Summary Basis of Decision for Kevzara

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 Kevzara is located below.

Recent Activity for Kevzara

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 Kevzara

Updated: 2023-12-06

The following table describes post-authorization activity for Kevzara, a product which contains the medicinal ingredient sarilumab. 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 02460521 - 150 mg/1.14 mL, solution, single-dose pre-filled syringe, subcutaneous injection

DIN 02460548 - 200 mg/1.14 mL, solution, single-dose pre-filled syringe, subcutaneous injection

DIN 02472961 - 150 mg/1.14 mL, solution, single-dose pre-filled pen, subcutaneous injection

DIN 02472988 - 200 mg/1.14 mL, solution, single-dose pre-filled pen, subcutaneous injection

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 275894

2022-05-26

Issued NOL 2022-10-21

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

SNDS # 264562

2023-06-01

Issued NOC 2023-07-13

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reaction, sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued.

DIN 02460521 cancelled post market

Not applicable

Discontinuation date: 2022-08-02

The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DIN(s) pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.

NC # 246010

2020-10-28

Issued NOL 2021-01-11

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

SNDS # 238963

2020-05-04

Issued NOC 2020-07-28

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

NC # 231855

2019-09-23

Issued NOL

2019-12-20

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 # 231742

2019-09-19

Issued NOL

2019-12-19

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

SNDS # 211993

2017-12-11

Issued NOC

2019-08-08

Submission filed as a Level I - Supplement for an expansion of the indication. The authorized indication is for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more biologic or non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Kevzara should be used in combination with methotrexate or other traditional DMARDs. Kevzara may be given as monotherapy in cases of intolerance or contraindication to methotrexate or DMARDs. Regulatory Decision Summary published.

NC # 220834

2018-10-10

Issued NOL

2019-01-11

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to propose the implementation of a new Working Cell Bank. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 221030

2018-10-19

Issued NOL

2018-12-21L

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

SNDS # 219508

 

2018-08-29

Issued NOC

2018-11-08

Submission filed as a Level I – Supplement to revise the location of the lot and expiry date and to request revisions to the design elements of the outer labels. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DINs 02472961, 02472988) market notification

Not applicable

Date of first sale: 2018-06-21

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

SNDS # 207004

2017-07-04

Issued NOC

2018-02-14

Submission filed as a Level I – Supplement to introduce new pre-filled pen presentations (auto-injectors) for the two currently approved strengths (150 mg/1.14 mL and 200 mg/1.14mL) for the same indication. The submission was reviewed and considered acceptable, and an NOC was issued. Two new DINs (02472961, 02472988) were issued for the new presentations.

SNDS # 203672

2017-03-17

Issued NOC

2017-05-30

Submission filed as a Level I – Supplement to correct the dose information on the 200 mg outer carton label. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02460521) market notification

Not applicable

Date of first sale:

2017-03-29

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 02460548) market notification

Not applicable

Date of first sale:

2017-02-28

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

NDS # 191745

2016-01-29

Issued NOC 2017-01-12

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

Date SBD issued: 2017-03-03

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

Sarilumab
150 mg/1.14 mL or 200 mg/1.14 mL solution, subcutaneous injection

Drug Identification Number (DIN):

  • DIN 02460521 - 150 mg/1.14 mL
  • DIN 02460548 - 200 mg/1.14 mL

Sanofi-aventis Canada Inc.

New Drug Submission Control Number: 191745

 

On January 12, 2017, Health Canada issued a Notice of Compliance to Sanofi-aventis Canada Inc. for the drug product Kevzara.

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 Kevzara is favourable for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more biologic or non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

 

1 What was approved?

 

Kevzara, an interleukin-6 receptor antagonist, is indicated in the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more biologic or non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Efficacy of Kevzara has not been studied in children less than 18 years of age.

