerbations:

Fasenra significantly reduced the rate of clinically relevant annual asthma exacerbations compared with placebo in patients with baseline blood eosinophils greater than or equal to 300 cells/µL. In SIROCCO, Fasenra significantly reduced the annual asthma exacerbation rate compared to placebo by 51% (rate ratio: 0.49; 95% confidence interval [CI]: 0.37, 0.64; p<0.001). In CALIMA, Fasenra significantly reduced the annual asthma exacerbation rate compared to placebo by 28% (rate ratio: 0.72; 95% CI: 0.54, 0.95; p = 0.019). The observed reductions in annual asthma exacerbation rates were considered clinically meaningful.

Additionally, the time to first asthma exacerbation was longer for the patients receiving Fasenra compared with placebo in both trials. In SIROCCO, the risk of having an asthma exacerbation was reduced by 40% (hazard ratio [HR]: 0.60; 95% CI: 0.46, 0.78) and in CALIMA, by 27% (HR: 0.73; 95% CI: 0.55, 0.95). While this endpoint was not a primary endpoint or a planned secondary endpoint controlled for multiplicity, it was considered an important and informative measure with clinical meaning.

Lung Function:

Fasenra significantly improved baseline pre-bronchodilator FEV1 compared to placebo and provided consistent improvements over time in the mean change from baseline in FEV1.

Asthma Symptoms:

Fasenra improved baseline ACQ-6 scores compared to placebo and provided improvements over time in the mean change from baseline in the ACQ-6 score. Additionally, Fasenra improved baseline AQLQ(S)+12 scores compared to placebo and provided improvements over time in the mean change from baseline in the AQLA(S)+12 score.

Low-eosinophil stratum (patients with blood eosinophil counts fewer than 300 cells/µL)

Fasenra demonstrated a relatively robust trend towards reduction of asthma exacerbation rate in patients with baseline blood eosinophils fewer than 300 cells/µL. Although this important analysis is not controlled for multiplicity, the robust trend is suggestive of clinically meaningful improvements in asthma management for these patients. The trend in reduction of asthma exacerbation rate was supported by key secondary endpoints, including FEV1, ACQ-6 and AQLQ(S)+12 scores, which generally demonstrated trends consistent with the findings in patients from the high-eosinophil stratum.

Supportive Study

The supportive Phase III oral corticosteroid reduction study (ZONDA) was a randomized, double-blind, parallel-group, placebo-controlled clinical trial of 28-week duration. The trial included an 8-week run-in period in which the oral corticosteroid dose was titrated to the minimum effective dose without losing asthma control. ZONDA enrolled a total of 220 severe asthma patients. The patients had blood eosinophil counts greater than or equal to 150 cells/µL, a history of at least one exacerbation in the past 12 months, and were being treated with a daily oral corticosteroid (7.5 mg to 40 mg per day) in addition to regular use of high-dose inhaled corticosteroids and long-acting β2-agonists with or without additional controller(s) to maintain asthma control. The primary endpoint was the percent reduction from baseline of the final oral corticosteroid dose during Weeks 24 to 28, while maintaining asthma control.

Reductions of 50% or higher in the oral corticosteroid dose were observed in 66% (48 of 73) of patients receiving Fasenra compared to 37% (28 of 75) of those receiving placebo. The proportion of patients with a mean final dose lower than or equal to 5 mg at Weeks 24 to 28 was 59% (43 of 73) for Fasenra and 33% (25 of 75) for placebo (odds ratio: 2.74; 95% CI: 1.41, 5.31).

Indication

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

  • Fasenra (benralizumab) is indicated as an add-on maintenance treatment for severe asthma with an eosinophilic phenotype in adult patients.

  • Fasenra has been shown to significantly reduce asthma exacerbations, improve lung function and relieve asthma symptoms in these patients. Fasenra has also been shown to significantly reduce the use of oral corticosteroids while maintaining asthma control in patients requiring systemic corticosteroids.

The proposed indication was revised to include terminology for the target disease (i.e., severe eosinophilic asthma) similar to the labelling of two other authorized agents that target the interleukin-5 (IL-5) pathway, Nucala (mepolizumab) and Cinqair (reslizumab). Accordingly, Health Canada approved the following indication:

  • Fasenra (benralizumab injection) is indicated as an add-on maintenance treatment of adult patients with severe eosinophilic asthma.

