Summary Basis of Decision for Cinqair

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 Cinqair is located below.

Recent Activity for Cinqair

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 Cinqair

Updated: 2024-02-09

The following table describes post-authorization activity for Cinqair, a product which contains the medicinal ingredient reslizumab. 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 02456419 - 10 mg/mL reslizumab, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 268587 2022-10-07 Issued NOL 2022-12-23 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the reference standard qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 262681 2022-03-23 Issued NOL 2022-06-16 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was considered acceptable, and an NOL was issued.
NC # 262311 2022-03-11 Issued NOL 2022-05-02 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an extension of the reference standard shelf-life or retest period for the drug substance. The submission was considered acceptable, and an NOL was issued.
NC # 258526 2021-11-10 Issued NOL 2022-02-01 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug substance and drug product (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 239313 2020-05-07 Issued NOL 2020-06-08 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 234425 2019-12-13 Cancellation Letter Received 2020-01-20 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance and drug product release or shelf-life specifications. The changes were not in scope of an NC but were considered to be Level III changes. The sponsor cancelled the submission administratively.
NC # 207924 2017-07-26 Issued NOL
2017-10-12		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update an in-process control used in the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 203153 2017-02-22 Issued NOL
2017-04-20		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a new testing site for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 202064 2017-01-19 Issued NOL
2017-03-16		 Submission filed as a Level II (120 day) Notifiable Change to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Detailed Pharmacology section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 202671 2017-02-07 Issued NOL
2017-02-22		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 200935 2016-12-06 Issued NOL
2017-01-11		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02456419) market notification Not applicable Date of first sale:
2016-12-19		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 185873 2015-07-03 Issued NOC
2016-07-20		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Cinqair

Date SBD issued: 2016-10-25

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

Reslizumab, 10 mg/mL, solution, intravenous

Drug Identification Number (DIN):

  • 02456419

Teva Canada Ltd.

New Drug Submission Control Number: 185873

 

On July 20, 2016, Health Canada issued a Notice of Compliance to Teva Canada Limited for the drug product Cinqair.

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 Cinqair is favourable as an add-on maintenance treatment of adult patients with severe eosinophilic asthma who:

  • are inadequately controlled with medium-to-high-dose inhaled corticosteroids and an additional asthma controller(s) (for example [e.g.], long-acting beta-agonist [LABA]) and
  • have a blood eosinophil count of ≥400 cells/µL at initiation of the treatment.

 

1 What was approved?

 

Cinqair, an interleukin-5 (IL-5) inhibitor, was authorized as an add-on maintenance treatment of adult patients with severe eosinophilic asthma who:

  • are inadequately controlled with medium-to-high-dose inhaled corticosteroids and an additional asthma controller(s) (e.g., long-acting beta-agonist [LABA]) and
  • have a blood eosinophil count of ≥400 cells/µL at initiation of the treatment.

Cinqair is not indicated for other eosinophilic conditions or for relief of acute bronchospasm or status asthmaticus. It should be administered by a qualified healthcare professional who is experienced in the monitoring of signs and symptoms of hypersensitivity after administration of biologic agents and prepared to manage anaphylaxis that can be life-threatening.

Cinqair is contraindicated in patients with known hypersensitivity to reslizumab or any component of the formulation.

Cinqair is not indicated in patients younger than 18 years. Limited data are available on the use of Cinqair in patients older than 65 years.

Cinqair was approved for use under the conditions stated in the Cinqair Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Cinqair (10 mg/mL reslizumab) is presented as a preservative-free, sterile aqueous solution for intravenous infusion. Each 10 mL single-use glass vial of Cinqair is formulated as 10 mg/mL reslizumab in an aqueous solution containing 2.45 mg/mL sodium acetate trihydrate, 0.12 mg/mL glacial acetic acid, and 70 mg/mL sucrose, with a pH of 5.5.

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

 

2 Why was Cinqair approved?

 

Health Canada considers that the benefit/risk profile of Cinqair is favourable as an add-on maintenance treatment of adult patients with severe eosinophilic asthma who are inadequately controlled with medium-to-high-dose inhaled corticosteroids and an additional asthma controller, and have a blood eosinophil count of ≥400 cells/µL at initiation of the treatment.

Asthma is a chronic heterogeneous lung disease characterised by airway inflammation, narrowing of the airways, and reversible airway obstruction. Some patients experience uncontrolled asthma despite attempts to control their disease following the step-wise treatment recommendations (e.g., high-dose inhaled corticosteroids and additional controllers). Studies in these patients have shown a presence of persistent eosinophilic (>300 cells/µL) airway inflammation, despite corticosteroid therapy.

The first in class interleukin-5 (IL-5) inhibitor Nucala (mepolizumab), a humanised immunoglobulin G1 (IgG1) kappa monoclonal antibody (administered subcutaneously), was recently authorized as an add-on maintenance treatment for adult patients with severe eosinophilic asthma.

Cinqair (reslizumab), another IL-5 inhibitor, is a humanized IgG4 kappa monoclonal antibody which binds to human IL-5 and prevents its binding to the IL-5 receptor, thereby reducing the production and survival of eosinophils. Cinqair has been shown to be efficacious as an add-on treatment in adult patients with severe eosinophilic asthma who are inadequately controlled with medium-to-high dose of inhaled corticosteroids and additional asthma controller medications, and have a blood eosinophil count of ≥400 cells/µL. The market authorization of Cinqair was primarily based on data derived from two pivotal Phase III, randomized, double-blind, placebo-controlled studies, Study I (3082) and Study II (3083), of 52 weeks duration. In addition, the results from two non-pivotal, Phase III studies of 16 weeks duration (with inclusion criteria and primary endpoints different from those in the pivotal studies) were considered as supportive data for the safety and efficacy of Cinqair. The pivotal studies involved a total of 953 patients, 12 years of age and older, with moderate to severe asthma that was inadequately controlled on medium-to-high-dose inhaled corticosteroids with or without another controller. All enrolled patients had a history of at least one asthma exacerbation requiring systemic corticosteroid use over the preceding twelve months and a blood eosinophil count of at least 400/µL at screening. Maintenance oral corticosteroids (up to 10 mg per day prednisone or equivalent) and allergen immunotherapy were allowed. The studies evaluated Cinqair 3 mg/kg administered intravenously once every 4 weeks for a total of 13 doses as compared to placebo.

The primary efficacy measure for Studies I and II was the frequency of asthma exacerbations for each patient during the 52-week treatment period. Compared to the placebo group, patients who received Cinqair 3 mg/kg administered intravenously once every 4 weeks had a statistically significant reduction (p<0.0001) in the rates of all asthma exacerbations and asthma exacerbations requiring systemic corticosteroid use. The reduction in the rate of exacerbations that required hospitalization or emergency room visits was not statistically significant for Cinqair. Overall, Cinqair demonstrated a clinically meaningful effect in reduction of the number of asthma exacerbations, as an add-on maintenance treatment of adult patients with severe eosinophilic asthma whose symptoms were inadequately controlled, despite a medium-to-high dose of inhaled corticosteroids.

Integrated safety results from 13 studies conducted with Cinqair support the safety of reslizumab at a dose of 3 mg/kg intravenously for treatment of severe eosinophilic asthma. The overall adverse event profile of Cinqair was comparable to that of placebo.

The main safety concern related to the use of Cinqair was anaphylaxis. Anaphylaxis to Cinqair was reported in 0.19% (3/1611) of asthma patients during or within 20 minutes after completion of Cinqair infusion and as early as the second dose of Cinqair. None of these patients had a positive anti-reslizumab-antibody response. This serious safety concern has been appropriately labelled in a Serious Warnings and Precautions box in the Cinqair Product Monograph. The Serious Warnings and Precautions box highlights that patients should be observed for an appropriate period of time during and after Cinqair infusion and healthcare professionals should be prepared to manage anaphylaxis that can be life-threatening.

Commonly reported adverse events in the Cinqair-treated patients were asthma, nasopharyngitis, upper respiratory tract infections, headache and sinusitis. The incidence of myalgia was 0.97% in Cinqair- vs. 0.55% in placebo-treated patients. Malignancies occurred in less than 1% of patients in both the Cinqair- and placebo-treated patients; the incidence of malignancies in Cinqair-treated patients over the longer term (up to 3 years) was 1%. Infections were overall more frequent in the placebo group. Immunogenicity to Cinqair was reported in 7% of Cinqair-treated patients and the detected anti-reslizumab-antibody responses were of low titer and often transient.

A Risk Management Plan (RMP) for Cinqair was submitted by Teva Canada Limited to Health Canada. All safety/risk issues were adequately addressed as outlined in the Cinqair Product Monograph. 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. In addition, as part of the marketing authorization for Cinqair, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to) providing an updated Canadian RMP for Cinqair (see What follow-up measures will the company take? section).

A Look-alike Sound-alike brand name assessment was performed and the proposed name Cinqair was accepted.

Overall, the therapeutic benefits of Cinqair seen in the pivotal studies are considered to outweigh the potential risks. Cinqair 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 Cinqair 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 Cinqair?

 

Submission Milestones: Cinqair

Submission Milestone Date
Pre-submission meeting: 2015-04-30
Submission filed: 2015-07-03
Screening  
Screening Deficiency Notice issued: 2015-08-20
Response filed: 2015-09-09
Screening Acceptance Letter issued: 2015-09-25
Review  
Quality Evaluation complete: 2016-07-12
Clinical Evaluation complete: 2016-07-13
Labelling Review complete: 2016-07-12
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2016-07-20

 

The Canadian regulatory decision on the non-clinical and clinical review of Cinqair was based on a critical assessment of the Canadian data package. 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 Cinqair, 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):

  • Submitting to Health Canada, in accordance with Canadian Regulations, all serious adverse events (including malignancies, hypersensitivity reactions, etc.) that occur in all clinical trials with Cinqair.
  • Providing Health Canada with Cinqair medical educational materials for review prior to the launch of the product.
  • Providing Health Canada with all reports/correspondence pertaining to post-approval commitments from major Regulatory Authorities, e.g., the United States Food and Drug Administration (FDA), European Medicines Agency (EMA), Australia's Therapeutic Goods Administration (TGA), etc.
  • Providing Health Canada with an updated Canadian Risk Management Plan (RMP) to reflect the Canadian labelling and to capture the post-approval commitments made to Health Canada and other regulatory agencies.
  • Providing Health Canada with Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRERs) for Cinqair on a yearly basis. Each PSUR/PBRER should include an analysis of all adverse drug events as per the pharmacovigilance plan and safety updates from all ongoing clinical trials with Cinqair.
  • Providing Health Canada, within the PSURs, regular safety updates from Cinqair's Pregnancy "Teva Support Solutions™" Program from all data sources.

 

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

 

Summary Basis of Decision documents 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 Cinqair 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

Reslizumab, the medicinal ingredient in Cinqair, is an interleukin-5 (IL-5) antagonist, a humanised immunoglobulin G4 (IgG4) kappa monoclonal antibody that binds to IL-5 (with a dissociation constant of 81 pM), 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. The reduction of eosinophilic inflammation may play an important role in the therapeutic effect in severe eosinophilic asthma. The precise mechanism of reslizumab action in asthma has not been definitively established.

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

The clinical pharmacokinetic and pharmacodynamic properties of the proposed dosage form of reslizumab for intravenous administration were investigated in healthy subjects and in subjects with moderate to severe eosinophilic asthma. Data from the pharmacokinetic and pharmacodynamic studies were pooled with four Phase II and III studies (290, 10, 3081 and 3082) conducted in the target patient population (that is [i.e.], patients with moderate to severe eosinophilic asthma) for pharmacokinetic estimates, covariates effect on pharmacokinetics, and dose/exposure-response relationship analysis using population pharmacokinetic/pharmacodynamic modelling approach.

The population pharmacokinetic modelling results suggest comparable pharmacokinetics of reslizumab between healthy subjects and patients with asthma. Age, gender, and race had no significant impact on the pharmacokinetics of reslizumab. There was no apparent impact of treatment-emergent anti-drug antibodies on the pharmacokinetics of reslizumab. Reslizumab clearance increased with body weight.

Dose/exposure-response analysis demonstrated the predicted reduction of blood eosinophil count was maximal for the 3 mg/kg dose (compared to 0.3 mg/kg and 1 mg/kg). Exposure-response analysis suggested an exposure-response relationship between reslizumab steady state average concentration (Cav,ss) and forced expiratory volume in one second (FEV1) improvement from baseline. No apparent correlation between Cav,ss and clinical asthma exacerbation could be established. The exposure-safety analysis showed no significant trend of increase of muscle disorder adverse events with Cav,ss and no apparent dose-response trend for serum creatine phosphokinase concentration could be identified.

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

Clinical Efficacy

The efficacy of Cinqair as an add-on maintenance treatment of adult patients with severe eosinophilic asthma on currently available therapies was demonstrated in two pivotal randomized, double-blind, placebo-controlled studies, Study I (3082) and Study II (3083), of 52 weeks duration.

The pivotal studies involved a total of 953 patients, 12 years of age and older, with moderate to severe asthma that was inadequately controlled on medium-to-high-dose inhaled corticosteroids with or without another controller. All enrolled patients had a history of at least one asthma exacerbation requiring systemic corticosteroid use over the preceding twelve months and a blood eosinophil count of at least 400/µL at screening. Maintenance oral corticosteroids (up to 10 mg per day prednisone or equivalent) and allergen immunotherapy were allowed. Cinqair 3 mg/kg administered intravenously once every 4 weeks for a total of 13 doses was evaluated compared with placebo.

The primary efficacy measure for Studies I and II was the frequency of asthma exacerbations for each patient during the 52-week treatment period. An asthma exacerbation was defined as a worsening of asthma that required the following medical intervention:

  1. use of systemic, or an increase in the use of inhaled, corticosteroid treatment for 3 or more days; and/or
  2. asthma-related emergency treatment including at least one of the following: an unscheduled visit to a healthcare professional for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms, a visit to the emergency room for asthma-related treatment, or an asthma-related hospitalization.

The medical intervention had to be corroborated with at least one of the following:

  1. a decrease in forced expiratory volume in 1 second (FEV1) by 20% or more from baseline;
  2. a decrease in peak expiratory flow rate (PEFR) by 30% or more from baseline on 2 consecutive days; or
  3. worsening of symptoms or other clinical signs per physician evaluation of the event.

Compared to the placebo group, patients who received Cinqair 3 mg/kg administered intravenously once every 4 weeks had a statistically significant reduction (p<0.0001) in the rate of the following:

  • all asthma exacerbations: rate ratio of 0.5010 (95% confidence interval [CI]: 0.3726; 0.6737) in Study I, and 0.4063 (95% CI: 0.2819; 0.5855) in Study II; and
  • asthma exacerbations requiring systemic corticosteroid use: rate ratio of 0.4499 (95% CI: 0.3255; 0.6220) in Study I, and 0.3893 (95% CI: 0.2621; 0.5782) in Study II.

However, compared to placebo, the reduction in the rate of exacerbations that required hospitalization or emergency room visits was not statistically significant for Cinqair: rate ratio of 0.6595 (95% CI: 0.3210; 1.3550) (p = 0.2572) and 0.6886 (95% CI: 0.2828; 1.6479) (p = 0.4020) in Studies I and II, respectively.

Overall, Cinqair demonstrated a clinically meaningful effect in reduction of the number of asthma exacerbations and the efficacy data provided in this submission support the authorization of Cinqair as an add-on maintenance treatment of adult patients with severe eosinophilic asthma (with a blood eosinophil count of ≥400 cells/µL) who are inadequately controlled with medium-to-high-dose inhaled corticosteroids and an additional controller.

Indication

The original New Drug Submission (NDS) for Cinqair was filed with the following proposed indication:

Cinqair (reslizumab) is indicated for the treatment of adults and adolescents (12 years of age and above) with asthma and elevated blood eosinophils and whose symptoms are inadequately controlled with inhaled corticosteroids. Cinqair has been shown to reduce asthma exacerbations, relieve symptoms and improve lung function in these patients.

Due to insufficient clinical data in adolescent patients, Health Canada limited the proposed indication to adult patients, and approved the following indication:

Cinqair (reslizumab) is indicated as an add-on maintenance treatment of adult patients with severe eosinophilic asthma who:

  • are inadequately controlled with medium-to-high-dose inhaled corticosteroids and an additional asthma controller(s) (e.g., long-acting beta-agonist [LABA]) and
  • have a blood eosinophil count of ≥400 cells/µL at initiation of the treatment.

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

Clinical Safety

Safety results from 13 studies conducted with Cinqair were compiled in an Integrated Summary of Safety (ISS). For the purpose of summarization, 6 cohorts were defined for the integrated data. Of those, Cohort 3 (number of patients [n] = 1,861) included all asthma patients who received at least one dose of Cinqair in controlled studies through 52 weeks. Cohort 4 (n = 1,611) included all Cinqair-treated asthma patients, except those from single-dose and two-dose studies. Cohort 6 (n = 2,187) included all studies with Cinqair administration irrespective of baseline disease or inclusion of healthy subjects.

The safety analysis set included all patients who received at least one dose of study drug. The overall adverse event profile of reslizumab was similar to that of placebo.

The main safety concern related to the use of Cinqair was anaphylaxis. Anaphylaxis to Cinqair was reported in 0.19% (3/1,611) of asthma patients during or within 20 minutes after completion of Cinqair infusion and as early as the second dose of Cinqair. None of these patients had a positive anti-reslizumab-antibody response. This serious safety concern has been appropriately reflected in the Serious Warnings and Precautions box in the Cinqair Product Monograph.

Commonly reported adverse events in the Cinqair 3 mg/kg group were: asthma (23% versus [vs.] 40% in the placebo group), nasopharyngitis (10% vs. 14% in the placebo group), upper respiratory tract infections (9% vs. 10% in the placebo group), headache (8% vs. 9% in the placebo group), and sinusitis (6% vs. 7% in the placebo group).

The incidence of myalgia was 0.97% in Cinqair- vs. 0.55% in placebo-treated patients. There were no deaths related to Cinqair (Cohort 6). Malignancies occurred in less than 1% of patients in both the Cinqair- and placebo-treated patients. In addition, the incidence of malignancies in Cinqair-treated patients over the longer term (up to 3 years of treatment) including the open-label extension (Cohort 4) was 1%. Infections were overall more frequent in the placebo group. Immunogenicity to Cinqair was reported in 7% of patients and the detected anti-reslizumab-antibody responses were of low titer and often transient.

The proportion of patients who discontinued treatment due to any adverse event during the controlled clinical trials was 5% for both the 3 mg/kg Cinqair and placebo groups. Anaphylactic reaction (<1%) was the most common adverse reaction resulting in discontinuation in the 3 mg/kg Cinqair group.

Data on long-term safety of Cinqair are limited and will be further assessed by evaluating the Periodic Safety Update Reports/Periodic Benefit Risk Evaluation Reports for Cinqair, adverse drug events as per the pharmacovigilance plan, and all ongoing clinical trials with Cinqair. Notably, the sponsor has established pharmacovigilance procedures for pregnancy reporting, which will be complemented by proactive identification of pregnancies through Cinqair's "Teva Support Solutions™" program. The program is outlined in the Cinqair Product Monograph and the Risk Management Plan for Cinqair.

For more information, refer to the Cinqair 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 Cinqair for the specified indication.

Pivotal non-clinical studies were conducted in pharmacologically relevant CD-1 mice and cynomolgus monkeys. Non-clinical pharmacology studies demonstrated that reslizumab attenuates allergen induced eosinophilia when administered over a range of doses from 0.03 mg/kg to10 mg/kg via multiple routes of administration. Safety pharmacology studies conducted in monkeys did not indicate any adverse effects up to dose levels of 25 mg/kg. No significant repeat-dose toxicity was observed in CD-1 mice and monkeys administered reslizumab intravenously up to dose levels of 25 mg/kg once every 4 weeks for 6 months.

No toxicity effects on embryo-fetal development (studied in CD-1 mice and rabbits), pre- and postnatal development or fertility (studied in CD-1 mice) were observed up to dose levels of 50 mg/kg every 2 weeks. Reslizumab was shown to cross the placenta. Serum concentrations in the offspring on postnatal day 14 were approximately 6% to 8% of maternal serum concentrations. Reslizumab was also found in the milk of lactating mice following dosing during pregnancy at levels approximately 5% to 7% of maternal serum concentrations. 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 Cinqair in pregnant and lactating women. Notably, the sponsor has established pharmacovigilance procedures for pregnancy reporting, which will be complemented by proactive identification of pregnancies through Cinqair's "Teva Support Solutions™" program. The program is outlined in the Cinqair Product Monograph and the Risk Management Plan for Cinqair.

No evidence of carcinogenicity was observed in transgenic mice (Tg.rasH2) administered reslizumab intravenously up to dose levels of 516 mg/kg every 2 weeks for 6 months.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Cinqair Product Monograph. In view of the intended use of Cinqair, 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 Cinqair Product Monograph to address the identified safety concerns.

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

 

 

7.3 Quality Basis for Decision

 

Cinqair (reslizumab) is a humanized anti-human interleukin 5 (anti-IL-5) monoclonal antibody of the immunoglobulin G4 kappa (IgG4к) isotype. The therapeutic effect of reslizumab is achieved by blocking IL-5 binding capability to its specific receptor.

Characterization of the Drug Substance

Extensive characterization studies were performed to provide assurance that reslizumab 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

Drug Substance

The drug substance, reslizumab, is produced by recombinant deoxyribonucleic acid (DNA) technology in murine myeloma NS0 cells. The manufacturing process is divided into upstream cell culture process and downstream purification process. The upstream process consists of inoculum expansion, production cell culture, and harvest stages. The purification process which leads to a formulated drug substance consists of three chromatography column steps, three ultrafiltration/diafiltration steps, and two viral control steps. The in-process controls and process intermediate hold times are established and qualified.

The results from process validation studies demonstrated that the process is robust and capable of consistently and reproducibly producing the drug substance that meets the desired product quality.

Drug Product

The manufacturing process for the drug product, Cinqair, consists of dilution of the formulated drug substance, sterile filtration, and aseptic filling steps. The in-process controls and process intermediate hold times are established and qualified.

The results from process validation studies demonstrated that the process is robust and capable of consistently and reproducibly producing Cinqair that meets the desired quality.

Cinqair is a preservative-free, colourless to slightly yellow sterile aqueous solution presented as 100 mg in a single-use 10 mL glass vial. It is formulated as 10 mg/mL reslizumab in 20 mM sodium acetate, 7% sucrose, pH 5.5. Cinqair is diluted in sterile 0.9% normal saline solution prior to infusion.

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 reslizumab with the excipients was demonstrated.

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 and analytical procedures are validated.

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 shelf life of 36 months at 2°C-8°C for Cinqair is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance (reslizumab) was waived as there was no drug substance production during the review period and the manufacturing site was previously evaluated in good standing.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug product (Cinqair) was waived as the manufacturing site was previously evaluated in good standing.

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

Adventitious Agents Safety Evaluation

The reslizumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

 

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