Kevzara is contraindicated for patients with known hypersensitivity to sarilumab or to any of the excipients. Kevzara was approved for use under the conditions stated in the Kevzara Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Kevzara (sarilumab, 150 mg/1.14 mL or 200 mg/1.14 mL) is presented as a solution for injection in a single-dose pre-filled syringe. In addition to the medicinal ingredient, the solution contains arginine, histidine, polysorbate 20, sucrose, and water for injection.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Kevzara Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Kevzara approved?

 

Health Canada considers that the benefit/risk profile of Kevzara is favourable in the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more biologic or non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease primarily targeting the synovial membrane of diarthrodial joints, and is characterized by persistent synovitis and progressive destruction of cartilage and bone in multiple joints. Rheumatoid arthritis affects women twice as often as men, and the incidence is highest among women over 40 years of age. The hallmark of RA is a symmetric polyarthritis characteristically involving the small joints of the hands and feet, with 65% to 70% of patients having progressive disease that leads to joint destruction, disability, and reduced physical function. Systemic inflammation is associated with increases in acute phase reactants and anemia, hypoalbuminemia, fatigue, weight loss, and fever.

Current guidelines recommend treatment with non-biologic DMARDs, preferably methotrexate (MTX), for patients with moderate to high disease activity or who have poor prognostic factors (functional limitation, extra-articular disease, rheumatoid factor positivity, positive anti-cyclic citrullinated peptide (CCP) antibodies, or bony erosion on radiographs). A biologic DMARD should be added to the treatment regimen of patients who fail to achieve low disease activity after 3 to 6 months of non-biologic DMARD therapy. Patients who either fail to achieve low disease activity or who lose benefit over time should switch to another biologic DMARD.

Kevzara has been shown to be efficacious in adult patients with moderately to severely active RA diagnosed according to the American College of Rheumatology (ACR) criteria. The market authorization was based on two randomized, double-blind, placebo-controlled multicentre studies (MOBILITY and TARGET). The efficacy was demonstrated by achieving the co-primary endpoints consisting of improvement in signs and symptoms of RA as measured by the ACR 20% improvement (ACR20) response at Week 24, improvement in physical function as measured by the change from baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) score at Week 12 and Week 16; and for the MOBILITY Part B study only, inhibition of progression of structural damage as measured by the change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Week 52.

The safety profile of Kevzara is in line with that of other biological products authorized for treatment of rheumatoid arthritis.

Patients treated with Kevzara are at increased risk for developing serious infections. Warnings and precautions regarding this risk are listed in a Serious Warnings and Precautions Box in the Kevzara Product Monograph.

In order to ensure that the benefit continues to outweigh any risks after authorization, Health Canada has required standard post-approval activities to be carried out (see What follow-up measures will the company take?).

A Risk Management Plan (RMP) for Kevzara 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 name Kevzara has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Kevzara therapy are considered to outweigh the potential risks. Kevzara 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 Kevzara 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 Kevzara?

 

Submission Milestones: Kevzara

Submission Milestone Date
Submission filed: 2016-01-29
Screening  
Screening Acceptance Letter issued: 2016-03-18
Review  
On-Site Evaluations:  
Quality Evaluation complete: 2016-12-14
Clinical Evaluation complete: 2017-01-12
Biostatistics Evaluation complete: 2017-01-11
Labelling Review complete: 2017-01-11
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-01-12

 

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

 

4 What follow-up measures will the company take?

 

As part of the marketing authorization for Kevzara, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) providing Health Canada with:

  • Periodic Safety Update Reports/Periodic Benefit Risk Evaluation Reports for Kevzara every 6 months as per the pharmacovigilance plan, including those which may potentially be related to the immunogenicity profile of Kevzara (for example, [e.g.], adverse drug reactions (ADRs) related to immune system disorders, skin and subcutaneous tissue disorders, etc.), malignancies, serious infections, gastrointestinal (GI) perforations, and/or laboratory abnormalities (neutrophil counts, platelet counts, liver enzymes, lipids). Safety updates from all ongoing clinical trials with Kevzara should be included.
  • An updated Canadian Risk Management Plan (RMP) in accordance with Canadian labelling in order to capture the post-approval commitments to Health Canada and other regulatory agencies.
  • Regular safety updates from the Kevzara pregnancy registry.
  • Kevzara Medical Educational materials for review prior to the launch of the product.
  • All reports/correspondence pertaining to post-approval commitments from major Regulatory Authorities.
  • A summary safety report as part of a Benefit Risk Evaluation Report (as much as feasible) for Kevzara when used as monotherapy, 6 months after the launch of the product onto the market. The ADRs which may be potentially related to the immunogenicity profile of Kevzara (e.g., ADRs related to immune system disorders, skin and subcutaneous tissue disorders, etc.), malignancies, serious infections, GI perforations, and/or laboratory abnormalities (neutrophil counts, platelet counts, liver enzymes, lipids) should be reported.
  • Periodic Safety Update Reports/Periodic Benefit Risk Evaluation Reports for monotherapy treatment with Kevzara annually, including ADRs which may be potentially related to the immunogenicity profile of Kevzara (e.g., ADRs related to immune system disorders, skin and subcutaneous tissue disorders, etc.), malignancies, serious infections, GI perforations, and/or laboratory abnormalities (neutrophil counts, platelet counts, liver enzymes, lipids).

 

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

 

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Kevzara 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

Sarilumab, the medicinal ingredient of Kevzara, binds to both soluble and membrane-bound interleukin 6 (IL-6) receptors (sIL-6Rα and mIL-6Rα), and inhibits IL-6-mediated signaling. IL-6 is a pleiotropic proinflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes, and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as migration and activation of T-cells, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. Local production of IL-6 by synovial and endothelial cells in joints affected in chronic inflammatory disease, such as rheumatoid arthritis (RA), may play an important role in development of the inflammatory processes.

The human pharmacodynamic and pharmacokinetic studies adequately characterized sarilumab in patients with rheumatoid arthritis. The studies analyzed the impact of intrinsic factors (e.g., age, gender, race, body weight, or hepatic and renal function) and extrinsic factors (e.g., interaction with methotrexate [MTX], prior biologic therapies) on the pharmacokinetics of sarilumab, and explored exposure-response relationships.

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

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

Clinical Efficacy

The efficacy and safety of Kevzara were assessed in two randomized, double-blind, placebo-controlled multicentre studies (MOBILITY and TARGET) in adult patients with moderately to severely active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline.

MOBILITY Part B evaluated 1,197 patients with moderately to severely active rheumatoid arthritis who had inadequate clinical response to MTX. Part B was a 52-week study, intended to confirm the efficacy and safety of the two-dose regimens (150 mg once every 2 weeks [q2w] and 200 mg q2w) selected from the 12-week, dose-ranging part of the study (Part A). Only results from Part B, the confirmatory phase, were used in support of the proposed indication. Patients received subcutaneous Kevzara 200 mg, Kevzara 150 mg, or placebo every 2 weeks with concomitant MTX. All patients continued to receive MTX throughout the study. Starting at Week 16, patients with a lack of efficacy, defined as less than 20% improvement compared to baseline in swollen joints count (SJC) or tender joints count (TJC) for two consecutive visits, or any other clear lack of efficacy based on the clinical investigator's judgment could discontinue the randomized treatment and receive open-label Kevzara at 200 mg. The maximum duration of the study per patient was up to 52 weeks for treatment. The age of the patients ranged from 18 to 75 years, with a mean of 51 years. The majority of patients were female (82%). At baseline, the mean number of tender and swollen joints was 27 and 17, respectively.

The primary endpoints were the proportion of Kevzara patients who achieved an ACR 20% improvement (ACR20) response at Week 24, changes from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 16, and change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Week 52. The key secondary endpoint was a major clinical response (defined as ACR70 response maintained for 24 weeks).