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

Clinical Safety

The overall safety assessment of Fasenra as an add-on maintenance treatment of severe eosinophilic asthma was based on an integrated safety summary of data derived from the pivotal Phase III studies SIROCCO and CALIMA (described in the Clinical Efficacy section). In addition, the assessment included a comparative discussion of key safety results from the study ZONDA (also described in the Clinical Efficacy).

A total of 3,882 patients with asthma were included across the entire Phase II and III clinical program. Of those, 2,575 patients received at least one dose of Fasenra. Overall, a total of 1,387 patients received Fasenra for ≥48 weeks.

The most commonly reported adverse reactions during treatment with Fasenra in clinical trials were headache, pharyngitis, pyrexia and hypersensitivity reactions. There were no increased incidences of events of interest such as anaphylaxis, opportunistic infections, or malignancy that would merit a specific warning/precaution.

An incidence of anti-drug antibodies to benralizumab (the medicinal ingredient of Fasenra) ranging from approximately 7% to 14% was observed in Fasenra-treated patients. Neutralizing antibodies were detected in 12% of the patients. Anti-benralizumab antibodies were associated with increased clearance of benralizumab and increased blood eosinophil levels in patients with high anti-drug antibody titers compared to anti-drug antibody negative patients. No evidence of an association of anti-drug antibodies with efficacy or safety of Fasenra was observed.

An incidence of anti-drug antibodies to benralizumab (the medicinal ingredient of Fasenra) ranging from approximately 7% to 14% was observed in Fasenra-treated patients. Neutralizing antibodies were detected in 12% of the patients. Anti-benralizumab antibodies were associated with increased clearance of benralizumab and increased blood eosinophil levels in patients with high anti-drug antibody titers compared to anti-drug antibody negative patients. No evidence of an association of anti-drug antibodies with efficacy or safety of Fasenra was observed.

The risk of hypersensitivity reactions and the immunogenicity are addressed in the Fasenra Product Monograph and through routine pharmacovigilance.

Overall, the data from the clinical studies support the safety of Fasenra at the recommended dose for the add-on maintenance treatment of adult patients with severe eosinophilic asthma.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical data support the use of Fasenra for the specified indication.

In vitro and in vivo primary pharmacodynamic studies demonstrated proof of concept for the indicated clinical use of benralizumab, the medicinal ingredient in Fasenra. Cynomolgus monkeys were determined to be the pharmacologically relevant species for use in the non-clinical toxicology studies of benralizumab.

Benralizumab was shown to bind to human and cynomolgus monkey IL-5Rα and FcγRIIIa receptors with high affinity. Benralizumab was also shown to bind to human peripheral eosinophils in vitro and to induce apoptosis via antibody-dependent cellular cytotoxicity in human peripheral eosinophils and basophils. While the data are limited, in vivo studies using an equivalent humanized afucosylated anti-IL-5Rα IgG1κ monoclonal antibody demonstrated inhibition of IL-5-induced eosinophilia in a monkey model of eosinophilia and reduction of infiltrated airway eosinophils in a monkey asthma model.

A 39-week repeat-dose toxicity study was conducted in sexually mature monkeys with intravenous doses of 10 and 25 mg/kg body weight and a subcutaneous dose of 30 mg/kg body weight, administered every two weeks. Reductions in blood eosinophil counts or eosinophil depletion were observed at all doses. In some animals, reversibility of this effect was not observed following a 12-week recovery period. Benralizumab-related adverse effects were limited to clinical signs of bruising/reddened areas around the eyes and on the face, chest, and lower abdomen (petechiae and ecchymosis), as well as a decreased platelet count and indicators of circulating erythrocyte mass in one animal following intravenous dosing at 25 mg/kg body weight. No other benralizumab-related adverse effects, including effects on the respiratory, cardiovascular, and central nervous systems, were observed. Therefore, the no-observed-adverse-effect level (NOAEL) for the general toxicity of benralizumab in cynomolgus monkeys is 10 mg/kg body weight every two weeks following intravenous administration and 30 mg/kg body weight every two weeks following subcutaneous administration.

Dedicated fertility studies with benralizumab were not conducted. In the 39-week repeat-dose toxicity study in monkeys, no benralizumab-related adverse effects were observed on male and female reproductive organs, testicular volume, sperm parameters (motility, concentration, count, and morphology), reproductive hormone patterns, or menstrual cycle length.

