Summary Basis of Decision for Adtralza

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 Adtralza is located below.

Recent Activity for Adtralza

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Adtralza, a product which contains the medicinal ingredient tralokinumab. 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 AnchorGuidance Document: The Management of Drug Submissions and Applications.

Updated: 2024-06-19

Drug Identification Number (DIN):

DIN 02521288 – 150 mg/mL tralokinumab, solution, subcutaneous administration (pre-filled syringe)

DIN 02540193 – 300 mg/2 mL tralokinumab, solution, subcutaneous administration (pre-filled pen)

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02540193) market notification Not applicable Date of first sale: 2024-06-03 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 281752 2023-12-01 Issued NOL 2024-01-23 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the parameters of an approved holding step or addition of a new holding step. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 281603 2023-11-29 Issued NOL 2024-01-17 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the auxiliary materials/reagents of biological origin. The submission was considered acceptable, and an NOL was issued.
NC # 281130 2023-11-15 Issued NOL 2023-12-14 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug product (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 270639 2022-12-14 Issued NOC 2023-08-04 Submission filed as a Level I – Supplement for a 2.0 mL pre-filled pen presentation (300 mg/2 mL). The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02540193) was issued for the new dosage form.
SNDS # 272285 2023-02-09 Issued NOC 2023-07-12 Submission filed as a Level II – Supplement (Safety) to update the Adverse Reactions section of the PM. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 261661 2022-02-18 Issued NOC 2023-02-03 Submission filed as a Level I – Supplement to expand the indication and update the PM to include drug-drug interaction information. The indication authorized was: the treatment of moderate-to-severe atopic dermatitis in adult and adolescent patients 12 years and older whose disease is 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 Regulatory Decision Summary was published.
NC # 262917 2022-03-30 Issued NOL 2022-04-27 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a new supplier of a starting material for the manufacture of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02521288) market notification Not applicable Date of first sale: 2022-03-17 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 245877 2020-10-30 Issued NOC 2021-10-13 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Adtralza

Date SBD issued: 2022-04-19

The following information relates to the New Drug​​​​ Submission for Adtralza.

Tralokinumab

Drug Identification Number (DIN):

  • DIN 02521288 - 150 mg/mL tralokinumab, solution, subcutaneous administration

LEO Pharma Inc.

New Drug Submission Control Number: 245877

 

On October 13, 2021, Health Canada issued a Notice of Compliance to LEO Pharma Inc. for the drug product Adtralza.

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

Adtralza can be used with or without topical corticosteroids.

 

1 What was approved?

 

Adtralza, an immunomodulator, was authorized for the treatment of moderate-to-severe atopic dermatitis in adult patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Adtralza can be used with or without topical corticosteroids.

Adtralza is not authorized for use in pediatric patients (younger than 18 years of age), as no clinical data are available to Health Canada for this population.

Of the 1,605 patients exposed to Adtralza in the initial 16-week treatment period of the atopic dermatitis clinical studies, 77 patients were 65 years of age or older. Although the number of patients aged 65 years and over is limited, evidence from clinical studies suggests there are no differences in safety and efficacy between older and younger subjects. No dose adjustment is recommended for elderly patients.

Adtralza (150 mg/mL tralokinumab) is presented as a solution. In addition to the medicinal ingredient, the solution contains acetic acid, polysorbate 80, sodium acetate trihydrate, sodium chloride, and water for injection.

Adtralza is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

The drug product Adtralza was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Adtralza Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

2 Why was Adtralza approved?

 

Health Canada considers that the benefit-risk profile of Adtralza is favourable for the treatment of moderate-to-severe atopic dermatitis in adult patients 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 are also at an increased risk for bacterial and viral infections of the skin. The clinical manifestations of atopic dermatitis can lead to psychological and sociological sequelae that have a negative impact on patients’ lives. Atopic dermatitis is the most common inflammatory skin disease in the developed world, affecting 15% to 30% of children and 2% to 10% of adults.