The TARGET study was a 24-week randomized, double-blind, placebo-controlled parallel-group study which evaluated 546 patients with moderately to severely active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more Tumor Necrosis Factor alpha (TNF-αantagonists. Patients received subcutaneous Kevzara 200 mg, Kevzara 150 mg, or placebo every 2 weeks with a concomitant traditional Disease-Modifying Anti-Rheumatic Drug (DMARD). The primary objective was to assess the clinical benefit of Kevzara compared to placebo in moderate to severe rheumatoid arthritis patients with an inadequate efficacy response (after at least 3 consecutive months of treatment) and/or intolerance of 1 or more TNF-α antagonists, when administered with background non-biologic DMARD treatment. The study was stratified by geographic region and the number of prior TNF-α antagonists used. Patients enrolling in the study were requested to continue treatment with at least one of the permitted background therapies that included MTX, sulfasalazine, leflunomide, and hydroxychloroquine. The overall study treatment duration was 24 weeks. After 12 weeks of blinded dosing, all patients in the study who had not shown a clinically meaningful improvement in their disease (defined as less than a 20% improvement from baseline in either SJC or TJC for two joint assessments that were at least 4 weeks apart) were offered the opportunity to receive open-label treatment with Kevzara in an ongoing long-term safety study. The age of the patients ranged from 19 to 88 years, with a mean of 53 years. The majority of patients were female (82%). At baseline, the mean number of tender and swollen joints at baseline was 29 and 20, respectively.

The primary endpoints were the proportion of Kevzara patients who achieved an ACR20 response at Week 24 and the changes from baseline HAQ-DI score at Week 12.

Clinical Response

In both clinical studies, the clinical response was defined as the number of patients who achieved an ACR 20 response at Week 24.

In the MOBILITY Part B study at Week 24, 33.4% of patients treated with placebo + MTX achieved clinical response compared to 58.0% of patients treated with Kevzara 150 mg + MTX (difference from placebo + MTX: 24.6%; 97.5% confidence interval [CI] 17.0%, 32.2%) and 66.4% of patients treated with Kevzara 200 mg + MTX (difference from placebo + MTX: 33.0%; 97.5% CI 25.5%, 40.5%).

In the TARGET study at Week 24, 33.7% of patients treated with placebo + DMARD achieved clinical response compared to 55.8% of patients treated with Kevzara 150 mg + DMARD (difference from placebo + DMARD: 22.1%; 97.5% CI 11.2%, 33.0%) and 60.9% of patients treated with Kevzara 200 mg + DMARD (difference from placebo + DMARD: 27.4%; 97.5% CI 16.4%, 38.4%).

Physical Function Response

In the MOBILITY Part B and TARGET studies, physical function and disability were assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI). Patients who received Kevzara 200 mg or 150 mg + MTX/DMARD every two weeks demonstrated greater improvement from baseline in physical function compared to placebo at Week 16 in the MOBILITY Part B study and at Week 12 in the TARGET study.

The least squares mean change from baseline in the HAQ-DI score at Week 12 in the TARGET study was -0.28 for patients treated with placebo + DMARD, -0.47 for patients treated with Kevzara 150 mg + DMARD (difference from placebo + DMARD: -0.197; 97.5% CI -0.331, -0.062), -0.47 for patients treated with Kevzara 200 mg + DMARD (difference from placebo + DMARD: -0.192; 97.5% CI -0.326, -0.057).

The least squares mean change from baseline in the HAQ-DI score at Week 16 in the MOBILITY Part B study was -0.31 for patients treated with placebo + MTX, -0.52 for patients treated with Kevzara 150 mg + MTX (difference from placebo + MTX: -0.210: 97.5% CI -0.299, -0.121), -0.53 for patients treated with Kevzara 200 mg + MTX (difference from placebo + MTX: -0.222: 97.5% CI -0.312, -0.133).