In an enhanced embryo-fetal development and prenatal and postnatal development toxicity study, no benralizumab-related maternal or developmental toxicity was observed at maternal intravenous doses of 10 and 30 mg/kg body weight administered every two weeks from gestation day 20 to one month postpartum. The NOAEL for these endpoints is the highest dose tested. Reduction or depletion of peripheral blood eosinophil counts was observed in maternal animals and their offspring. Reversibility of this effect by 6.5 months postpartum was not observed in some maternal animals at both doses and in one offspring in the high-dose group. The effect on eosinophil counts in offspring as a result of in utero or lactational exposure to benralizumab is not an intended effect, and it has been addressed in the Fasenra Product Monograph.

Carcinogenicity studies with benralizumab were not conducted.

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

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

 

 

7.3 Quality Basis for Decision

 

Benralizumab, the medicinal ingredient in Fasenra, is a recombinant humanized afucosylated immunoglobulin G1, kappa (IgG1κ) monoclonal antibody of approximately 150 kDa, including oligosaccharides. Benralizumab selectively binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with a low dissociation constant. The absence of fucose in the Fc domain of benralizumab results in higher affinity (45.5 nM) for FcγRIII receptors, which are expressed on immune effector cells such as natural killer cells.

Characterization of the Drug Substance

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

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

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

Benralizumab is produced in Chinese hamster ovary cells by recombinant deoxyribonucleic acid (DNA) technology. The expression cell line has been engineered to eliminate fucosylation.

The process validation strategy for the benralizumab manufacturing process is based on a life cycle management approach that includes a process design stage, a process qualification stage, and a continued process verification stage. All process validation study results, including release test results have met the pre-approved validation criteria confirming the validity of the process design, and demonstrating that the commercial process is reproducible and performs as expected. Trend analysis and analysis of process and product data will continue to be performed under a continued process verification program. Suitable supporting validation studies have been provided for the proposed hold times, resin and column lifetimes, and shipping.

The sponsor provided satisfactory analytical comparability data to link clinical materials to the proposed commercial process materials.

Fasenra is provided as an aqueous buffered solution containing: 30 mg/mL benralizumab in 20 mM histidine/histidine-HCl, 0.2 M trehalose dihydrate, 0.006% w/v polysorbate 20, pH 6.0. The drug product manufacturing process consists of two distinct stages: manufacture of the formulated bulk and manufacture of the accessorized prefilled syringe. The formulated bulk is filled into prefilled syringes with an appropriate overfill to allow delivery of the label claim volume. The prefilled syringe is then accessorized with device components (needle safety shield, extended finger flange, plunger rod) to produce the accessorized prefilled syringe. None of the accessories are in contact with the drug product solution or part of the fluid path of the delivery system.

The process validation strategy for the Fasenra drug product manufacturing process is based on a life cycle management approach that includes a process design stage, a process qualification stage, and a continued process verification stage. Process validation was successfully conducted with three consecutive process validation lots. The sponsor provided suitable media fill data to demonstrate the ability to fill aseptically. Assembly and packaging of the accessorized prefilled syringe was also validated. All process validation study results met the suitable pre-approved validation criteria confirming the validity of the process design, and demonstrating that the commercial process is reproducible and performs as expected.

Comparability studies were conducted to assess the potential impact of formulation and process changes on the quality attributes of Fasenra used in clinical trials. Overall, these studies demonstrated that Fasenra intended for commercial use is comparable to the material used in clinical studies.

The materials used in the manufacture of the drug substance and drug product, including materials of biological origin, are considered to 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 benralizumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Through Health Canada's lot release testing and evaluation program, three consecutively manufactured final product lots were tested using a subset of release methods. All results obtained during lot consistency testing were acceptable and within the sponsor's specifications.

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 2ºC-8ºC for Fasenra is considered acceptable when stored in the original package (to protect it from light).

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment 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 drug substance and the drug product have been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

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

Adventitious Agents Safety Evaluation

The benralizumab purification process demonstrates a high level of clearance for a variety of virus types. The process employs both viral clearance and viral inactivation steps. Appropriate small-scale studies have demonstrated that the benralizumab purification process is capable of achieving an acceptable adventitious agent safety profile.

 

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