Summary Basis of Decision for Dupixent

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 Dupixent is located below.

Recent Activity for Dupixent

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 Dupixent

Updated:

2023-02-28

The following table describes post-authorization activity for Dupixent, a product which contains the medicinal ingredient dupilumab. 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 02470365 – 150 mg/mL dupilumab, solution, subcutaneous administration (pre-filled syringe)
  • DIN 02492504 – 200 mg/1.14 mL dupilumab, solution, subcutaneous administration (pre-filled syringe)
  • DIN 02510049 – 150 mg/mL dupilumab, solution, subcutaneous administration (pre-filled pen)
  • DIN 02524252 – 200 mg/1.14 mL dupilumab, solution, subcutaneous administration (pre-filled pen)
  • DIN 02526190 – 100 mg/0.67 mL dupilumab, solution, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 266752 2022-08-05 Issued NOL 2022-11-03 Submission filed as a Level II (90 day) Notifiable Change for changes to the manufacturing process and controls for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 266107 2022-07-15 Issued NOL 2022-09-13 Submission filed as a Level II (90 day) Notifiable Change for a change in supplier for a primary container closure component. The submission was considered acceptable, and an NOL was issued.
NC # 265104 2022-06-10 Issued NOL 2022-08-03 Submission filed as a Level II (90 day) Notifiable Change for changes to the manufacturing process and in scale for the drug product. The submission was considered acceptable, and an NOL was issued.
Drug product (DIN 02524252) market notification Not applicable Date of first sale: 2022-06-23 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 262316 2022-03-11 Issued NOL 2022-05-19 Submission filed as a Level II (90 day) Notifiable Change for alternate sites for quality control testing of the drug product. The submission was considered acceptable, and an NOL was issued.
SNDS # 257119 2021-09-29 Issued NOC 2022-05-05 Submission filed as a Level I – Supplement to add alternate sites for manufacturing and testing of the of the drug substance and storage of the working cell bank. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 252306 2021-04-30 Issued NOC 2022-03-25 Submission filed as a Level I – Supplement for a new indication and a new presentation The indication authorized was: as add-on maintenance treatment in patients aged 6-11 years with severe asthma with a type 2/eosinophilic phenotype or oral corticosteroid-dependent asthma. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02526190) was issued for the new presentation. A Regulatory Decision Summary was published.
SNDS # 251729 2021-04-15 Issued NOC 2022-03-09 Submission filed as a Level I – Supplement to update the PM with new clinical data from the asthma study TRAVERSE and the atopic dermatitis study AD-1225. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions, Clinical Pharmacology, and Clinical Trials sections of the PM. An NOC was issued.
SNDS # 253234 2021-05-31 Issued NOC 2022-01-13 Submission filed as a Level I – Supplement to add a new presentation. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02524252) was issued for the new presentation
SNDS # 251622 2021-04-12 Issued NOC 2021-08-17 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 248890 2021-01-28 Issued NOC 2021-06-24 Submission filed as a Level I – Supplement to add an alternate site for manufacturing of the drug product. The data were reviewed and considered acceptable, and an NOC was issued.
Drug product (DIN 02510049) market notification Not applicable Date of first sale: 2021-05-27 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 243966 2020-09-15 Issued NOC 2021-03-24 Submission filed as a Level I – Supplement to add an alternate site for manufacturing and testing of the drug substance. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 237081 2020-03-17 Issued NOC 2021-02-22 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as an add-on maintenance treatment for children (aged >6 and <12 years) with moderate to severe atopic dermatitis. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 246167 2020-11-05 Issued NOL 2021-02-17 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 243767 2020-09-09 Issued NOC 2021-01-20 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
NC # 244653 2020-09-28 Issued NOL 2021-01-07 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to generate a new working cell bank. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 239184 2020-05-11 Issued NOC 2020-12-23 Submission filed as a Level I – Supplement to add a filling line for the drug product, and a new presentation. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02510049) was issued for the new presentation.
NC # 241953 2020-07-20 Issued NOL 2020-11-12 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update in-process controls used in the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 234105 2019-12-02 Issued NOC 2020-11-12 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as an add-on maintenance treatment for adult and adolescents (12 years of age and older) with severe asthma characterized by a Type 2/eosinophilic phenotype or asthma requiring oral corticosteroid. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 240037 2020-05-27 Issued NOC 2020-10-23 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 231268 2019-09-04 Issued NOC 2020-08-12 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as an add-on maintenance treatment with intranasal corticosteroids in adult patients with severe chronic rhinosinusitis with nasal polyposis (CRSwNP) inadequately controlled by systemic corticosteroids and/or sino-nasal surgery. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 236044 2020-02-12 Issued NOL 2020-05-04 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 and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 231996 2019-09-27 Issued NOL 2019-12-09 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 02492504) market notification Not applicable Date of first sale: 2019-11-29 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 221043 2018-10-16 Issued NOC 2019-09-25 Submission filed as a Level I – Supplement for a new indication and a new presentation. The indication authorized was: the treatment of patients aged 12 to 18 years with moderate-to-severe atopic dermatitis (AD) whose disease was not adequately controlled with topical prescription therapies or when those therapies are not advisable. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02492504) was issued for the new presentation. A Regulatory Decision Summary was published.
SNDS # 220709 2018-10-03 Issued NOC 2019-09-04 Submission filed as a Level I – Supplement to update the PM with data from a drug-drug interaction study. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Drug Interactions section of the PM. An NOC was issued.
NC # 228256 2019-05-31 Issued NOL 2019-07-11 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 and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02470365) market notification Not applicable Date of first sale:
2018-02-06		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 201285 2016-12-16 Issued NOC
2017-11-30		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Dupixent

