Summary Basis of Decision for Taltz

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 Taltz is located below.

Recent Activity for Taltz

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

Post-Authorization Activity Table (PAAT) for Taltz

Updated: 2024-06-04

The following table describes post-authorization activity for Taltz, a product which contains the medicinal ingredient ixekizumab 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 Numbers (DINs):

  • DIN 02455102 - 80 mg/mL, ixekizumab, solution for injection (pre-filled autoinjector), subcutaneous administration
  • DIN 02455110 - 80 mg/mL, ixekizumab, solution for injection (pre-filled syringe), subcutaneous administration

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 282233

2023-12-19

Issued NOL 2024-01-29

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug substance (release and stability). The submission was considered acceptable, and an NOL was issued.

NC # 276848

2023-06-30

Issued NOL 2023-09-20

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug substance fermentation process and a change in the controls (in‐process tests and/or acceptance criteria) applied during the drug substance manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 268782

2022-10-17

Cancellation Letter Received 2023-09-08

Submission filed as a Level I – Supplement to update the PM with new safety and efficacy data. A number of issues were identified with the submission during review. The submission was cancelled by the sponsor.

Drug product (DIN 02455110) market notification

Not applicable

Date of first sale: 2023-04-12

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

Drug product (DIN 02455102) market notification

Not applicable

Date of first sale: 2023-03-20

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

SNDS # 268706

2022-10-18

Issued NOC 2023-03-07

Submission filed as a Level II – Supplement (Safety) to update the PM to include the adverse event of esophageal candidiasis. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.

SNDS # 260994

2022-01-31

Issued NOC 2022-09-21

Submission filed as a Level I – Supplement for a change in the drug product formulation and manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 257287

2021-10-05

Issued NOL 2021-11-03

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 submission was considered acceptable, and an NOL was issued.

NC # 250240

2021-03-05

Issued NOL 2021-04-28

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

SNDS # 238580

2020-04-17

Issued NOC 2021-03-29

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Taltz for the treatment of pediatric patients from 6 to less than 18 years of age with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. The submission was reviewed and considered acceptable, and an NOC was issue. Regulatory Decision Summary was published.

SNDS # 233071

2019-11-01

Issued NOC 2020-10-14

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Taltz for the treatment of adult patients with active non-radiographic axial spondyloarthritis with objective signs of inflammation who have responded inadequately to, or are intolerant to conventional therapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

SNDS # 237329

2020-03-19

Cancellation Letter Received 2020-04-14

Submission filed as a Level I – Supplement for a new indication. The sponsor cancelled the submission before it was reviewed.

SNDS # 225178

2019-02-28

Issued NOC 2020-02-04

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Taltz for the treatment of adult patients with active ankylosing spondylitis who have responded inadequately to, or are intolerant to conventional therapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

SNDS # 223859

2019-01-18

Issued NOC 2019-06-19

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

NC # 222711

2018-12-04

Issued NOL

2018-12-24

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a new site for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 218108

2018-07-10

Issued NOL

2018-09-28

The submission was filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM. As a result of the NC, modifications were made to the Drug Interactions, Storage and Stabilty, and Instructions for Use sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 220182

2018-09-13

Cancellation Letter Received

2018-09-24

Submission filed as a Level II (120 day) Notifiable Change to update the PM with new information. The proposed revisions exceeded the scope of an NC. The submission was therefore cancelled administratively by the sponsor, so as to be filed as an SNDS.

SNDS # 210016

2017-10-06

Issued NOC 2018-09-19

Submission filed as a Level I – Supplement to provide an update to the PM based on clinical data from a placebo-controlled trial conducted in patients with psoriasis affecting the genital area. Sufficient evidence supports the efficacy and safety of Taltz for the treatment of adult patients with moderate-to-severe plaque psoriasis affecting the genital area. The data were reviewed and considered acceptable. Appropriate changes were made to the PM. An NOC was issued.

NC # 218992

2018-08-07

Issued NOL

2018-09-05

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.

