Summary Basis of Decision for Brenzys

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 Brenzys is located below.
Recent Activity for Brenzys

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 Brenzys

Updated:

2023-02-16

The following table describes post-authorization activity for Brenzys a product which contains the medicinal ingredient etanercept. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Drug Identification Number (DIN):

  • DIN 02455331 - 50 mg/mL etanercept, solution (pre-filled auto-injector), subcutaneous administration
  • DIN 02455323 - 50 mg/mL etanercept, solution (pre-filled syringe), subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 265557 2022-06-24 Issued NOL 2022-09-09 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the working cell bank manufacturing site, add an alternate site for quality control testing of the drug substance and drug product, change testing procedures, and extend the shelf-life of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 257726 2021-10-18 Issued NOC 2022-03-17 Submission filed as a Level II – Supplement (Safety) 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 Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 231313 2019-09-06 Issued NOC 2020-08-19 Submission filed as a Level I – Supplement to extend the indication to all those held by the reference biologic drug. The indications authorized were: the treatment of juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA) and plaque psoriasis (PsO) in adults and pediatric patients aged 4 to 17 years. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 237494 2020-03-25 Issued NOL 2020-06-01 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf life of the reference standards and change the stability protocol of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 227467 2019-05-03 Issued NOC 2019-10-23 Submission filed as a Level I – Supplement to add an alternate site for manufacturing and testing of the drug substance. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 224765 2019-02-15 Issued NOL 2019-05-08 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the storage conditions for the drug substance, and to change the controls applied during the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 223347 2018-12-31 Issued NOL
2019-02-28
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 222280 2018-11-30 Issued NOL
2019-02-05
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.
SNDS # 215201 2018-04-05 Issued NOC
2018-06-18
Submission filed as a Level I - Supplement to modify the package design and package insert documents. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 207205 2017-07-05 Issued NOC
2018-06-14
Submission filed as a Level I - Supplement to provide a safety and efficacy update to the PM based on longer term follow up of patients in the pivotal trial (SB4-G31-RA). As a result of the submission, the following sections of the PM were updated: Dosage and Administration, and Clinical Trials sections of the PM. The benefit/risk profile for Brenzys remains positive when used for its approved indication. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 214279 2018-03-07 Issued NOL
2018-04-27
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a new manufacturing site, and to propose the implementation of a new Working Cell Bank. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 207750 2017-07-20 Issued NOL
2017-09-12
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 # 206004 2017-05-26 Issued NOC
2017-08-28
Submission filed as a Level I - Supplement for a new drug product manufacturing site. Drug product manufactured at the new site is comparable to product manufactured at the current site. The information was reviewed and considered acceptable. An NOC was issued.
SNDS # 206813 2017-06-19 Issued NOC
2017-08-24
Submission filed as a Level I - Supplement to revise the package inserts. The package inserts were reviewed and considered acceptable, and an NOC was issued.
NC # 205159 2017-04-28 Cancellation Letter Received
2017-05-11
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a new site. The proposed revisions exceeded the scope of a Notifiable Change. The submission was therefore cancelled by the sponsor so as to be filed as a SNDS.
NC # 204359 2017-04-03 Issued NOL
2017-05-09
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change testing procedures for the drug product and to add a new site. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 202416 2017-02-01 Issued NOL
2017-03-13
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to a release test for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 200090 2016-11-08 Issued NOL
2016-12-28
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance and storage conditions. The submission was reviewed and considered acceptable, and an NOL was issued.
Health product advertising complaint closed Not applicable Date received:
2017-02-04
A health product advertising complaint regarding an article focussing on Brenzys was closed. No follow-up was required as material had already been modified/removed/discontinued.
Drug product (DIN  02455323) market notification Not applicable Date of first sale:
2016-09-23
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Health product advertising complaint closed Not applicable Date received:
2016-09-20
A health product advertising complaint regarding a press release about Brenzys was closed. No follow-up was required as material had already been modified/removed/discontinued.
Drug product (DIN 02455331) market notification Not applicable Date of first sale:
2016-09-13
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 184793 2015-06-08 Issued NOC
2016-08-31
Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Brenzys

Date SBD issued: 2016-11-03

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

Etanercept, 50 mg/mL , solution, subcutaneous

Drug Identification Number (DIN):

  • DIN 02455331 - 50 mg/mL solution (pre-filled auto-injector)
  • DIN 02455323 - 50 mg/mL solution (pre-filled syringe)

Samsung Bioepis Co., Ltd.

New Drug Submission Control Number: 184793

 

On August 31, 2016, Health Canada issued a Notice of Compliance to Samsung Bioepis Co., Ltd. for the drug product Brenzys, a subsequent entry biologic to Enbrel (etanercept, marketed by Immunex Corporation). The term “subsequent entry biologic” is used by Health Canada to describe a biologic drug that enters the market subsequent to a version previously authorized in Canada, with demonstrated similarity to a reference biologic drug. In this drug submission, Enbrel is the reference product. Similarity between Brenzys and Enbrel was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), for the authorized indications. This drug submission requested the authorization of Brenzys for two of the indications that are currently held by Enbrel.

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 Brenzys is favourable for:

  • treatment of moderately to severely active rheumatoid arthritis (RA) in adults. Treatment is effective in reducing the signs and symptoms of RA, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function. Brenzys can be initiated in combination with methotrexate in adult patients or used alone.
  • reducing signs and symptoms of active ankylosing spondylitis (AS).
1 What was approved?

Brenzys, a biological response modifier, (a tumour necrosis factor alpha, TNF-α inhibitor) was authorized for:

  • treatment of moderately to severely active rheumatoid arthritis (RA) in adults. Treatment is effective in reducing the signs and symptoms of RA, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function. Brenzys can be initiated in combination with methotrexate in adult patients or used alone.
  • reducing signs and symptoms of active ankylosing spondylitis (AS).

Brenzys is a subsequent entry biologic (SEB) to Enbrel. Both drugs contain the medicinal ingredient, etanercept, a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumour necrosis factor receptor (TNFR) linked to the Fc portion of human immunoglobulin (IgG1). Etanercept is produced by recombinant deoxyribonucleic acid (DNA) technology in a Chinese hamster ovary (CHO) mammalian cell expression system. Etanercept binds specifically to soluble and cell surface tumour necrosis factor (TNF) and blocks its interaction with cell surface TNF receptors. The protein TNF is a naturally occurring cytokine, or immune system protein, that is implicated in the development and progression of inflammatory, infectious, and autoimmune diseases. This cytokine plays an important role in the inflammatory processes of RA, AS and the resulting joint pathology. Elevated levels of TNF are found in the synovial fluid of RA patients, and in serum and synovial tissue of patients with AS.

Comparability between Brenzys and the reference product, Enbrel, has been established on the basis of comparative chemistry and manufacturing studies, comparative non-clinical studies, a comparative pharmacokinetics study and clinical trials in patients with RA. Indications in RA and AS have been granted on the basis of similarity between Brenzys and the reference product, in product quality, mechanism of action, disease pathophysiology, safety profile, dosage regimen, and clinical experience with the reference product.

Four hundred and eighty RA patients were 65 years of age and older in clinical studies with the reference product, Enbrel. No overall differences in safety or effectiveness were observed between these patients and younger patients. Because there is greater sensitivity and predisposition of older individuals to infection, caution should be used in treating the elderly.

Brenzys is not indicated for use in children less than 18 years of age.

Brenzys is contraindicated for:

  • patients who are hypersensitive to etanercept or to any of the excipients.
  • patients with, or at risk of, sepsis syndrome, such as immunocompromised patients and human immunodeficiency virus (HIV)-positive patients.

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

Brenzys (50 mg/mL etanercept) is presented as sterile solution for injection, 50 mg/mL pre-filled syringe (0.98 mL), and 50 mg/mL pre-filled auto-injector (0.98 mL). In addition to the medicinal ingredient, the solution contains sodium chloride, sodium phosphate and sucrose. Pre-filled syringes and auto-injectors are intended for subcutaneous 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 Brenzys Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Brenzys approved?

Health Canada considers that the benefit/risk profile of Brenzys is favourable for:

  • treatment of moderately to severely active rheumatoid arthritis (RA) in adults. Treatment is effective in reducing the signs and symptoms of RA, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function. Brenzys can be initiated in combination with methotrexate (MTX) in adult patients or used alone.
  • reducing signs and symptoms of active ankylosing spondylitis (AS).

Brenzys is considered to be similar to Enbrel, the reference product. Enbrel is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Enbrel is authorized are: rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis. The New Drug Submission (NDS) filed for Brenzys requested authorization for two of the indications and clinical uses (RA and AS) that are currently authorized for Enbrel. Similarity between Brenzys and Enbrel was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), for the authorized indications.

Sufficient evidence of similarity between Brenzys and the reference product was provided to support the market authorization of Brenzys for use in patients with moderately to severely active RA and for use in patients with active AS.

The pharmacokinetic similarity of Brenzys and Enbrel was demonstrated in healthy volunteers. Furthermore, no clinically meaningful differences were detected between Brenzys and the reference product in the pivotal Phase III clinical trial (SB4-G31-RA) entitled “A randomised, double-blind, parallel group, multicentre clinical study to evaluate the efficacy, safety, pharmacokinetics and immunogenicity of Brenzys compared to Enbrel in subjects with moderate to severe rheumatoid arthritis despite methotrexate therapy”. A total of 596 patients were randomly allocated in a 1:1 ratio to receive either Brenzys 50 mg (n = 299) or Enbrel 50 mg (n = 297) once-weekly for 52 weeks via subcutaneous injection. In addition to etanercept, each patient also received a stable dose of oral or parenteral MTX (10 mg to 25 mg weekly) and was required to take folic acid 5 mg to 10 mg weekly while taking MTX. The primary study objective was to demonstrate the equivalence of Brenzys to Enbrel at Week 24 in terms of American College of Rheumatology 20% response criteria (ACR20) response rate in subjects with moderate to severe RA despite MTX therapy. Secondary objectives were:

  • To evaluate the efficacy of Brenzys compared to Enbrel using relevant efficacy endpoints other than ACR20 at Week 24 in patients with moderate to severe RA despite MTX therapy;
  • To evaluate the safety and tolerability of Brenzys compared to Enbrel in patients with moderate to severe RA despite MTX therapy;
  • To evaluate the pharmacokinetics of Brenzys compared to Enbrel in patients with moderate to severe RA despite MTX therapy;
  • To evaluate the immunogenicity of Brenzys compared to Enbrel in patients with moderate to severe RA despite MTX therapy.

The trial showed no clinically meaningful differences in efficacy and safety between Brenzys and Enbrel in patients with moderate to severe RA. Moreover, this data, in combination with data demonstrating physicochemical, biological and pharmacological similarity, was deemed sufficient to allow for the authorization of the second indication (AS). In order to support the authorization of Brenzys for use in the treatment of AS, the sponsor also provided scientific rationales that adequately addressed the principles of extrapolation as outlined in the guidance document Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs).

Brenzys has demonstrated a comparable safety profile with its reference product, Enbrel. The major identified safety concerns include infections and malignancies. They are specifically addressed in a Serious Warnings and Precautions box in the Brenzys Product Monograph. Serious infections leading to hospitalization or death, including sepsis, tuberculosis, invasive fungal and other opportunistic infections, have been observed with the use of TNF blocking agents, including etanercept.

In post-marketing studies of the reference product in patients with juvenile idiopathic arthritis, for which Brenzys is not indicated, serious infections have been reported in approximately 3% of patients. Sepsis has also been reported in the post-market setting of etanercept (0.8%). Brenzys is contraindicated in patients with, or at risk of, sepsis syndrome, such as immunocompromised patients and human immunodeficiency virus (HIV)-positive patients.

Although Brenzys is not indicated for use in children less than 18 years of age, lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including etanercept.

The adverse drug reaction profile reported in the clinical trials that compared Brenzys to Enbrel did not show meaningful clinical differences, therefore the Adverse Reactions section of the Brenzys Product Monograph is based on the clinical experience with the reference product Enbrel. Consequently, one of the post-market commitments by the sponsor refers to periodically reviewing the Brenzys Product Monograph to ensure that the safety information therein remains current with respect to relevant safety information captured within the most up-to-date Product Monograph for the reference product Enbrel (see the What follow-up measures will the company take? section).

A Risk Management Plan (RMP) for Brenzys was submitted by Samsung Bioepis Co., Ltd. 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. In addition, as part of the marketing authorization for Brenzys, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to) updating the RMP as per Health Canada’s recommendations (see the What follow-up measures will the company take? section).

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

Overall, Brenzys is considered to have a benefit/risk profile comparable to that which has been established for the claimed indications (RA, AS) for its reference product, Enbrel. The benefits of Brenzys therapy are considered to outweigh the potential risks. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Brenzys 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 Brenzys?

Submission Milestones: Brenzys

Submission Milestone Date
Pre-submission meeting: 2014-10-09
Submission filed: 2015-06-08
Screening  
Screening Acceptance Letter issued: 2015-08-06
Review  
On-Site Evaluation: 2015-12-07 - 2015-12-11
Quality Evaluation complete: 2016-05-24
Clinical Evaluation complete: 2016-05-24
Labelling Review complete: 2016-05-27
Patent Hold  
Submission placed on Patent Hold: 2016-05-31
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2016-08-31

The Canadian regulatory decision on the non-clinical and clinical review of Brenzys was based on a critical assessment of the Canadian data package. The foreign review completed by the European Medicines Agency (EMA) was used as an added reference.

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

4 What follow-up measures will the company take?

As part of the marketing authorization for Brenzys, 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):

  • Reviewing periodically the Brenzys Product Monograph to ensure that the safety information therein remains current with respect to relevant safety information captured within the most up-to-date Product Monograph for the reference product (Enbrel). It is recommended that the Brenzys Product Monograph be reviewed once per year at a minimum. Changes to the Product Monograph related to safety should be submitted to Health Canada as a Notifiable Change together with a rationale explaining the change.
  • Updating the Risk Management Plan (RMP) as per the following recommendations made by Health Canada (and sending the revised RMP to Health Canada):
    • Include the interaction of Brenzys with vaccines as a potential interaction in the RMP.
    • Since Brenzys is a biosimilar, the sponsor is requested to include the information regarding the importance of recording the product by both the brand name and batch number to ensure traceability of the product in the education material for the healthcare professionals.
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

Etanercept, the medicinal ingredient of Brenzys, is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumour necrosis factor receptor (TNFR) linked to the Fc portion of human immunoglobulin G1 (IgG1). It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons.

Etanercept binds specifically to soluble and cell surface tumour necrosis factor (TNF) and blocks its interaction with cell surface TNF receptors. Etanercept inactivates TNF without causing in vitro lysis of cells involved in the immune response. The protein, TNF, is a naturally occurring cytokine, or immune system protein, that is implicated in the development and progression of inflammatory, infectious, and autoimmune diseases. This cytokine plays an important role in the inflammatory processes of rheumatoid arthritis (RA), ankylosing spondylitis (AS) and the resulting joint pathology. Elevated levels of TNF are found in the synovial fluid of RA patients, and in serum and synovial tissue of patients with AS.

The clinical pharmacological data support the use of Brenzys for its specified indications.

Brenzys is a subsequent entry biologic (SEB) to the Canadian authorized reference product, Enbrel. The pharmacokinetics, safety/tolerability, and immunogenicity of three formulations of etanercept (Brenzys, European Union [EU] Enbrel, United States Enbrel) were compared in Study SB4-G11-NHV, a Phase I controlled, randomized, single-blind, three-part, two-period, two-sequence, single-dose, cross-over study in 138 healthy male subjects. The analyses were conducted according to the recommendations set forth in the Canadian guidance document Conduct and Analysis of Comparative Bioavailability Studies. The study included three parts (Part A, B, and C), each involving 46 subjects, with a purpose to demonstrate comparability between Brenzys and EU Enbrel, between Brenzys and United States Enbrel and between EU Enbrel and United States Enbrel, respectively. Only Part A of the study used the reference product suitable for the Canadian context (EU Enbrel), and the evaluation of comparative bioavailability was focused on this comparison (Brenzys versus [vs.] EU Enbrel).

In each treatment period, a single dose of 50 mg was given by subcutaneous injection and then followed for 21 days to assess the pharmacokinetics, safety, tolerability and immunogenicity of each of the formulations of etanercept. Treatment periods were separated by 7 days, resulting in a 28-day washout period between administrations. The study demonstrated pharmacokinetic comparability (between Brenzys and EU Enbrel), in healthy subjects, as evidenced by the mean ratios (expressed as percentages) for the area under the concentration-time curve up to the last measurable concentration, AUClast (98.62 [90% CI: 94.17; 103.28]) and the maximum plasma concentration, Cmax (103.71), which were within the acceptance interval of 80.00% to 125.00%.

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

Clinical Efficacy

The comparative clinical efficacy of Brenzys and its reference product Enbrel was evaluated in a pivotal Phase III clinical trial (SB4-G31-RA) entitled “A randomised, double-blind, parallel group, multicentre clinical study to evaluate the efficacy, safety, pharmacokinetics and immunogenicity of Brenzys compared to Enbrel in subjects with moderate to severe rheumatoid arthritis despite methotrexate therapy”. It was an international, multicentre trial involving ten countries. Patients were not recruited for this trial in Canada. The primary study objective was to demonstrate the equivalence of Brenzys to Enbrel at Week 24 in terms of American College of Rheumatology 20% response criteria (ACR20) response rate in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. Secondary objectives were as follows:

  • To evaluate the efficacy of Brenzys compared to Enbrel using relevant efficacy endpoints other than ACR20 at Week 24 in patients with moderate to severe RA despite MTX therapy;
  • To evaluate the safety and tolerability of Brenzys compared to Enbrel in patients with moderate to severe RA despite MTX therapy;
  • To evaluate the pharmacokinetics of Brenzys compared to Enbrel in patients with moderate to severe RA despite MTX therapy;
  • To evaluate the immunogenicity of Brenzys compared to Enbrel in patients with moderate to severe RA despite MTX therapy.

A total of 596 patients were randomly allocated in a 1:1 ratio to receive either Brenzys 50 mg (n = 299) or Enbrel 50 mg (n = 297) once-weekly for 52 weeks via subcutaneous injection. In addition to etanercept, each patient also received a stable dose of oral or parenteral MTX (10 mg to 25 mg weekly) and was required to take folic acid 5 mg to 10 mg weekly while taking MTX.

The difference in ACR20 response rates at Week 24 between the Brenzys and Enbrel treatment arms was -2.37% (95% CI: -9.54%; 4.80%), which was contained within the pre-defined equivalence margin of [-15%, 15%]. In addition, no major differences were observed between the Brenzys and Enbrel treatment arms for the secondary efficacy variables:

  • ACR20 at Week 52;
  • 50% improvement according to the ACR criteria, ACR50 and 70% improvement according to the ACR criteria, ACR70 response at Week 24 and Week 52;
  • The numeric index of the ACR response (ACR-N) at Week 24 and Week 52;
  • Area under the concentration-time curve (AUC) of ACR-N up to Week 24;
  • The disease activity score based on a 28 joint count (DAS28 score) at Week 24 and Week 52;
  • The European League Against Rheumatism (EULAR) response at Weeks 24 and 52;
  • AUC of the change in DAS28 from baseline up to Week 24;
  • “Major clinical response” (ACR70 response for 6 consecutive months) at Week 52;
  • Change from baseline in modified Total Sharp Score (mTSS) at Week 52.

The submitted clinical data, in combination with the results derived from comparative physicochemical and biological assays, provide sufficient evidence of similarity to support the authorization of Brenzys for use in patients with moderate to severe RA.

Randomized clinical trials have not been conducted to compare Brenzys to Enbrel in patients with adult AS. However, to support the authorization of Brenzys for use in the treatment of AS, the sponsor provided scientific rationales that adequately addressed the principles of extrapolation as outlined in the guidance document Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). The extrapolation of the data derived from comparative studies in patients with RA to support uses of Brenzys in adult AS was based on the demonstrated comparability, in terms of product quality, non-clinical, human pharmacokinetic and clinical characteristics.

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

Indications

This new drug submission was submitted to support the authorization of Brenzys, a subsequent entry biologic, for two of the indications and clinical uses currently authorized for its reference product, Enbrel (RA, AS). Indications in RA and AS have been granted on the basis of similarity between Brenzys and the reference product, in product quality, mechanism of action, disease pathophysiology, safety profile, dosage regimen, and clinical experience with the reference product. Similarity between Brenzys and Enbrel was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs).

Clinical Safety

The clinical safety of Brenzys was evaluated in comparison to its reference product, Enbrel, in a pivotal Phase III clinical trial (SB4-G31-RA) entitled “A randomised, double-blind, parallel group, multicentre clinical study to evaluate the efficacy, safety, pharmacokinetics and immunogenicity of Brenzys compared to Enbrel in subjects with moderate to severe rheumatoid arthritis despite methotrexate therapy” (described in Clinical Efficacy section).

No unexpected adverse events were reported during the study period. Two deaths were reported in the Brenzys treatment group (one secondary to cardiopulmonary failure and one secondary to gastric adenocarcinoma). The deaths were not considered to be related to the study drug. No cases of tuberculosis were reported in either study arm. The rates of occurrence for treatment-emergent serious infections and malignancies were similar between the two treatment arms. 

In terms of immunogenicity, the cumulative incidence of antibodies against etanercept was 1% in the Brenzys treatment group compared to 13.2% in the Enbrel treatment arm at Week 52. The difference in the cumulative incidence of anti-etanercept antibodies was driven by an increased incidence of transient, non-neutralising antibodies observed at Week 4 and Week 8 among patients that received Enbrel. In both treatment arms, antibodies were typically detected at Week 4 and/or Week 8 and were transient, as most subjects had no detectable anti-etanercept antibodies from Week 12 onward. Antibodies were generally non-neutralising except for those detected in one patient in the Enbrel treatment arm.

The adverse drug reaction profiles reported in the clinical trials that compared Brenzys to Enbrel did not show meaningful clinical differences. No new adverse reactions were reported. Accordingly, the Adverse Reactions section of the Brenzys Product Monograph provides description of adverse reactions based on clinical experience with the reference product Enbrel.

Etanercept has been studied in 1,442 patients with RA who have been followed for over 6 years, including 225 patients who have been followed for more than 10 years. Etanercept has been studied in 222 patients with AS for up to 48 months. Etanercept has over three million patient-years of post-market exposure. Among patients with RA in placebo‑controlled studies, serious adverse events occurred at a frequency of 4% in 349 patients treated with etanercept compared to 5% of 152 placebo-treated patients. In a subsequent study, serious adverse events occurred at a frequency of 6% in 415 patients treated with etanercept compared to 8% of 217 methotrexate-treated patients. In long-term open-label studies in adults with RA, there were no new or unexpected serious adverse events reported.

In studies with RA patients in placebo-controlled, active-controlled, and open-label trials of etanercept, infections and malignancies were the most common serious adverse events observed. Therefore, infections and malignancies are specifically referred to in a Serious Warnings and Precautions box and the Warnings and Precautions section of the Brenzys Product Monograph. These sections highlight that serious infections leading to hospitalization or death, including sepsis, tuberculosis, invasive fungal and other opportunistic infections have been observed with the use of TNF blocking agents, including etanercept. Treatment with Brenzys should not be initiated in patients with active infection, including tuberculosis, chronic or localized infections. Caution should be exercised when considering the use of Brenzys in patients with a history of recurring or latent infections, including tuberculosis, or with underlying conditions, which may predispose patients to infections, such as advanced or poorly controlled diabetes. Before starting treatment with Brenzys, all patients should be evaluated for both active and inactive (‘latent’) tuberculosis. Patients should be monitored for the development of signs and symptoms of infection during and after treatment with Brenzys, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

In post-marketing studies of the reference product, etanercept, in patients with juvenile idiopathic arthritis, for which Brenzys is not indicated, serious infections have been reported in approximately 3% of patients. Sepsis has also been reported in the post‑market setting of etanercept (0.8%). Brenzys is contraindicated in patients with, or at risk of, sepsis syndrome, such as immunocompromised and human immunodeficiency virus (HIV)-positive patients.

Furthermore, the Serious Warnings and Precautions box points out that, although Brenzys is not indicated for use in children less than 18 years of age, lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including etanercept.

In controlled trials, the proportion of patients who discontinued treatment due to adverse events was approximately 4% in both etanercept and placebo treatment groups. Among patients with RA in placebo-controlled studies, deaths occurred in 10 of 2,696 (0.37%) etanercept-treated patients compared to 3 of 1,167 (0.26%) placebo-treated patients. In controlled and uncontrolled RA studies there were 58 deaths in 6,973 patients treated with at least one dose of etanercept over an exposure period of 11,765 patient-years (exposure-adjusted rate of 0.49). In the long-term open-label RA studies, the rate of death did not increase over time with increasing exposure to etanercept.

Adverse reactions reported during AS trials were similar to those reported in RA clinical trials.

Overall, the safety profile of Brenzys is considered comparable to that which has been established for its reference product Enbrel. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions box and the Warnings and Precautions section of the Brenzys Product Monograph.

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

7.2 Non-Clinical Basis for Decision

The non-clinical database submitted for Brenzys was in compliance with the requirements for non-clinical studies of subsequent entry biologics, as presented in the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). Comparative in vitro studies and a mouse in vivo study supported the pharmacodynamics. A comparative 4-week repeat-dose toxicity study in cynomolgus monkeys was also conducted. The non-clinical data indicates that Brenzys and Enbrel have comparable pharmacological, toxicological, and toxicokinetic effects in animals.

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

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

7.3 Quality Basis for Decision

Brenzys is a subsequent entry biologic to the reference product, Enbrel. Both drugs contain the medicinal ingredient, etanercept, a recombinant fusion protein consisting of the extracellular ligand-binding domain of the human 75 kilodalton (p75) tumour necrosis factor receptor (TNFR) and the Fc portion of human immunoglobulin G1 (IgG1). Etanercept consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. It binds specifically to soluble TNF-α and thereby down-regulates TNF-α induced immune responses.

Characterization of the Drug Substance

The sponsor performed head-to-head characterization, stability (long-term, accelerated, stressed conditions), forced degradation and photostability studies to compare the drug substance (etanercept) and drug product (Brenzys) to the reference product, Enbrel. Brenzys was found to be highly similar to Enbrel in terms of its structure, physicochemical and biophysical properties, glycan profiles, biological activities and stability, and forced degradation profiles.

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

The drug substance, etanercept is produced by recombinant deoxyribonucleic acid (DNA) technology in a Chinese hamster ovary (CHO) mammalian cell expression system. Upstream processes include inoculation, cell expansion, harvest, and viral inactivation. Downstream operations include a series of chromatographic steps, virus inactivation and filtration steps and an ultrafiltration/diafiltration step. The final drug substance formulation is identical to the drug product formulation.

The results from process validation studies and the batch analysis data demonstrated that the manufacture of etanercept is consistent and yields a product of suitable quality. Release specifications were set for identity, content, potency (bioassay), impurities (product-related) and safety. Specifications were set based on a combination of historical data and results of characterisation, stability, and structure-activity relationship studies. The specifications were harmonized with those of the European Medicines Agency (EMA) and are considered acceptable.

Manufacturing of the drug product (Brenzys) is a multi-step process which includes thawing of the drug substance, transfer into cold storage (2ºC-8ºC), equilibration at 15ºC‑25ºC before transfer, bioburden reduction pre-filtration into a pooling vessel, pooling/mixing, sterile filtration, aseptic filling, plunger placement and visual inspection. Once inspected, the semi-finished syringes can either 1) be finished into pre-filled syringes where they undergo labelling, plunger rod assembly, manual backstop assembly and finished product packaging, or 2) be finished into pre-filled auto-injectors (pens) where they undergo assembly into auto-injectors, labelling and finished product packaging.

The results from process validation studies demonstrate that the manufacturing process is capable of consistently manufacturing lots of pre-filled syringes and pre-filled auto‑injectors that meet pre-established specifications. Specifications for Brenzys in its pre-filled syringe and pre-filled auto-injector presentations were revised to be harmonized with those agreed upon with the EMA. Release and shelf life specifications were set based on manufacturing experience, stability data or compendial requirements. The specifications are considered acceptable.

Brenzys is a clear to opalescent, colourless to pale yellow, sterile and preservative-free solution, intended for subcutaneous administration. There may be small white particles of protein in the solution. It is available in 1 ml pre-filled syringes or pre-filled auto-injectors. Each pre-filled syringe or pre-filled auto-injector is filled with a solution that contains 50 mg/ml of etanercept, 1% sucrose, 140 mM sodium chloride and 10 mM sodium phosphate and has a pH of 6.2. Brenzys is supplied in a carton that may contain four syringes or auto-injectors with 27-gauge, ½ inch needles.

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 etanercept with the excipients was demonstrated.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) 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 shelf life of 24 months at 2°C to 8°C for Brenzys in its pre-filled syringe and pre-filled auto-injector presentations is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

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

An OSE of the facility involved in the manufacture and testing of Brenzys (drug product) was considered not warranted on the basis of factors related to the site such as its Good Manufacturing Practices status, its overall approach to the drug product process validation studies and the use of disposable or dedicated manufacturing equipment.

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

Adventitious Agents Safety Evaluation

The etanercept manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate viruses are adequately validated.