Date SBD issued: 2018-02-09

The following information relates to the new drug submission for Dupixent.

Dupilumab
150 mg/mL, solution, subcutaneous

Drug Identification Number (DIN):

  • 02470365

Sanofi-aventis Canada Inc.

New Drug Submission Control Number: 201285

 

On November 30, 2017, Health Canada issued a Notice of Compliance to Sanofi-aventis Canada Inc. for the drug product Dupixent.

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 Dupixent is favourable for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

1 What was approved?

Dupixent is an immunomodulator, a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signalling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. It was authorized for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Dupixent can be used with or without topical corticosteroids.

Dupixent is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.

Of the 1,472 patients with atopic dermatitis exposed to Dupixent in a Phase II dose-ranging study or Phase III placebo-controlled studies, only 67 were 65 years of age or older. While no differences in safety or efficacy were observed between older and younger patients, the number of patients aged 65 years and over was not sufficient to determine whether they respond differently from younger patients.

Safety and efficacy in pediatric patients (younger than 18 years of age) have not been established.

Dupixent 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.

Dupixent (150 mg/mL dupilumab) is presented as a solution. In addition to the medicinal ingredient, the solution contains L-arginine hydrochloride, L-histidine, polysorbate 80, sodium acetate, sucrose, and water for injection, adjusted to pH 5.9 with acetic acid.

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

2 Why was Dupixent approved?

Health Canada considers that the benefit-risk profile of Dupixent is favourable for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Atopic dermatitis, also known as atopic eczema, is a chronic, relapsing inflammation of the skin that is characterized by intractable pruritus (itch), extensive xerosis (abnormally dry and scaly skin), and skin lesions. The pathophysiology of the disease involves genetic, environmental, and immunologic factors that trigger hypersensitivity reactions. Patients with moderate-to-severe atopic dermatitis have an increased risk for bacterial and viral infections of the skin. The clinical manifestations of atopic dermatitis can also lead to psychological and sociological sequelae with a negative impact on patients' lives. Atopic dermatitis affects 15-30% of children and 2-10% of adults in developed countries. Males and females are equally affected.

Non-pharmacological management of atopic dermatitis includes measures for controlling environmental factors, skin hydration, and phototherapy. Topical corticosteroids are used as the first-line topical treatment and are effective in controlling mild atopic dermatitis. Side effects related to topical corticosteroids include skin atrophy, dyspigmentation, and acneiform eruptions. Topical calcineurin inhibitors, such as tacrolimus and pimecrolimus, are used as short-term therapy or long-term treatment intermittently, as needed; however, they are associated with an increased risk for skin malignancies and lymphomas.

Dupixent is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signalling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupixent inhibits IL-4 signalling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signalling through the Type II receptor (IL-4Rα/IL-13Rα). Both IL-4 and IL-13 are key type 2 cytokines involved in atopic disease.

Dupixent has been shown to be efficacious in patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies. The market authorization of Dupixent was based on data derived from three randomized, double-blind, placebo-controlled Phase III pivotal trials, which evaluated the efficacy and safety of Dupixent when used as monotherapy (SOLO 1 and SOLO 2 trials), and concomitantly with topical corticosteroids (CHRONOS trial). In all three trials, patients in the Dupixent group received subcutaneous injections of Dupixent 600 mg at Week 0, followed by 300 mg every other week (Q2W). In the SOLO 1 and SOLO 2 trials, patients received Dupixent or placebo for 16 weeks. In the CHRONOS trial, patients received Dupixent or placebo with concomitant topical corticosteroids and, as needed, topical calcineurin inhibitors for problem areas only, such as the face, neck, intertriginous and genital areas, for 52 weeks.