The main goal of treatment in atopic dermatitis is the reduction of inflammation and symptoms, in particular, pruritus. Management of moderate-to-severe atopic dermatitis is challenging because of the chronicity of the disease and the limited therapeutic options that are both efficacious and safe, with a tolerable long-term safety profile. Non-pharmacological management of atopic dermatitis includes measures for controlling environmental factors, skin hydration, and phototherapy. Pharmacological management of atopic dermatitis primarily includes topical corticosteroids, which are used as the first-line topical treatment and are effective in controlling mild atopic dermatitis. Side effects related to the use of 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. Biological treatment options include dupilumab (Dupixent), a monoclonal antibody inhibiting interleukin (IL)-4 and IL-13, authorized for the treatment of patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Tralokinumab, the medicinal ingredient in Adtralza, is a human immunoglobulin G4 (IgG4) monoclonal antibody that specifically binds to IL-13 and inhibits IL-13 signalling, thereby blocking the stimulation of inflammatory responses characteristic for atopic dermatitis.

Adtralza 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 Adtralza was based on data derived from three randomized, double-blind, placebo-controlled Phase III pivotal trials, which evaluated the efficacy and safety of Adtralza when used as monotherapy (ECZTRA 1 and ECZTRA 2 trials) and concomitantly with topical corticosteroids (ECZTRA 3 trial).

In all three pivotal trials, the superiority of Adtralza compared to placebo was assessed based on the following primary endpoints: the proportion of patients with an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) at Week 16, and the proportion of patients with Eczema Area and Severity Index (EASI)-75 (improvement of at least 75% in EASI score from baseline) at Week 16.

Secondary endpoints included a reduction in itch as defined by at least a 4-point improvement in the Worst Daily Pruritus Numeric Rating Scale (NRS) score, a reduction in the SCORing Atopic Dermatitis (SCORAD) scale, a change in Dermatology Life Quality Index (DLQI), and a reduction of at least 50% and 90% in the EASI (EASI-50 and EASI-90) from baseline to Week 16.

In all three trials, patients in the Adtralza group received subcutaneous injections of Adtralza 600 mg at Week 0, followed by Adtralza 300 mg every two weeks (Q2W) until at least Week 16.

To evaluate the maintenance of response in ECZTRA 1 and ECZTRA 2 trials, patients responding to initial 16-week treatment with Adtralza (i.e., those who achieved IGA 0 or 1, or EASI-75) were rerandomized to receive the following for 36 weeks:

  • Adtralza 300 mg Q2W, or
  • Adtralza 300 mg every 4 weeks (Q4W) (alternating Adtralza 300 mg and placebo Q2W), or
  • placebo Q2W

Patients responding to the initial 16-week treatment with placebo continued on placebo. Patients not achieving IGA 0 or 1 or EASI-75 at Week 16 and patients who did not maintain the response during the maintenance period were transferred to open-label treatment with Adtralza 300 mg Q2W with optional use of topical corticosteroids.

In ECZTRA 3, to evaluate the maintenance of response, patients responding to the initial 16-week treatment with Adtralza plus topical corticosteroids (TCS) were rerandomized to receive the following for 16 weeks:

  • Adtralza 300 mg Q2W + TCS, or
  • Adtralza 300 mg Q4W + TCS (alternating placebo 300 mg Q2W + TCS)

Patients responding to the initial 16-week treatment with placebo + TCS continued on placebo + TCS. Patients, who at Week 16 did not achieve IGA 0 or 1 or EASI-75, continued on Adtralza 300 mg Q2W + TCS treatment, irrespectively of their initial treatment.

The trial duration was 52 weeks for the monotherapy trials (ECZTRA 1 and ECZTRA 2) and 32 weeks for the concomitant topical corticosteroids trial (ECZTRA 3).

While the effect size was relatively modest, results from all three trials showed that compared to placebo, both Adtralza as monotherapy and Adtralza in combination with topical corticosteroids were associated with a clinically relevant and statistically significant effect in terms of patients achieving IGA 0 or 1 and EASI-75 responses at Week 16. The maintenance of efficacy was observed up to 52 weeks. Secondary endpoints measuring specific symptoms (i.e., pruritus), anxiety and depression, sleep disturbances, and quality of life were all supportive of the favourable effects seen in the primary endpoints.

The safety of Adtralza was evaluated based on a pool of 5 randomized, double-blind, placebo controlled studies in patients with moderate-to-severe atopic dermatitis. From these trials 1,991 patients were evaluated, including 807 subjects that were exposed to the study drug for at least one year. The safety profile reported in the Adtralza monotherapy trials was similar to the safety profile observed in the trial of Adtralza with concomitant topical corticosteroids. An increased incidence of eye disorders (conjunctivitis and keratitis), as well as eosinophilia in Adtralza-treated patients, of mild to moderate severity, rarely required treatment discontinuation. Overall, Adtralza was generally well tolerated.

A Risk Management Plan (RMP) for Adtralza was submitted by LEO Pharma 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 Adtralza was accepted.

Based on the clinical and non-clinical data, the therapeutic benefits of Adtralza outweigh its risks for the target population and the indication sought. The overall benefit-risk profile of Adtralza 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 Adtralza 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 Adtralza?

 

Submission Milestones: Adtralza

Submission Milestone Date
Pre-submission meeting 2020-09-16
New Drug Submission filed 2020-10-30
Screening  
Screening Acceptance Letter issued 2020-11-23
Review  
Review of Risk Management Plan completed 2021-09-17
Quality evaluation completed 2021-09-21
Non-clinical evaluation completed 2021-10-08
Clinical/medical evaluation completed 2021-10-12
Biostatistics evaluation completed 2021-10-12
Labelling review completed 2021-10-12
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2021-10-13

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Adtralza was based on a critical assessment of the data package submitted to Health Canada. Various documents related to the review conducted at 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?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

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

 

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 life cycle.Anchor

The PAAT for Adtralza 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 tralokinumab, the medicinal ingredient in Adtralza, were assessed in single-dose and repeat-dose studies in healthy volunteers and patients with asthma and atopic dermatitis. At the recommended dosing regimen, maximum serum concentrations were achieved after 5 to 8 days (after the loading dose administered on Day 1), and steady-state levels within 6 weeks. Clearance was linear; however, there was a correlation between higher body weight and decreased tralokinumab serum concentrations.

The clinical pharmacology data adequately support the proposed dosage regimen, with an initial 600 mg dose followed by 300 mg every two weeks. In certain patients who demonstrate an efficacious response after 16 weeks, dosing of 300 mg every four weeks may be considered. However, due to the correlation between higher body weight and decreased tralokinumab serum concentrations, dosing every other week may be more appropriate than dosing every fourth week for patients who weigh more than 100 kg.

Anti-drug antibodies (ADA) were detected in 1.4% of patients who received tralokinumab and 1.3% of patients who received placebo during the initial 16 weeks of treatment in the three pivotal Phase III clinical trials and the vaccine-response study. The ADA incidence for patients who received tralokinumab up to 52 weeks in these trials was 4.4%; 0.7% of patients had persistent ADA and 0.9% had neutralizing antibodies (nAbs). The presence of ADAs (including nAbs) was not generally associated with a notable impact on tralokinumab exposure, safety, or efficacy.

No drug interaction studies were conducted.

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

Clinical Efficacy

The clinical efficacy of Adtralza was primarily based on data from three randomized, double-blind, placebo-controlled Phase III clinical trials (ECZTRA 1, ECZTRA 2, and ECZTRA 3) that enrolled 1,976 patients, 18 years of age and older, with moderate-to-severe atopic dermatitis not adequately controlled by topical medications.

In all three pivotal trials, the superiority of Adtralza compared to placebo was assessed based on the following primary endpoints: 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) at Week 16, and the proportion of patients with Eczema Area and Severity Index (EASI)-75 (improvement of at least 75% in EASI score from baseline) at Week 16.

Secondary endpoints included a reduction in itch as defined by at least a 4-point improvement in the Worst Daily Pruritus Numeric Rating Scale (NRS) score, a reduction in the SCORing Atopic Dermatitis (SCORAD) scale, a change in Dermatology Life Quality Index (DLQI), and a reduction of at least 50% and 90% in the Eczema Area and Severity Index (EASI-50 and EASI-90) from baseline to Week 16.

In all three trials, patients in the Adtralza group received subcutaneous injections of Adtralza 600 mg at Week 0, followed by Adtralza 300 mg every two weeks (Q2W) until at least Week 16.

To evaluate the maintenance of response in ECZTRA 1 and ECZTRA 2 trials, patients responding to initial 16-week treatment with Adtralza (i.e., patient achieving IGA 0 or 1, or EASI-75) were rerandomized to receive the following for 36 weeks:

  • Adtralza 300 mg Q2W, or
  • Adtralza 300 mg every 4 weeks (Q4W) (alternating Adtralza 300 mg and placebo Q2W), or
  • placebo Q2W

Patients responding to the initial 16-week treatment with placebo continued on placebo. Patients not achieving IGA 0 or 1, or EASI-75 at Week 16, and patients who did not maintain the response during the maintenance period were transferred to open-label treatment with Adtralza 300 mg Q2W with optional use of topical corticosteroids.

In ECZTRA 3, to evaluate the maintenance of response, patients responding to the initial 16-week treatment with Adtralza plus use of topical corticosteroids (TCS) were rerandomized to receive the following for 16 weeks:

  • Adtralza 300 mg Q2W + TCS, or
  • Adtralza 300 mg Q4W + TCS (alternating placebo 300 mg Q2W + TCS)

Patients responding to the initial 16-week treatment with placebo + TCS continued on placebo + TCS. Patients who at week 16 did not achieve IGA 0 or 1, or EASI-75, continued on Adtralza 300 mg Q2W + TCS treatment, irrespectively of their initial treatment.

The monotherapy trials (ECZTRA 1 and ECZTRA 2) were 52 weeks in length. The concomitant topical corticosteroids trial (ECZTRA 3) was 32 weeks in length.

In all three trials, efficacy results at Week 16 showed that while the effect size was relatively modest, both Adtralza monotherapy and Adtralza in combination with topical corticosteroids were associated with a clinically relevant and statistically significant effect in terms of patients achieving IGA 0 or 1 and EASI-75 responses compared to placebo. At Week 16, the proportion of patients with IGA 0 or 1 was 15.8% (ECZTRA 1), 22.2% (ECZTRA 2), and 38.9% (ECZTRA 3) in the Adtralza Q2W groups as compared to 7.1% (ECZTRA 1), 10.9% (ECZTRA 2), and 26.2% (ECZTRA 3) in the placebo groups. In addition, the proportion of patients with EASI-75 was 25.0% (ECZTRA 1), 33.2% (ECZTRA 2), and 56.0% (ECZTRA 3) in the Adtralza Q2W groups as compared to 12.7% (ECZTRA 1), 11.4% (ECZTRA 2), and 35.7% (ECZTRA 3) in the placebo groups. As observed by indirect comparison between the concomitant topical corticosteroids trial and monotherapy trials, the presence of concomitant topical corticosteroids resulted in a more pronounced efficacy response.

Secondary efficacy endpoints for the initial treatment period (change in the Worst Daily Pruritus Numeric Rating Scale [weekly average] score by at least a 4-point improvement, change in SCORing Atopic Dermatitis score from baseline to Week 16, and change in Dermatology Life Quality Index score from baseline to Week 16) demonstrated statistically significant improved results in patients receiving Adtralza as compared to patients receiving placebo. These results were consistent with and supportive of the effects seen in the primary endpoints.

Among patients achieving clinical response at Week 16 in the monotherapy pool (ECZTRA 1 and ECZTRA 2), the favourable response (as measured by IGA 0 or 1, or EASI-75), was maintained at Week 52, with response rates of 56.2% and 50.0% for Adtralza 300 mg Q2W and Adtralza 300 mg Q4W, respectively. Similarly, the favourable response was maintained at Week 32 in the concomitant topical corticosteroids trial (ECZTRA 3) across Adtralza 300 mg Q2W + TCS and Adtralza 300 mg Q4W + TCS among patients achieving clinical response at Week 16. Overall, treatment with Adtralza 300 mg Q2W demonstrated adequate maintenance of efficacy through Week 52. Switching to Adtralza 300 mg Q4W at Week 16 resulted in adequate, albeit numerically smaller responses as measured by IGA 0 or 1 and EASI-75.

Patient-reported outcomes in both the Adtralza monotherapy studies (ECZTRA 1 and ECZTRA 2) and in the Adtralza concomitant topical corticosteroids trial (ECZTRA 3) were consistent with statistically significant improvements observed in the physician-reported outcomes.

Indication

The New Drug Submission for Adtralza was filed by the sponsor with the following indication, which Health Canada subsequently approved:

Adtralza (tralokinumab injection) is indicated for the treatment of moderate-to-severe atopic dermatitis in adult patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

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

Clinical Safety

The safety of Adtralza was evaluated based on a pool of 5 randomized, double-blind, placebo-controlled studies in patients with moderate-to-severe atopic dermatitis including the three phase 3 studies (ECZTRA 1, ECZTRA 2, and ECZTRA 3 described in the Clinical Efficacy section), a dose-ranging study and a vaccine-response study. In these 5 atopic dermatitis trials, 1991 patients were treated with subcutaneous injections of Adtralza, with or without concomitant topical corticosteroids (TCS). A total of 807 patients were treated with Adtralza for at least 1 year.

Based on the pooled data, notable treatment-emergent adverse events (TEAEs) occurring in ≥1% of patients, and reported more frequently in the Adtralza-treated patients compared to placebo-treated patients through Week 16, included viral upper respiratory tract infection (16% vs. 12%, respectively), conjunctivitis (5.4% vs. 1.9%, respectively), and injection site reactions (3.5% vs. 0.3%, respectively).

Two deaths were reported across the clinical development programme. Both deaths were in patients who received Adtralza. However, based on the patients’ medical history and comorbid conditions, neither death was considered to be related to Adtralza.

Eye disorders, including conjunctivitis, keratitis, blepharitis, and keratoconjunctivitis were identified as areas of interest due to increased incidences in Adtralza-treated patients. Generally, these events were mild-to-moderate in severity and did not lead to discontinuation of treatment.

Increased blood eosinophil counts were observed in the Adtralza treated patients, which is a known effect of biologics that inhibit interleukin13. Generally, the increased blood eosinophil count was transient and did not result in clinical sequelae.

The frequency of adverse events leading to study drug discontinuation in the Adtralza and placebo groups were 2.3% and 2.8%, respectively.

Overall, the safety profile of Adtralza when administered as monotherapy was similar to the safety profile observed when used with concomitant topical corticosteroids.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Tralokinumab, the medicinal ingredient in Adtralza, is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that specifically binds to the type 2 cytokine interleukin-13 (IL-13).

Key studies in the non-clinical data package included primary pharmacodynamic, repeat-dose toxicity, and reproductive and developmental toxicity studies. Overall, no major issues in the non-clinical data package were identified.

In in vitro primary pharmacodynamic studies, tralokinumab was shown to bind to human IL-13 and inhibit IL-13 interaction with the IL-13 receptors, interleukin-13 receptor α1 (IL-13Rα1) and interleukin-13 receptor α2 (IL-13Rα2). Tralokinumab was also shown to inhibit IL-13-induced functional activity in cell-based assays.

Pivotal toxicology studies were conducted in cynomolgus monkeys, a pharmacologically relevant species, and included a 13-week subcutaneous repeat-dose toxicity study, a 26-week intravenous repeat-dose toxicity study, a 13-week repeat-dose subcutaneous study assessing male fertility-related endpoints, a subcutaneous repeat-dose study assessing female fertility-related endpoints, and an intravenous enhanced pre- and post-natal developmental study. No adverse effects were observed up to the highest doses tested in these studies. Exposures (area under the concentration time curve) at the no-observed-adverse-effect levels were at minimum 27-fold greater than the estimated human exposure. Carcinogenicity and genotoxicity studies were not conducted, which was considered acceptable and in accordance with relevant International Council for Harmonisation guidelines.

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

 

 

7.3 Quality Basis for Decision

 

Tralokinumab, the medicinal ingredient in Adtralza, is a recombinant human IgG4 monoclonal antibody that inhibits IL-13 signalling, which blocks the stimulation of inflammatory responses characteristic for atopic dermatitis.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that tralokinumab 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

Drug Substance

The drug substance, tralokinumab, is manufactured using recombinant deoxyribonucleic acid technology in a well characterized murine myeloma cell line that is commonly used for the manufacture of monoclonal antibodies.

The tralokinumab drug substance manufacturing process is initiated by thawing and inoculating cells from one single vial from the working cell bank. This is followed by culture expansion, fermentation, cell culture harvest, purification, low pH viral inactivation, viral filtration, concentration/diafiltration, formulation, filtration, dispensing and storage (at -40 °C).

The drug substance manufacturing process was developed through seven different processes, with the manufacture of non-clinical, clinical, and commercial scale batches. Comparability studies (side-by-side characterization, release, and/or stability testing) were performed throughout development to demonstrate that the changes made with each successive process did not impact the drug substance critical quality attributes, and that the drug substance manufactured using the proposed commercial process is comparable to the materials used for the manufacture of drug product for clinical trials.

Drug Product

The drug product formulation was developed based on experience with the solubility, structural integrity, and stability of the product. The drug product is intended for single-dose, subcutaneous administration and does not contain any preservatives. All excipients used in the drug product formulation are of compendial grade and are commonly used in biopharmaceutical drug products for parenteral administration.

The changes made throughout development included increasing tralokinumab concentration, formulation modifications, target fill volume, filling facility, and change in container closure from vial to accessorized prefilled syringe. Three comparability studies were carried out to assess the changes made throughout development, with results from side-by-side characterization testing, release and stability testing, meeting pre-established acceptance criteria, demonstrating that the drug product manufactured using the proposed commercial scale process is comparable to the drug product materials used in clinical trials.

The proposed drug product manufacturing process starts with a controlled thaw of the drug substance followed by shipping (at 2 °C to 8 °C) to the multi-product fill/finish facility. Upon receipt at the fill/finish facility, the drug substance is warmed, pooled, mixed, and subjected to bioburden reduction filtration. After temperature equilibration, the drug substance undergoes sterile filtration, followed by aseptic filling into syringes. Once stoppered, the filled syringes are subjected to visual inspection and acceptable quality limit inspection. The filled syringes are stored at 2 °C to 8 °C until the start of the labelling, assembly into the accessorized prefilled syringes, and packaging processes. Any product-contact equipment used in the manufacture of the drug product is either dedicated or intended for single-use.

Manufacturing Controls

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product were appropriately validated 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 tralokinumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The control strategy for the drug substance manufacturing process includes control of starting materials (including master and working cell banks), control of critical steps and intermediates (by maintaining operational process parameters, critical process parameters, and in-process controls within proven acceptable ranges and acceptance criteria, respectively), as well as release and stability testing. Similarly, the control strategy for the drug product manufacturing process involves control of critical process steps through operational process parameters, critical process parameters, in-process controls, and release and stability testing.

All non-compendial analytical methods for drug substance and drug product release and stability testing were appropriately validated in accordance with International Council for Harmonisation guidelines.

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 long-term shelf life of 36 months for Adtralza when stored at 5 °C ± 3 °C, as well as the proposed optional short-term (in-use) shelf life of 14 days at ≤30 °C, after storage at 2 °C to 8 °C, are 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.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug substance and drug product manufacturing facilities was not deemed necessary.

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

Adventitious Agents Safety Evaluation

Viral clearance studies, conducted at small scale representative of the commercial scale process, demonstrate that the purification steps in the drug substance manufacturing process is capable of achieving an acceptable adventitious agents safety profile.

 

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