Radiographic Response

In the MOBILITY Part B study, structural joint damage was assessed radiographically and expressed as change in van der Heijde-modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score at Week 52. Radiographs of hands and feet were obtained at baseline, 24 weeks, and 52 weeks, and scored independently by at least two well-trained readers who were blinded to treatment group and visit number.

Treatment with Kevzara + MTX was associated with less radiographic progression of structural damage as compared with placebo. At Week 52, 55.6% of patients receiving Kevzara 200 mg and 47.8% of patients receiving Kevzara 150 mg had no progression of structural damage (as defined by a change in the mTSS of zero or less) compared with 38.7% of patients receiving placebo.

Overall Analysis of Efficacy

The two pivotal studies, MOBILITY Part B and TARGET, support Kevzara in the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more biologic or non-biologic DMARDs.

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

Clinical Safety

The clinical safety assessment was based on Phase II/III data and data from a long-term extension study, all reported in the Integrated Safety Summary (ISS). A total of 3,019 patients had ≥1 dose of Kevzara, consisting of 4,405.7 patient-years of exposure. Adverse events (AEs) attributable to IL-6 inhibition were infections, decreased absolute neutrophil count, thrombocytopenia, increased aminotransferase levels, and elevated lipid levels. Laboratory abnormalities did not result in clinical consequences.

In the placebo-controlled safety population, the incidence of AEs was 73.8% (252.0/100 person-years) in patients treated with Kevzara 200 mg q2w, 70.5% (215.7/100 person- years) in patients treated with Kevzara 150 mg q2w, and 57.2% (173.3/100 person- years) in patients treated with placebo. Neutropenia/leukopenia drove the higher incidence in the 200 mg group.

Most AEs were infections (respiratory, urinary, nasopharyngeal, oral herpes, herpes zoster, cellulitis, and erysipelas) and were more often of a serious nature in patients >65 years, >100 kg, or on MTX >20 mg. Opportunistic infections included non-disseminated herpes zoster, tuberculosis, and candidiasis.

Patients treated with Kevzara are at increased risk for developing serious infections. Warnings and precautions regarding this risk are listed in a Serious Warnings and Precautions Box in the Kevzara Product Monograph. Opportunistic infections have also been reported in patients receiving Kevzara. Most patients who developed infections were taking concomitant immunosuppressants such as MTX or corticosteroids.

Serious AEs arose in 8.9% (13.8/100 person- years), 6.4% (9.7/100 person-years), and 4.7% (8.3/100 person- years) of patients treated with Kevzara 200 mg q2w, 150 mg q2w, and placebo, respectively.

The AEs that led to treatment discontinuation occurred in 12.6% (19.4/100 person-years), 10.9% (16.8/100 person- years), and 4.7% (8.2/100 person-years) of patients treated with Kevzara 200 mg q2w, 150 mg q2w, and placebo respectively. The most frequent events were infection, neutropenia, elevated aminotransferases, and herpes zoster.

In the placebo-controlled safety population, 6 patients died, 1 (0.2%) (0.2/100 person-years) taking 200 mg Kevzara, 2 (0.3%) (0.5/100 person-years) taking 150 mg Kevzara, and 3 (0.5%) (0.8/100 person-years) taking placebo. Nineteen (19) more deaths (0.7%) (0.4/100 person-years) occurred in the long-term safety population (all taking Kevzara + DMARD), plus 1 on monotherapy (Kevzara).

There were 3 additional deaths, 1 after Month 52, and 2 deaths after database cut-off. Infections, cardiovascular disease, and malignancy were the most common causes. Rates for the latter two were consistent with those in both general and rheumatoid arthritis populations.

The overall rates of treatment-emergent AEs in the long-term extension study were comparable to those in the placebo-controlled safety population.

Seven (7) patients had either complicated diverticulitis or gastrointestinal perforation unrelated to surgery (0.16/100 person-years). Injection site rash/pruritus, other rash, and urticaria were the most frequent hypersensitivity reactions, but there was no anaphylaxis during the study period.