In each trial, the primary endpoint was the change from baseline to Week 16 in the proportion of patients with an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) and at least a 2-point improvement on the IGA from the baseline score.

Other endpoints included the proportion of subjects with Eczema Area and Severity Index (EASI)-75 (improvement of at least 75% in EASI score from baseline), and reduction in itch as defined by at least a 4-point improvement in the peak pruritus Numeric Rating Scale (NRS) score from baseline to Week 16.

Dupixent was superior to placebo in all three clinical trials in the target atopic dermatitis population for the primary endpoint and for key secondary endpoints. Patient-reported outcomes were consistent with physician-reported outcomes.

The safety profile of Dupixent in the target population, as evaluated in over 2,500 patients in the three pivotal trials and over 52 weeks of treatment (740 patients), is considered acceptable. The safety profile reported in the Dupixent monotherapy trials was similar to the safety profile observed in the trial of Dupixent with concomitant topical corticosteroids. An increased incidence of conjunctivitis, keratitis, blepharitis, and dry eye in the Dupixent arms, of mild to moderate severity, rarely required treatment discontinuation. Dupixent was generally well tolerated.

A Risk Management Plan (RMP) for Dupixent was submitted by Sanofi-aventis 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.

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

Overall, the therapeutic benefits of Dupixent, in the target population and for the indication sought, outweigh its risks. The overall benefit-risk profile of Dupixent is considered to be favourable for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Appropriate warnings and precautions are in place in the Dupixent 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 Dupixent?

Submission Milestones: Dupixent

Submission Milestone Date
Pre-submission meeting: 2016-10-19
Submission filed: 2016-12-16
Screening  
Screening Acceptance Letter issued: 2017-02-03
Review  
Quality Evaluation complete: 2017-11-30
Clinical Evaluation complete: 2017-11-30
Review of Risk Management Plan complete: 2017-11-20
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-11-29
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-11-30 - 2017-12-05

The Canadian regulatory decision on the quality, non-clinical and clinical review of Dupixent was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

As part of the marketing authorization for Dupixent, 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):

  • Including Canadian patients in the planned pregnancy registry.
  • Providing Health Canada with the results of the two pharmacovigilance studies (3183-5 and 3183-6) mandated by the United States Food and Drug Administration (FDA), when available.
  • Providing Health Canada with the final clinical study report of the trial CHRONOS, when available.
  • Providing Health Canada with the results of the four FDA-mandated pediatric studies (3183-1, 3183-2, 3183-3, and 3183-4), when available.
  • Submitting the results of the aforementioned studies as a Supplement to a New Drug Submission, and updating the Canadian Product Monograph, as needed.
  • Providing Health Canada with Periodic Safety Update Reports on Dupixent every six months for the first two years and every 12 months thereafter.
5 What post-authorization activity has taken place for Dupixent?

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 Dupixent 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 pharmacokinetic properties of dupilumab, the medicinal ingredient in Dupixent, were assessed in single-dose and repeat-dose studies conducted in healthy volunteers and patients with atopic dermatitis. At the recommended dosing regimen, maximum blood levels were achieved within 3-7 days (after the loading dose administered on Day 1), and steady-state levels within 10 weeks. Clearance was nonlinear and dose-dependent. There was a correlation between body weight and dupilumab blood concentrations. Mean trough concentration in patients weighing <70 kg was more than halved compared to the group weighing ≥100 kg. The clinical pharmacology data support the dosing regimen of 600 mg as a loading dose followed by 300 mg every other week (Q2W).

Anti-drug antibodies (ADA) were detected in <2% of patients in the SOLO 1 and CHRONOS trials. The presence of ADA generally did not lower the dupilumab blood concentrations at the recommended dosing regimen. However, more frequent (i.e., weekly) administration of dupilumab resulted in high ADA titers and the presence of neutralizing antibodies. Neutralizing antibodies were not generally associated with loss of efficacy, except in patients who exhibited high-titer ADA responses.

No drug interaction studies were conducted.

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

Clinical Efficacy

The clinical efficacy of Dupixent was evaluated in three randomized, double-blind, placebo-controlled Phase III trials (SOLO 1, SOLO 2, and CHRONOS) that enrolled a total of 2,119 patients, 18 years of age and older, with moderate-to-severe atopic dermatitis not adequately controlled by topical medications.

Disease severity was defined by the Investigator's Global Assessment (IGA) score ≥3 in the overall assessment of atopic dermatitis lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16 on a scale of 0 to 72, and a minimum body surface area involvement of ≥10%. At baseline, there were 52% of patients with an IGA score of 3 (moderate atopic dermatitis), and 48% of patients had an IGA score of 4 (severe atopic dermatitis). The baseline mean EASI score was 33 and the baseline weekly averaged peak pruritus Numeric Rating Scale (NRS) score was 7 on a scale of 0-10.

Dupixent was administered as monotherapy in the SOLO 1 and SOLO 2 trials, whereas in the CHRONOS trial it was given concomitantly with topical therapy. In all three trials, patients in the Dupixent group received subcutaneous injections of Dupixent 600 mg at Week 0, followed by 300 mg every other week (Q2W). In the monotherapy trials (SOLO 1 and SOLO 2), patients received Dupixent or placebo for 16 weeks. In the concomitant therapy trial (CHRONOS), patients received Dupixent or placebo with concomitant topical corticosteroids and, as needed, topical calcineurin inhibitors for problem areas only, such as the face, neck, intertriginous and genital areas, for 52 weeks.

In each trial, the primary endpoint was the change from baseline to Week 16 in the proportion of patients with an IGA score of 0 (clear) or 1 (almost clear) and at least a 2-point improvement on the IGA from the baseline score.

Other endpoints included the proportion of patients with EASI-75 (improvement of at least 75% in EASI score from baseline), and reduction in itch as defined by at least a 4-point improvement in the peak pruritus NRS score from baseline to Week 16.

The primary endpoint was met in all three trials. A statistically significantly greater proportion of patients randomized to Dupixent achieved an IGA 0 or 1 response and had at least a 2-point improvement on the IGA from the baseline score. In SOLO 1, 37.9% of Dupixent-treated patients achieved the IGA response as compared to 10.3% of the placebo-treated patients. Similarly, in SOLO 2, 36.1% of the patients treated with Dupixent were IGA responders vs. 8.5% in the placebo group. In CHRONOS, among the patients treated with Dupixent and topical corticosteroids, there were 38.7% IGA responders as compared to 12.4% in the group treated with placebo and topical corticosteroids.

In addition, in all three trials, a statistically significantly greater proportion of patients randomized to Dupixent achieved EASI-75, and/or an improvement of >4 points on the pruritus NRS as compared to placebo.

The CHRONOS trial is ongoing. At the time of data analysis, out of 421 patients, 353 had been in the trial for 52 weeks. Of these 353 patients, treatment responders at Week 52 included patients who had maintained their response from Week 16, and patients who were non-responders at Week 16 but responded later to treatment.

Patient-reported outcomes in both monotherapy trials (SOLO 1 and SOLO 2) and in the Dupixent with topical corticosteroids trial (CHRONOS) were consistent with the significant improvements observed in the physician-reported outcomes.

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

Clinical Safety

A total of 2,526 patients with atopic dermatitis were treated with Dupixent in controlled and uncontrolled clinical trials. Of these, 740 patients were exposed to the drug for at least one year.

The safety of Dupixent monotherapy was evaluated through Week 16 based on data from the trials SOLO 1 and SOLO 2 (described in the Clinical Efficacy section), and a Phase II dose-ranging study, which included overall 1,564 adult patients with moderate-to-severe atopic dermatitis. The safety of Dupixent administered with concomitant topical corticosteroids was evaluated based on data from the CHRONOS trial (described in the Clinical Efficacy section). The safety profile of Dupixent when administered as monotherapy was similar to the safety profile observed when used with concomitant topical corticosteroids.

Notable adverse drug reactions that occurred in ≥1% of patients with atopic dermatitis treated with Dupixent through Week 16 included injection site reactions, conjunctivitis, and oral herpes.

Injection site reactions were reported in 9.6% of the patients treated with Dupixent monotherapy (vs. 5.4% of the placebo-treated patients), and in 10% of the patients treated with Dupixent and concomitant topical corticosteroids (vs. 5.7% of the patients receiving placebo and concomitant topical corticosteroids).

Conjunctivitis occurred in 9.6% of the patients receiving Dupixent monotherapy and in 9.1% of the patients receiving Dupixent and concomitant topical corticosteroids, as compared to 2.3% and 4.8% in the respective placebo groups.

Oral herpes was reported in 3.8% of patients in the Dupixent monotherapy group (vs.1.5% in the placebo group), and in 2.7% of patients treated with Dupixent and concomitant topical corticosteroids (vs.1.6% in the placebo and concomitant topical corticosteroids group).

No treatment-related deaths were reported. The highest incidence rates of treatment-emergent adverse events were reported in the infections and infestations category; the incidence rates were similar for Dupixent and placebo. The most common adverse events in that category included nasopharyngitis, upper respiratory tract infection, conjunctivitis, and oral herpes. Adverse events relating to the eye were reported, which included conjunctivitis (as mentioned above), as well as keratitis, blepharitis, and dry eye. These events were generally mild to moderate in severity and rarely required discontinuation of treatment.

In the monotherapy studies, the proportion of patients who discontinued treatment due to adverse events was 1.9% of the Dupixent 300 mg Q2W group and 1.9% of the placebo group. In the Dupixent with concomitant topical corticosteroids trial, the proportion of patients who discontinued treatment due to adverse events was 1.8% of the Dupixent 300 mg Q2W with topical corticosteroids group and 7.6% of the placebo with topical corticosteroids group.

The safety profile of Dupixent with topical corticosteroids through Week 52 was consistent with the safety profile observed at Week 16.

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

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

7.2 Non-Clinical Basis for Decision

Dupilumab, the medicinal ingredient in Dupixent, binds specifically to human interleukin-4 receptor α (IL-4Rα) and does not react with any other animal species. Therefore, pivotal toxicology studies were conducted using surrogate antibodies against the IL-4Rα of cynomolgus monkeys and CD-1 mice.

No significant adverse effects were observed in cynomolgus monkeys when administered a surrogate antibody against IL-4Rα by subcutaneous or intravenous injection up to dose levels of 100 mg/kg/week for 6 months.

No significant adverse embryo-fetal, morphological, functional or immunological developmental effects were observed in the offspring of pregnant cynomolgus monkeys up to dose levels of 100 mg/kg/week. Concentrations of the surrogate antibody observed in the infant monkeys at birth indicated placental transfer.

No effects on fertility parameters were observed in sexually mature mice receiving a murine surrogate antibody against IL-4Rα by subcutaneous injection up to dose levels of 200 mg/kg/week.

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

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

7.3 Quality Basis for Decision

Dupilumab, the medicinal ingredient in Dupixent, is a recombinant human IgG4 monoclonal antibody that binds specifically to the alpha subunit of the Type I and II interleukin-4 receptors (IL-4Rα). Dupilumab inhibits IL-4 signalling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signalling through the Type II receptor (IL-4Rα/IL-13Rα). Both IL-4 and IL-13 are key type 2 cytokines involved in atopic disease.

Characterization of the Drug Substance

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

Data from process validation studies demonstrate 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

The drug substance, dupilumab, is manufactured using recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary (CHO) cell suspension culture. The manufacturing process consists of two distinct stages: manufacture of the drug substance and manufacture of the formulated drug substance. The growth medium, containing the recombinant protein product, is harvested by centrifugation followed by depth and polish filtration. Dupilumab protein is then purified via protein A affinity chromatography, low pH viral inactivation, depth filtration, cation-exchange chromatography, anion-exchange chromatography, hydrophobic interaction chromatography, virus-retentive filtration, and concentration/diafiltration to 150 mg/mL, followed by dispensing and storage.

The formulated drug substance is thawed, pooled and mixed, then filtered using redundant sterilizing filters, or prefiltered for bioburden reduction and sterile-filtered during filling. Dupixent is provided as an aqueous buffered solution containing: 150 mg/mL dupilumab, 12.5 mM acetate, 20 mM histidine, 25 mM arginine, and 5% (w/v) sucrose, 0.2% super refined polysorbate 80, at pH 5.9. Two different presentations are available: a prefilled syringe (PFS) and a prefilled syringe with safety system (PFS-S) for injury prevention.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and considered to be adequately controlled within justified limits.

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 dupilumab 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 the International Council for Harmonisation (ICH) guidelines.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf life at 2°C to 8°C for Dupixent is considered acceptable.

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.

An On-Site Evaluation of the facilities involved in the manufacture and testing of the drug substance and the drug product was not warranted since the facilities were recently evaluated and obtained a satisfactory rating.

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

Adventitious Agents Safety Evaluation

The dupilumab purification process demonstrates a high level of viral clearance for a variety of virus types. The process employs both viral clearance and viral inactivation steps (protein A chromatography, viral inactivation by low pH, anion-exchange chromatography, and virus-retentive filtration). Appropriate small-scale studies demonstrated that the dupilumab purification process is capable of achieving an acceptable adventitious agent safety profile.

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