SNDS # 204690

2017-04-20

Issued NOC 2018-03-29

Submission filed as a Level I – Supplement for a new indication: the treatment of adult patients with active psoriatic arthritis who have responded inadequately to, or are intolerant to one or more disease-modifying antirheumatic drugs (DMARD). Taltz can be used alone or in combination with a conventional DMARD (cDMARD) (e.g., methotrexate).

Regulatory Decision Summary published.

NC # 207866

2017-07-25

Issued NOL

2017-11-02

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

NC # 207872

2017-08-03

Issued NOL

2017-08-18

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

NC # 202957

2017-02-16

Issued NOL

2017-03-09

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

Drug product (DINs 02455102, 02455110)  market notification

Not applicable

Date of first sale: 2016/08/11

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

NDS # 184993

2015/06/05

Issued NOC 2016/05/25

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

Date SBD issued: 2016-08-02

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

Ixekizumab, 80 mg/mL, solution for injection, subcutaneous

Drug Identification Number (DIN):

  • 02455102, 80 mg/mL, solution for injection (pre-filled autoinjector)
  • 02455110, 80 mg/mL, solution for injection (pre-filled syringe)

Eli Lilly Canada Inc.

New Drug Submission Control Number: 184993

 

On May 25, 2016, Health Canada issued a Notice of Compliance to Eli Lilly Canada Inc. for the drug product Taltz.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (clinical pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit/risk profile of Taltz is favourable for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

 

1 What was approved?

 

Taltz is an immunomodulator, a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) which selectively binds and neutralizes the proinflamatory cytokine interleukin-17A (IL-17A). Taltz was authorized for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Taltz is contraindicated in patients with known serious hypersensitivity to ixekizumab or to any of the excipients.

While no differences in safety or efficacy were observed between older and younger patients, the number of patients aged 65 years and over who were exposed to Taltz in clinical trials is not sufficient to determine whether they respond differently from younger patients.

Safety and effectiveness of Taltz in pediatric patients (<18 years of age) have not been evaluated. Therefore, Taltz is not indicated in this patient population.

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

Taltz (80 mg/mL ixekizumab, a humanized IgG4 mAb) is presented as a sterile solution for injection in a single-dose prefilled autoinjector or single-dose prefilled syringe. The Taltz prefilled autoinjector and prefilled syringe each contain a 1 mL glass syringe with a fixed 27 gauge ½ inch needle and are manufactured to deliver 80 mg ixekizumab. In addition to the medicinal ingredient, each prefilled autoinjector or prefilled syringe contains the inactive ingredients, citric acid anhydrous, polysorbate 80, sodium chloride, sodium citrate dihydrate, and water for injection. Taltz is for single use and, therefore, contains no antimicrobial preservative. Also, Taltz prefilled autoinjector and prefilled syringe do not contain latex.

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

 

2 Why was Taltz approved?

 

Health Canada considers that the benefit/risk profile of Taltz is favourable for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Psoriasis is a common skin disease affecting 2% to 3% of the general population. It is a complex disorder, characterized by inflammation, keratinocyte hyperproliferation, and altered epidermal differentiation. Approximately 80% to 90% of psoriasis patients have chronic plaque psoriasis, characterized by recurrent exacerbations and remissions of thickened, erythematous, scaly patches of skin that can occur anywhere on the body.

Several pharmaceutical drugs (including acitretin, cyclosporin, and methotrexate) have been authorized in Canada for the treatment of psoriasis. In addition, biologic agents that target various functions of pathogenic T cells and proinflammatory cytokines, such as tumor necrosis factor alpha and interleukin (IL)-12/23 are utilized for the treatment of psoriasis. Cosentyx (secukinumab), another monoclonal antibody which selectively binds and neutralizes IL-17A, received an authorization for the treatment of moderate-to-severe plaque psoriasis in 2015. Drug-specific safety concerns associated with biologic agents with immunomodulatory properties comprise infections (including tuberculosis), malignancies (including lymphoma), immunogenicity and demyelinating neurologic events.

Taltz has been shown to be efficacious in the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. The market authorization was based on three pivotal multicentre, randomized, double-blind, placebo-controlled Phase III trials, UNCOVER-1 (RHAZ), UNCOVER-2 (RHBA) and UNCOVER-3 (RHBC), which evaluated the efficacy and safety of Taltz in plaque psoriasis patients. In addition to placebo, the UNCOVER-2 and UNCOVER-3 trials included etanercept as an active comparator treatment. The trials enrolled a total of 3,866 patients 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, a static Physician Global Assessment (sPGA) score of ≥3 and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. In all three pivotal trials, patients randomized to Taltz received a starting dose of Taltz of 160 mg at baseline followed by 80 mg every two weeks (Q2W) or 80 mg every 4 weeks (Q4W) for the total duration of 12 weeks (referred to as “an induction dosing period”). The co-primary endpoints were the proportion of patients who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and the proportion of patients with an sPGA of 0 (clear) or 1 (minimal) with at least a 2-point improvement from baseline. In each of the pivotal trials, the treatment with Taltz demonstrated efficacy by achieving the co-primary endpoints of PASI 75 and sPGA of 0 or 1, as well as the secondary endpoint of PASI 90 (a reduction of at least 90% in PASI).

In addition, two of the pivotal trials, UNCOVER-1 and UNCOVER-2, evaluated the maintenance of Taltz efficacy for an additional 48 weeks after induction treatment, up to Week 60, using a randomized withdrawal design for Taltz-treated patients who met response criteria (defined as sPGA [0,1] at Week 12). In the maintenance dosing period, Taltz responders in the induction dosing period were re-randomised in a 1:1:1 ratio to receive either 80 mg Taltz Q4W, 80 mg Taltz every 12 weeks (Q12W), or placebo. In the UNCOVER-1 trial, the proportion of patients who maintained an sPGA (0,1) at week 60 was 74.8% for Taltz patients treated with the recommended induction and maintenance dose regimen compared to 7.7% in placebo-treated patients (difference 67.1%; 98.75% confidence interval [CI] [55.4%, 78.8%]).

Based on the efficacy data from the pivotal trials, the authorised dosing regimen for Taltz is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg (one injection) at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg (one injection) every 4 weeks.

The three pivotal trials in plaque psoriasis patients (UNCOVER-1, UNCOVER-2, and UNCOVER-3) were integrated to evaluate the safety of Taltz in comparison to placebo up to 12 weeks following treatment initiation. In two of the trials (UNCOVER-2 and UNCOVER-3), the safety of Taltz was also compared with an active comparator, etanercept, for up to 12 weeks of treatment duration. In total, 3,858 patients were evaluated (1,167 patients in Taltz 80 mg Q2W group, 1,161 patients in Taltz 80 mg Q4W group, 739 patients in etanercept 50 mg twice weekly group, and 791 patients in the placebo group).

Across blinded and open-label clinical trials conducted a total of 4,204 plaque psoriasis patients were treated with Taltz. Of these, 2,190 psoriasis patients were exposed to Taltz for at least one year.

The safety profile of Taltz is consistent with that of other biological products authorized for treatment of psoriasis. Main safety observations that are reflected in the Taltz Product Monograph include serious hypersensitivity, infections, inflammatory bowel diseases, neutropenia, and immunogenicity.

Taltz-treated patients in clinical trials have been reported to experience serious hypersensitivity reactions, including angioedema and urticaria. Therefore, Taltz is contraindicated in patients with known serious hypersensitivity to ixekizumab or to any of the excipients.

In the integrated data obtained from the three pivotal trials, the most commonly reported adverse reactions (in = 1% of patients) were injection site reactions, infections, nausea, and oropharyngeal pain. Injection site reactions were predominantly mild-to-moderate in severity and did not lead to discontinuation of Taltz. Among infections, the most frequently reported were upper respiratory tract infections, including nasopharyngitis. The potential of Taltz to increase the risk of infection has been appropriately reflected in the Warnings and Precautions section of the Product Monograph. Moreover, the section explicitly points out that Taltz should not be given to patients with active tuberculosis (TB), and prior to initiating treatment with Taltz, patients should be evaluated for TB infection.

Neutropenia was also observed in clinical trials. In general, neutropenia was transient and did not require discontinuation of Taltz and was not associated with an increased rate of infections.

In clinical trials, Taltz has also exhibited a potential for immunogenicity, generally attributed to all therapeutic proteins. Approximately 22% of patients treated with Taltz at the recommended dosing regimen developed antibodies to ixekizumab during the 60 week treatment period. Higher antibody titers were associated with decreasing drug concentration and clinical response. Of the patients who developed anti-drug antibodies to ixekizumab during the 60-week treatment period, approximately 9% had antibodies that were classified as neutralizing; this is about 2% of subjects treated with Taltz at the recommended dosing regimen. Neutralizing antibodies were associated with low drug concentrations and reduced clinical response. An association between immunogenicity and treatment-emergent adverse events has not been established.

New cases or exacerbations of Crohn’s disease and ulcerative colitis were reported in Taltz-treated patients during clinical trials. These findings have been appropriately reflected in the Warnings and Precautions section of the Taltz Product Monograph.

A Risk Management Plan (RMP) for Taltz was submitted by Eli Lilly 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 Taltz was accepted.

Overall, the benefits of Taltz therapy are considered to outweigh the potential risks. Taltz 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 Taltz Product Monograph to address the identified safety concerns. Furthermore, in order to ensure that the benefits continue to outweigh any risks after authorization, Health Canada has required several post-approval activities to be carried out by the sponsor (described in What follow-up measures will the company take? section)

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 Taltz?

 

Submission Milestones: Taltz

Submission Milestone Date
Pre-submission meeting: 2015-05-05
Submission filed: 2015-06-05
Screening  
Screening Acceptance Letter issued: 2015-07-30
Review  
On-Site Evaluation:: 2016-04-25 - 2016-04-29
Quality Evaluation complete: 2016-05-20
Clinical Evaluation complete: 2016-05-25
Biostatistics Evaluation complete: 2016-05-25
Labelling Review complete: 2016-05-06
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2016-05-25

 

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 Taltz, 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 serious adverse events related to immunogenicity, serious infections, malignancies, other autoimmune diseases, et cetera (etc.), that occur in all clinical trials with Taltz.
  • Providing Health Canada with Periodic Safety Update Reports/Periodic Benefit Risk Evaluation Reports for Taltz every 6 months as per pharmacovigilance plan, including those which may be potentially related to the immunogenicity profile of Taltz (for example [e.g.], adverse drug reactions related to immune system disorders, skin and subcutaneous tissue disorders, etc.); malignancies; serious infections; Crohn’s disease and ulcerative colitis flares.
  • Providing Health Canada with an updated Canadian Risk Management Plan in accordance with Canadian labelling and in order to capture the post-approval commitments to Health Canada.
  • Providing safety updates as well as final reports of the registry-based observation exposure cohort study that compares the maternal, fetal and infant outcomes of women exposed to Taltz during pregnancy to an unexposed control population, as per the commitment to the United States Food and Drug Administration (FDA).
  • Providing Health Canada with regular safety updates from the ongoing clinical trials and the final reports of the studies RHAZ, RHBA, and RHBC (and any other relevant studies).
  • Submitting to Health Canada the final report (when available) of the study UNCOVER-2 (RHBA) in psoriasis patients.
  • Providing Health Canada with all reports pertaining to post-approval commitments from major regulatory authorities (e.g., the United States FDA, European Medicines Agency (EMA), Australia’s Therapeutic Goods Administration (TGA) etc.), plus specifically:
    • Three year clinical follow-through of all recipients of Taltz in the ongoing extensions of studies RHAZ, RHBA and RHBC, as per commitment to the EMA.
    • A prospective, observational study to assess the long-term safety of Taltz compared to other therapies used in the treatment of adults with moderate-to-severe plaque psoriasis who are candidate for systemic therapy or phototherapy in the course of actual clinical care, as per commitment to the United States FDA.

 

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

 

Summary Basis of Decision documents (SBDs) for eligible drugs 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 Taltz 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 medicinal ingredient of Taltz, ixekizumab, is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody that has a binding affinity of <3 pM to interleukin 17A (IL-17A), a naturally occurring proinflammatory cytokine. Elevated levels of IL 17A have been implicated in the pathogenesis of a variety of autoimmune diseases. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.

The clinical pharmacological data support the use of Taltz for the recommended indication.

Pooled pharmacokinetics data (with 6,059 ixekizumab serum concentrations from 1,399 psoriasis patients) from two early phase studies (studies RHAG and RHAJ) and one Phase III study (UNCOVER-1 [RHAZ]) were analyzed by the sponsor in a population pharmacokinetic modelling for exposure-response relationship exploration and pharmacokinetic characteristics following subcutaneous dose regimens. An additional exposure-response relationship analysis for efficacy and safety as well as an assessment of immunogenicity impact on pharmacokinetics was also performed by the sponsor using sparse pharmacokinetic samplings and efficacy and safety data from the three pivotal trials, UNCOVER-1 (RHAZ), UNCOVER-2 (RHBA), UNCOVER-3 (RHBC) (described in the Clinical Efficacy section).

Population pharmacokinetics analysis revealed that body weight and the status of immunogenicity have significant impact on the exposure of ixekizumab. There was an overall trend of decreasing exposure with increasing body weight. Anti-drug antibodies at higher titers ( = 160) and neutralizing antibodies were associated with decreasing drug concentration and clinical response. However, a definite relationship between immunogenicity and treatment-emergent adverse events, including hypersensitivity reactions, has not been established based on the currently available data.

Exposure-response simulation analysis based on efficacy and safety data across the three pivotal Phase III trials supported the authorised dose regimen. No apparent exposure-response relationships were observed for most treatment-emergent adverse events between the two ixekizumab dose levels and placebo across the three pivotal Phase III trials, except that the incidence of neutropenia Grade 2 (≥1,000 to <1,500 cells/mm3) showed a relationship with exposure but only during the induction treatment and did not require discontinuation of ixekizumab.

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

Clinical Efficacy

The clinical efficacy of Taltz in adult patients with moderate-to-severe plaque psoriasis has been evaluated in three pivotal multicentre, randomized, double-blind, placebo-controlled Phase III trials, UNCOVER-1 (RHAZ), UNCOVER-2 (RHBA) and UNCOVER-3 (RHBC). The trials enrolled a total of 3,866 patients 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, a static Physician Global Assessment (sPGA) score of ≥3 and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Patients with guttate, erythrodermic, or pustular psoriasis were excluded from the clinical trials.

Each pivotal study evaluated short-term efficacy (up to 12 weeks) of Taltz compared to placebo. In addition to placebo, the UNCOVER-2 and UNCOVER-3 trials included etanercept as an active comparator treatment.

In all three trials, subjects were randomized to either placebo or Taltz (80 mg every two weeks [Q2W] or 80 mg every four weeks [Q4W]) for 12 weeks, following a 160 mg starting dose. In the two active comparator trials (UNCOVER-2 and UNCOVER-3), subjects were also randomized to receive etanercept 50 mg twice weekly for 12 weeks. The co-primary endpoints were the proportion of patients who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and the proportion of patients with an sPGA of 0 (clear) or 1 (minimal) with at least a 2-point improvement from baseline. In each of the pivotal trials, the treatment with Taltz demonstrated efficacy by achieving the co-primary endpoints of PASI 75 and sPGA of 0 or 1, as well as the secondary endpoint of PASI 90 (a reduction of at least 90% in PASI).

Specifically, among patients who received Taltz 80 mg Q2W during the induction dosing period of 12 weeks (the authorized induction regimen), the proportions of sPGA of 0 or 1 responders were:

  • 81.8% versus (vs.) 3.2% in placebo-treated patients (difference 78.5%; 97.5% confidence interval [CI] [73.9%, 83.1%]) in the UNCOVER-1 trial;
  • 83.2% vs. 2.4% in placebo-treated patients (difference 80.8%; 97.5% CI [75.6%, 86.0%]) and 36.0% in etanercept-treated patients (difference 47.2%; 97.5% CI [39.9%, 54.4%]) in the UNCOVER-2 trial; and
  • 80.5% vs. 6.7% in placebo-treated patients (difference 73.8%; 97.5% CI [67.7%, 79.9%]) and 41.6% in etanercept-treated patients (difference 38.9%; 97.5% CI [31.7%, 46.1%]) in the UNCOVER-3 trial.

Similarly, the other co-primary endpoint, PASI 75 was achieved by the following proportions of Taltz-treated patients:

  • 89.1% compared to 3.9% in placebo-treated patients (difference 85.2%; 97.5% CI [81.2%, 89.2%]) in the UNCOVER-1 trial;
  • 89.7% compared to 2.4% in placebo-treated patients (difference 87.4%; 97.5% CI [82.9%, 91.9%]) and 41.6% in etanercept-treated patients (difference 48.1%; 97.5% CI [41.2%, 55%]) in the UNCOVER-2 trial; and
  • 87.3 % compared to 7.3% in placebo-treated patients (difference 80.0%; 97.5% CI [74.4%, 85.7%]) and 53.4% in etanercept-treated patients (difference 33.9%; 97.5% CI [27.0%, 40.7%]) in the UNCOVER-3 trial.

In each of the pivotal trials, Taltz-treated patients also met the key secondary endpoint of PASI 90. The proportions of PASI 90 responders were:

  • 70.4% compared to 0.5% in placebo-treated patients (difference 70.4%; 97.5% CI [65.5%, 75.4%]) in the UNCOVER-1 trial;
  • 70.7% compared to 0.6% in placebo-treated patients (difference 70.7%; 97.5% CI [64.4%, 75.7%]) and 18.7% in etanercept-treated patients (difference 51.9%; 97.5% CI [44.8%, 59.1%]) in the UNCOVER-2 trial; and
  • 68.1% compared to 3.1% in placebo-treated patients (difference 64.9%; 97.5% CI [58.9%, 71.0%]) and 25.7% in etanercept-treated patients (difference 42.4%; 97.5% CI [35.1%, 49.1%]), in the UNCOVER-3 trial.

Two of the pivotal trials, UNCOVER-1 and UNCOVER-2, also evaluated the maintenance of Taltz efficacy for an additional 48 weeks after induction treatment, up to Week 60, using a randomized withdrawal design for Taltz-treated patients who met response criteria (defined as sPGA [0,1] at Week 12). In the maintenance dosing period, Taltz responders in the induction dosing period were re-randomised in a 1:1:1 ratio to receive either 80 mg Taltz Q4W, 80 mg Taltz every 12 weeks (Q12W), or placebo. In the UNCOVER-1 trial, the proportion of patients who maintained an sPGA (0,1) at week 60 was 74.8% for Taltz patients treated with the recommended induction and maintenance dose regimen compared to 7.7% in placebo-treated patients (difference 67.1%; 97.5% CI [55.4%, 78.8%]). However, the results of the maintenance phase of the UNCOVER-2 trial were not reported in the approved Taltz Product Monograph given that they were derived from an interim data analysis following a database lock that occurred after the last patient enrolled completed the Week 36 visit of the maintenance dosing period. Consequently, not all patients had completed the blinded maintenance dosing period, and the interim data analysis was based on a subset of patients who had either completed Week 60, discontinued treatment prior to Week 60, or relapsed prior to Week 60 at the time of the 36-week interim database lock. The sponsor has agreed to submit the final study report with the maintenance phase results of the UNCOVER-2 trial (see What follow-up measures will the company take? section).

Based on the efficacy data from the pivotal trials, the recommended dosing regimen for Taltz is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg (one injection) at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg (one injection) every 4 weeks.

Overall, the efficacy data provided in this submission support the approval of Taltz for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

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

Clinical Safety

Three pivotal randomized, double-blind, placebo-controlled Phase III trials, UNCOVER-1, UNCOVER-2, and UNCOVER-3 in plaque psoriasis patients (described in the Clinical Efficacy section) were integrated to evaluate the safety of Taltz in comparison to placebo for up to 12 weeks following the treatment initiation. In two of the trials (UNCOVER-2 and UNCOVER-3), the safety of Taltz was also compared with an active comparator, etanercept, up to 12 weeks of treatment duration. In total, 3,858 patients were evaluated (1,167 patients in Taltz 80 mg every two weeks [Q2W] group, 1,161 patients in Taltz 80 mg every four weeks [Q4W] group, 739 patients in etanercept 50 mg twice weekly group, and 791 patients in the placebo group).

Across blinded and open-label clinical trials conducted a total of 4,204 plaque psoriasis patients were treated with Taltz. Of these, 2,190 psoriasis patients were exposed to Taltz for at least one year.

Main safety observations that are reflected in the Taltz Product Monograph include serious hypersensitivity, infections, inflammatory bowel diseases, neutropenia, and immunogenicity.

Taltz-treated patients in clinical trials have been reported to experience serious hypersensitivity reactions, including angioedema and urticaria. Therefore, Taltz is contraindicated in patients with known serious hypersensitivity to ixekizumab or to any of the excipients.

In the integrated data obtained from the three pivotal trials, the most commonly reported adverse reactions (>1% of patients) were injection site reactions, infections, nausea, and oropharyngeal pain.

The most frequent injection site reactions observed were erythema and pain. Injection site reactions were predominantly mild-to-moderate in severity and did not lead to discontinuation of Taltz.

Among infections, the most frequently reported were upper respiratory tract infections, including nasopharyngitis. Most were mild or moderate in severity and did not lead to early discontinuation. During the maintenance treatment period, the exposure-adjusted incidence rate of infections was 0.71 per patient year (56.0%) in patients treated with Taltz with the recommended dosing regimen (Q4W), compared with 0.78 per patient year (35.6%) in patients treated with placebo. The exposure-adjusted incidence rate of serious infections was 0.02 per patient year (1.4%) in patients treated with Taltz (Q4W) and 0.02 per patient year (0.7%) in patients treated with placebo.

Over the entire treatment period (across all psoriasis studies, a total of 4,204 plaque psoriasis patients were treated with Taltz for up to 60 weeks for the majority of patients), the exposure-adjusted incidence rate of infections was 0.47 per patient year (52.8%) in patients treated with Taltz. The exposure-adjusted incidence rate of serious infections was 0.02 per patient year (1.6%) in patients treated with Taltz. The increased risk of infection has been appropriately reflected in the Warnings and Precautions of the Taltz Product Monograph. Specifically, the section points out that Taltz should not be given to patients with active tuberculosis (TB), and that prior to initiating treatment with Taltz, patients should be evaluated for TB infection.

In the placebo-controlled and active-controlled period of the clinical trials (UNCOVER-2 and UNCOVER-3), neutropenia ≥Grade 3 (<1,000 cells/mm3) was observed in 0.3% of patients receiving Taltz Q2W, compared to 0.5% of patients treated with etanercept and 0.3% of patients treated with placebo. The remaining cases of neutropenia were low grade, either Grade 2 (2.6% for Taltz Q2W vs. 3.3% for etanercept; 0.3% for placebo; ≥1,000 to <1,500 cells/mm3) or Grade 1 (7.0% for Taltz Q2W vs. 9.9% for etanercept; 3.4% for placebo; ≥1,500 cells/mm3 up to normal). In general, neutropenia was transient and did not require discontinuation of Taltz and was not associated with an increased risk of infection.

Taltz also demonstrated a potential for immunogenicity, which is generally associated with all therapeutic proteins. Approximately 9% of patients treated with Taltz at the recommended dosing regimen developed anti-drug antibodies by Week 12. During the 60-week treatment period, anti-drug antibodies were detected in approximately 22% of Taltz-treated patients at the recommended dosing regimen. The clinical effects of antibodies to ixekizumab were dependent on the antibody titer. Higher antibody titers were associated with decreasing drug concentration and clinical response. Of the patients who developed anti-drug antibodies to ixekizumab during the 60-week treatment period, approximately 9% had antibodies that were classified as neutralizing; this is about 2% of subjects treated with Taltz at the recommended dosing regimen. Neutralizing antibodies were associated with low drug concentrations and reduced clinical response. An association between immunogenicity and treatment-emergent adverse events has not been established.

New cases or exacerbations of Crohn’s disease and ulcerative colitis were observed in Taltz-treated patients during clinical trials. This safety concern has been included in the Warnings and Precautions section of the Taltz Product Monograph.

Overall, the reported safety profile of Taltz is consistent with that of other biological products authorized for treatment of psoriasis. Appropriate warnings and precautions are in place in the approved Taltz Product Monograph to address the identified safety concerns. Additionally, in order to ensure that the benefit continues to outweigh any risks after authorization, Health Canada has required several post-approval activities to be carried out by the sponsor (described in What follow-up measures will the company take? section).

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical pharmacology and toxicology studies support the use of Taltz for the treatment of moderate-to-severe plaque psoriasis.

Pharmacodynamics, pharmacokinetics and general toxicity studies were conducted in cynomolgus monkeys, the sole pharmacologically relevant species. No significant adverse effects, including any organ toxicity or undesirable effects on immune function (for example [e.g.], T-cell dependent antibody response or natural killer [NK] cell activity) were observed in cynomolgus monkeys when administered ixekizumab by intravenous and subcutaneous injection up to dose levels of 50 mg/kg once per week (19 times the maximum recommended human dose on a mg/kg basis) for 8 and 39 weeks, respectively.

Carcinogenicity, mutagenicity and genotoxicity studies have not been conducted with ixekizumab.

Neonatal deaths occurred in the offspring of pregnant monkeys which were administered ixekizumab subcutaneously from the beginning of organogenesis until parturition. Surviving animals did not display any treatment related functional or immunological developmental effects. Ixekizumab was shown to cross the placenta and was present in the blood of offspring for up to 6 months of age. Low levels of ixekizumab were also detected in the breast milk of treated cynomolgus monkeys. The clinical significance of these findings is not known.

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

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

 

 

7.3 Quality Basis for Decision

 

Ixekizumab, the medicinal ingredient of Taltz, is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody designed and engineered to bind with high affinity (<3 pM) and specificity to human interleukin 17A (IL-17A), a pro-inflammatory cytokine.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that ixekizumab 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 manufacturing process of the drug substance, ixekizumab, consists of cell culture and primary recovery (upstream) and purification (downstream) components with a total of eleven unit operations. The production bioreactor contents are harvested by centrifugation and depth filtration. The clarified broth is purified and treated with combination of chromatograph and filtration steps and viral inactivation steps and subsequently frozen. It has been demonstrated that the drug substance quality has remained comparable throughout the development stages.

Drug Product

The drug substance is thawed, formulated, filtered and filled into pre-sterilized syringes. The syringes may then be assembled into autoinjectors or packaged as prefilled syringes. It has been demonstrated that the drug product quality has remained comparable throughout the development stages.

Taltz is supplied in the following presentations for subcutaneous injection:

  • 80 mg single-dose prefilled autoinjector
  • 80 mg single-dose prefilled syringe

The Taltz prefilled autoinjector and prefilled syringe each contain a 1 mL glass syringe with a fixed 27 gauge ½ inch needle and are manufactured to deliver 80 mg ixekizumab. In addition to ixekizumab (80 mg/mL), each prefilled autoinjector or prefilled syringe contains the inactive ingredients, citric acid anhydrous, polysorbate 80, sodium chloride, sodium citrate dihydrate, and water for injection.

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 ixekizumab 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; and analytical procedures are validated and in compliance with 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-8°C for Taltz is considered acceptable when the product is protected from light and freezing.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the drug substance, ixekizumab, has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

An OSE of the facility involved in the drug product manufacturing was not warranted since the facility was recently evaluated in good standing.

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

Adventitious Agents Safety Evaluation

The ixekizumab 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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