Nine (9) pregnancies occurred, 4 ending in fetal wastage, and a fifth resulting in the birth of a child with pneumonia.

Immunogenicity

In the placebo-controlled population, rates of anti-drug antibody (ADA) positivity were 14.0% in the Kevzara 200 mg q2w group, 19.3% in the Kevzara 150 mg q2w group, and 3.5% in the placebo group. The majority of these ADA responses were classified as transient and low titre. The percentage of patients exhibiting a persistent ADA response was 4.0% in the Kevzara 200 mg q2w group, 5.6% in the Kevzara 150 mg q2w group, and 2.0% in the placebo group. In the 200 mg q2w, 150 mg q2w, and placebo groups, the incidence of patients who also exhibited neutralizing antibodies was 1.0%, 1.6%, and 0.2%, respectively. The percentage of ADA-positive patients (16.3% overall on any dose) declined over time in the Kevzara + DMARD long-term safety population, and the rate of positive ADA responses after 1 year of treatment resembled the false positive rate (2.0%) observed with placebo.

Based on data provided, ADA did not appear to have a clinically meaningful impact on the efficacy or safety profile of Kevzara.

Overall Analysis of Safety

Overall, Kevzara has a tolerable and manageable safety profile. Appropriate warnings and precautions are in place in the approved Kevzara Product Monograph to address the identified safety concerns. Warnings of developing serious infections have been included in a Serious Warnings and Precautions box. The risks and benefits of treatment with Kevzara should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

The reported safety profile of Kevzara is in line with that of other biological products authorized for treatment of rheumatoid arthritis. In order to ensure that the benefit continues to outweigh any risks after authorization, Health Canada has required standard post-approval activities to be carried out. For the list of activities, see question 4. What follow-up measures will the company take?

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

Overall, sarilumab, the medicinal ingredient of Kevzara, was well-tolerated in the animal studies. There are no non-clinical toxicological findings that would preclude the authorization of Kevzara in human patients. Embryo-fetal, and prenatal and postnatal findings are described in the Kevzara Product Monograph and accurately reflect the potential risk to pregnant women, the developing fetus and infants in the context of all available information.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Kevzara Product Monograph.

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

 

 

7.3 Quality Basis for Decision

 

Kevzara (sarilumab) is a fully human immunoglobulin G (IgG) subclass 1 (IgG1) monoclonal antibody that binds specifically to both soluble and membrane-bound IL-6 receptors, and has been shown to inhibit IL-6-mediated signaling through these receptors.

Characterization of the Drug Substance

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

Impurities and degradation products arising from manufacturing and storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

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

Sarilumab is produced by recombinant deoxyribonucleic acid (DNA) technology in a Chinese Hamster Ovary cell suspension culture. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines.

The manufacturing process of the drug substance consists of cell culture, purification, and formulation stages. The purification process includes a combination of chromatographic steps, including viral inactivation and viral filtration. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use. The sponsor demonstrated that the drug substance and formulated drug substance manufacturing process is robust and capable of consistently producing product of the desired quality.

The drug product is presented in two strengths, 150 mg (131.6 mg/mL) and 200 mg (175 mg/mL). The drug product manufacturing process includes formulated drug substance thawing, pooling, sterile filtration, aseptic filling and stoppering of syringe. The sponsor has demonstrated that the drug product manufacturing process is capable of consistently producing drug product of the desired quality in both strengths.

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.

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 ICH guidelines.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively support the quality review recommendation.

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, formulated drug substance, and drug product were adequately supported and are considered to be satisfactory. The proposed 24 month shelf life for Kevzara is considered acceptable when the drug product is stored at 2°C to 8°C.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

On-Site Evaluations of the facilities involved in the manufacture and testing of the drug substance and drug product were not warranted as the facilities were recently evaluated in good standing.

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

Adventitious Agents Safety Evaluation

Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the product formulation are not of animal or human origin.

 

Date modified: