Summary Basis of Decision for Hyrimoz

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 Hyrimoz is located below.

Recent Activity for Hyrimoz

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 Hyrimoz

Updated: 2023-08-16

The following table describes post-authorization activity for Hyrimoz, a product which contains the medicinal ingredient adalimumab. 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 02492156 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, prefilled pen (auto-injector)

DIN 02492164 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, prefilled syringe

DIN 02505258 - 20 mg/0.4 mL adalimumab, solution, subcutaneous injection, prefilled syringe

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 267563 2022-09-01 Issued NOL 2022-11-23 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a formulation/filling suite to the drug product manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 258125 2021-10-28 Issued NOC 2022-10-11 Submission filed as a Level I – Supplement to expand the indication to include the treatment of pediatric ulcerative colitis. The submission was reviewed and considered acceptable, and an NOC was issued A Regulatory Decision Summary was published.
SNDS # 244618 2020-10-01 Issued NOC 2021-09-10 Submission filed as a Level I – Supplement to expand the indication to include the treatment of pediatric uveitis, pediatric Crohn’s disease, and adolescent hidradenitis. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 254106 2021-06-23 Issued NOL 2021-07-29 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a new testing site. The submission was considered acceptable, and an NOL was issued.
NC # 247840 2020-12-21 Issued NOL
2021-02-25

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in scale of the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DINs 02505258, 02492164, 02492156) market notification Not applicable Date of first sale:
2021-02-15

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 235712 2020-02-11 Issued NOC
2020-11-04

Submission filed as a Level I – Supplement to introduce a new presentation of Hyrimoz 20 mg/0.4 mL, for pediatric patients weighing less than 30 kg. In addition, this submission sought approval of a new manufacturing site for the drug product and final dosage form. The submission was reviewed and considered acceptable and an NOC was issued. A Regulatory Decision Summary was published.
NDS # 217314 2018-10-01 Issued NOC
2020-11-04

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Hyrimoz

Date SBD issued: 2021-06-10

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

Adalimumab

Drug Identification Number (DIN):

  • DIN 02492156 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, prefilled pen (auto-injector)
  • DIN 02492164 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, prefilled syringe
  • DIN 02505258 - 20 mg/0.4 mL adalimumab, solution, subcutaneous injection, prefilled syringe

Sandoz Canada Inc.orporated

New Drug Submission Control Number: 217314

 

On November 4, 2020, Health Canada issued a Notice of Compliance (NOC) to Sandoz Canada Incorporated for Hyrimoz, a biosimilar to Humira (the reference biologic drug). The terms “biosimilar biologic drug” and “biosimilar” are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as subsequent entry biologics in Canada. Hyrimoz contains the medicinal ingredient adalimumab, which has been demonstrated to be highly similar to adalimumab contained in the reference product, Humira. 

Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. For a biosimilar, the weight of evidence is provided by the structural and functional studies; the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic, pharmacodynamic, and clinical studies.

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor’s submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought.

For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

In this drug submission, Humira is the reference biologic drug. Similarity between Hyrimoz and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within this drug submission, the sponsor requested the authorization of Hyrimoz for all of the indications that are currently authorized for Humira. However, the available Hyrimoz presentations (prefilled syringe and prefilled auto-injector) did not allow for delivering less than the full 40 mg dose of adalimumab required for some polyarticular juvenile idiopathic arthritis dosing regimens and for the 20 mg maintenance dose for pediatric Crohn’s disease. Therefore, the recommended indications were modified to align with the available presentations of Hyrimoz. Specifically, the pediatric Crohn’s disease indication was not recommended, and the polyarticular juvenile idiopathic arthritis dosing was limited to patients who require the full 40 mg dose.

The market authorization of Hyrimoz was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the Hyrimoz and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada’s review, the benefit-risk profile of Hyrimoz is considered to be similar to the benefit-risk profile of the reference product, and is therefore considered favourable for the following indications:

Rheumatoid Arthritis

  • Reducing the signs and symptoms, inducing major clinical response and clinical remission, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Hyrimoz can be used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs.

When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Hyrimoz should be given in combination with methotrexate. Hyrimoz can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is contraindicated.

Polyarticular Juvenile Idiopathic Arthritis

  • In combination with methotrexate, reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients, 2 years of age and older who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs. Hyrimoz can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate (see Hyrimoz Product Monograph). Adalimumab has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis aged less than 2 years.

Psoriatic Arthritis

  • Reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis patients. Hyrimoz can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in patients with active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Adult Crohn’s Disease

  • Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants. Hyrimoz is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Ulcerative Colitis

  • Treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy including corticosteroids and/or azathioprine or 6-mercaptopurine or who are intolerant to such therapies. The efficacy of adalimumab in patients who have lost response to or were intolerant to tumour necrosis factor blockers has not been established.

Hidradenitis Suppurativa

  • Treatment of active moderate to severe hidradenitis suppurativa in adult patients, who have not responded to conventional therapy (including systemic antibiotics).

Plaque Psoriasis

  • Treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Hyrimoz should be used after phototherapy has been shown to be ineffective or inappropriate.

Adult Uveitis

  • Treatment of non-infectious uveitis (intermediate, posterior and panuveitis) in adult patients with inadequate response to corticosteroids or as corticosteroid sparing treatment in corticosteroid-dependent patients.

 

1 What was approved?

 

Hyrimoz, a biological response modifier, was authorized for the following indications:

Rheumatoid Arthritis

  • Reducing the signs and symptoms, inducing major clinical response and clinical remission, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Hyrimoz can be used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs.

When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Hyrimoz should be given in combination with methotrexate. Hyrimoz can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is contraindicated.

Polyarticular Juvenile Idiopathic Arthritis

  • In combination with methotrexate, reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients, 2 years of age and older who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs. Hyrimoz can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate (see Hyrimoz Product Monograph). Adalimumab has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis aged less than 2 years.

Psoriatic Arthritis

  • Reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis patients. Hyrimoz can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in patients with active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Adult Crohn’s Disease

  • Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants. Hyrimoz is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Ulcerative Colitis

  • Treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy including corticosteroids and/or azathioprine or 6-mercaptopurine or who are intolerant to such therapies. The efficacy of adalimumab in patients who have lost response to or were intolerant to tumour necrosis factor blockers has not been established.

Hidradenitis Suppurativa

  • Treatment of active moderate to severe hidradenitis suppurativa in adult patients, who have not responded to conventional therapy (including systemic antibiotics).

Plaque Psoriasis

  • Treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Hyrimoz should be used after phototherapy has been shown to be ineffective or inappropriate.

Adult Uveitis

  • Treatment of non-infectious uveitis (intermediate, posterior and panuveitis) in adult patients with inadequate response to corticosteroids or as corticosteroid sparing treatment in corticosteroid-dependent patients.

Hyrimoz has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis younger than 2 years of age or in pediatric patients with a weight below 10 kg.

Evidence from clinical studies and experience suggests that use of Hyrimoz in the geriatric population (65 years of age and older) is not associated with differences in effectiveness.

Hyrimoz is a biosimilar to Humira. Both drugs contain the medicinal ingredient, adalimumab. Adalimumab is a recombinant human immunoglobulin G1 monoclonal antibody directed against tumour necrosis factor alpha. Adalimumab is a biologic disease modifying anti-rheumatic agent used in the management of a variety of autoimmune conditions.

Similarity between Hyrimoz and the reference biologic drug, Humira, has been established based on data derived from comparative structural and functional studies, comparative non-clinical studies, two comparative pharmacokinetic studies in healthy adult males, and a comparative efficacy, safety, and immunogenicity study in patients with moderate to severe chronic plaque psoriasis, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Hyrimoz is contraindicated in:

  • Patients with known hypersensitivity to Hyrimoz (adalimumab injection) or any of its components.
  • Patients with severe infections such as sepsis, tuberculosis, and opportunistic infections.
  • Patients with moderate to severe heart failure (New York Heart Association [NYHA] class III/IV).

Hyrimoz was approved for use under the conditions stated in its product monograph taking into consideration the potential risks associated with the administration of this drug product.

Hyrimoz (40 mg/0.8 mL adalimumab) is presented as a solution in a single-dose prefilled syringe and a single-dose prefilled auto-injector. In addition to the medicinal ingredient, the solution contains adipic acid, citric acid monohydrate, sodium chloride, mannitol, polysorbate 80, and water for injection. Hydrochloric acid and sodium hydroxide are added as necessary to adjust pH.

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

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

 

2 Why was Hyrimoz approved?

 

Based on Health Canada’s review, the benefit-risk profile of Hyrimoz is considered to be similar to the benefit-risk profile of the reference biologic product, Humira, and is therefore considered favourable for the treatment of: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, and adult uveitis. Similarity between Hyrimoz and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Hyrimoz is considered to be biosimilar to Humira. In Canada, Humira is currently authorized for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, and uveitis.

The New Drug Submission filed for Hyrimoz requested authorization for all of the indications and clinical uses that are currently authorized for Humira. However, the available Hyrimoz presentations (prefilled syringe and prefilled auto-injector) did not allow for delivering less than the full 40 mg dose of adalimumab required for some polyarticular juvenile idiopathic arthritis dosing regimens and for the 20 mg maintenance dose for pediatric Crohn’s disease. Therefore, the recommended indications were modified to align with the available presentations of Hyrimoz. Specifically, the pediatric Crohn’s disease indication was not recommended, and the polyarticular juvenile idiopathic arthritis dosing was limited to patients who require the full 40 mg dose.

The target diseases for Hyrimoz include a host of immune-mediated conditions with shared inflammatory pathways involving tumour necrosis factor alpha (TNF-α). Elevated levels of TNF-α are found in the synovial fluid of rheumatoid arthritis patients, including those with polyarticular juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis. These elevated levels of TNF-α play an important role in the pathologic inflammation and joint destruction that are hallmarks of these diseases. Similarly, elevated levels of TNF-α are found in psoriasis plaques, which contribute to the inflammatory response, the proliferation and decreased maturation of keratinocytes, and the associated vascular damages that are characteristic of the disease. Increased levels of TNF-α are also found in hidradenitis suppurativa lesions.

Adalimumab, the medicinal ingredient in Hyrimoz, is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody that binds to soluble and membrane-bound TNF-α. Adalimumab is a biologic disease-modifying anti-rheumatic agent used in the management of a variety of autoimmune conditions.

Hyrimoz and Humira were judged to be highly similar in terms of quality attributes based on comparative structural and functional studies. Comparable pharmacokinetics between Hyrimoz and Humira was established in two comparative pharmacokinetic studies conducted in healthy male adults. Comparable efficacy, safety, and immunogenicity between the two products were also demonstrated in a Phase III randomized, double-blind study in adult patients with chronic moderate to severe plaque psoriasis. The study achieved its primary endpoint whereby the difference between the efficacy parameters of Hyrimoz and the reference biologic product was contained within the predefined comparability margins. A comparable safety and immunogenicity profile was demonstrated as well. This demonstration of similarity enables the sponsor’s submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought. Therefore, the Adverse Reactions section of the Hyrimoz Product Monograph is based on the clinical experience with the reference biologic drug, Humira.

As with Humira, a Serious Warnings and Precautions box describing reports of hepatosplenic T-cell lymphoma, infections, and pediatric malignancies in patients treated with TNF-blockers has been included in the Hyrimoz Product Monograph.

A Risk Management Plan (RMP) for Hyrimoz was submitted by Sandoz Canada Incorporated 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 Hyrimoz was accepted

Overall, the benefits of Hyrimoz therapy are expected to be similar to the known benefits of the reference biologic drug, Humira, and are considered to outweigh the potential risks. Appropriate warnings and precautions are in place in the Hyrimoz 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 Quality (Chemistry and Manufacturing), Non–clinical, and Clinical Basis for Decision sections.

 

3 What steps led to the approval of Hyrimoz?

 

Submission Milestones: Hyrimoz

Submission Milestone Date
Submission filed 2018-10-01
Screening  
Screening Acceptance Letter issued 2018-11-16
Review  
Review of Risk Management Plan complete 2019-07-03
Quality Evaluation complete 2019-09-03
Non-clinical Evaluation complete 2019-09-09
Clinical/Medical Evaluation complete 2019-09-10
Labelling Review complete 2019-09-11
Intellectual Property Hold  
Submission placed on Intellectual Property Hold 2019-09-11
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2020-11-04

 

The Canadian regulatory decision on the review of Hyrimoz was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration was used as an added reference.

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?

 

The onus is on the Hyrimoz sponsor to monitor the post-market safety profile of this biosimilar product as well as the product monograph of the reference biologic drug for safety signals that could impact the biosimilar, and make safety updates to the Hyrimoz Product Monograph, as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.

As part of the marketing authorization for Hyrimoz, 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 the following to Health Canada:

  • Educational materials for Hyrimoz, once available, including a reminder to healthcare professionals to prescribe Hyrimoz by brand name and non-proprietary name.
  • Periodic Benefit-Risk Evaluation Reports for Hyrimoz, every year after authorization, including adverse drug reaction reporting.

 

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

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Hyrimoz 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 Quality Basis for Decision

 

Hyrimoz was developed as a biosimilar to the reference biologic drug, Humira. For biosimilars, the weight of evidence is provided by structural and functional studies. Biosimilars are manufactured to the same regulatory standards as other biologic drugs. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity to the reference biologic drug.

The biological activity of Hyrimoz is considered to be representative of the mechanism of action and pharmacological effect of Humira.

Comparative Structural and Functional Studies

The sponsor assessed the comparability of Hyrimoz to the reference product, Humira, sourced from the United States (Humira-US) and the European Union (Humira-EU). A direct comparison of available data supported the conclusion that Humira-US and Humira-EU were comparable to Humira sourced from Canada. Therefore, the use of the Humira-US and Humira-EU as the reference biologic product has been sufficiently justified.

A combination of characterization and stability studies established a high degree of similarity in the primary, secondary, and tertiary structure, as well as the purity, biological activity, and stability and forced degradation profiles of Hyrimoz and Humira. Some minor analytical differences in biochemical attributes were observed, however, these differences were not considered clinically meaningful as they had no impact on the biological activity of the drug. Taken together, these studies suggest a high degree of similarity between Hyrimoz and Humira.

Characterization of the Drug Substance

The drug substance, adalimumab, is a recombinant, fully human immunoglobulin G1 (IgG1) type monoclonal antibody. It consists of 1,330 amino acids and has a molecular weight of 148 kDa. The primary mode of action of adalimumab is the specific binding and functional neutralization of tumour necrosis factor alpha (TNF-α) by blocking its interaction with p55 and p75 cell surface TNF receptors.

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

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

The drug substance, adalimumab, is expressed in recombinant Chinese hamster ovary cells using a fed-batch process. The manufacturing process of the drug substance includes initial culture steps, main-stage cell cultivation, and a series of chromatography and viral inactivation steps followed by ultrafiltration/diafiltration, filtration, and filling. Finally, the drug substance is frozen in a shock freezer and stored at ≤-60 °C.

The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use. 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 and acceptable limits. Further, the sponsor has demonstrated that appropriate in-process controls have been implemented throughout the manufacturing process and that the drug substance manufacturing facility is capable of consistently manufacturing the drug substance of acceptable quality.

The Hyrimoz drug product is a single-use, preservative-free, ready-to-use solution for subcutaneous injection at a concentration of 40 mg/0.8 mL. The primary container closure system is a sterile prefilled syringe.

The drug product manufacturing process consists of the dissolving of excipients and active ingredient, compounding, sterile filtration, and aseptic syringe filling. The prefilled syringe is further assembled with a needle safety device or an auto-injector, both of which are secondary components of the container closure system and have no contact with the sterile fluid path. Controls of critical steps in the drug product manufacturing process were appropriately defined throughout development, based on a risk assessment and current process understanding. All process parameters, process attributes, release testing results, and stability results met predefined criteria, acceptance limits, and specifications, demonstrating that the drug product manufacturing facility is capable of consistently producing Hyrimoz of acceptable quality.

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 the medicinal ingredient 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 in compliance with International Council for Harmonisation (ICH) guidelines.

Hyrimoz is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

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 for Hyrimoz of 24 months is considered acceptable when stored at 5 ± 3 °C and protected from light, with a potential temperature excursion to 25 ± 2 °C at a 60 ± 5% relative humidity for up to 14 days.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

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 the drug substance, adalimumab, was not warranted. An OSE of the drug product manufacturing facility has been successfully conducted by Health Canada.

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

Adventitious Agents Safety Evaluation

No raw materials of human or animal origin are used in the preparation of the master cell bank or the working cell banks, or in the manufacturing process of the drug substance and drug product. Small amounts of animal-derived materials are used in the manufacturing process of the following raw materials: insulin, resin, filter cartridges, and cryovials. These materials were assessed in detail and were all found to be compliant with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3) and therefore, considered to be of no concern with regard to bovine spongiform encephalopathy or transmissible spongiform encephalopathy risk and viral safety.

The manufacturing process involves master and working cell banks which have been thoroughly characterized and tested for microbial contamination in accordance with ICH guidelines.

The manufacturing process of the drug substance and drug product incorporates adequate control measures to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate viruses are adequately validated.

 

7.2 Non-Clinical Basis for Decision

 

For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.

The non-clinical data submitted for Hyrimoz were in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The non-clinical studies comparing Hyrimoz (adalimumab 40 mg/0.8 mL) to the reference biologic product, Humira, sourced from the United States and the European Union, included pharmacodynamic, pharmacokinetic, and toxicology comparability studies.

In in vitro pharmacodynamic studies, Hyrimoz and Humira demonstrated comparable binding to tumour necrosis factor alpha (TNF-α), C1q, and Fc receptors, and demonstrated no off-target binding to other cytokines. Similarity was also demonstrated in other cell-based assays such as the antibody-dependent cell-mediated cytotoxicity assay, the complement-dependent cytotoxicity assay, and the apoptosis assay.

In in vivo pharmacodynamic studies conducted in two transgenic mouse models of arthritis, intraperitoneal injections of Hyrimoz or Humira produced reductions in arthritic and histopathological scores compared to vehicle-treated mice.

In studies conducted in rabbits, Hyrimoz pharmacokinetics and local and systemic tolerability were comparable to Humira following a single subcutaneous dose. The pivotal comparative repeated-dose toxicity study was conducted in cynomolgus monkeys at a subcutaneous dose of 100 mg/kg body weight given once weekly for 4 weeks. Monkeys given Hyrimoz did not develop any unique adverse effects and did not develop anti-drug antibodies.

Overall, the non-clinical studies were supportive of the similarity between Hyrimoz and the reference product, Humira. In view of the intended use of Hyrimoz, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Clinical basis for decision

 

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor’s submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in support of the indications being sought, and therefore clinical trials are not required to support each indication.

For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the reference biologic drug and availability of a relevant and sensitive pharmacodynamic endpoint determine the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Hyrimoz (adalimumab) is a biosimilar to Humira (adalimumab), which has been authorized in Canada since 2004. In Canada, adalimumab is authorized for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, and uveitis.

Comparative Pharmacokinetic Studies

Adalimumab, the medicinal ingredient in Hyrimoz, binds specifically to tumour necrosis factor alpha (TNF-α) and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). Elevated levels of TNF, a naturally occurring cytokine that is involved in normal inflammatory and immune responses, are found in the synovial fluid of rheumatoid arthritis, including polyarticular juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an important role in the pathologic inflammation and joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques, which contribute to the inflammatory response, to the proliferation and decreased maturation of keratinocytes, and to the associated vascular damages that are characteristic of the disease. Increased levels of TNF are also found in hidradenitis suppurativa lesions.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (endothelial leukocyte adhesion molecule-1 [ELAM-1], vascular cell adhesion molecule-1 [VCAM-1], and intercellular adhesion molecule-1 [ICAM-1] with a half maximal inhibitory concentration [IC50] of 1 to 2 x 10-10 M).

Two pharmacokinetic studies, Study GP17-104 and Study GP17-102, supported comparability in the pharmacokinetics between Hyrimoz and Humira sourced from the European Union (Humira-EU), and between the auto-injector and prefilled syringe Hyrimoz presentations, respectively.

Study GP17-104 was a randomized, double-blind, single-dose, three-arm parallel study evaluating the pharmacokinetics of Hyrimoz, Humira-EU, and Humira sourced from the United States (Humira-US) in 318 healthy adult male participants. The primary objectives of this study were to demonstrate pharmacokinetic comparability between Hyrimoz and Humira-EU and between Humira-EU and Humira-US. Each participant received a single 40 mg subcutaneous dose of Hyrimoz, Humira-EU, or Humira-US. As this was the pivotal pharmacokinetic comparability study in the Hyrimoz development program, the following results focus on the comparison between Hyrimoz and Humira-EU.

Serum samples were collected up to Day 72 and a non-compartmental analysis method was used to estimate pharmacokinetic parameters. The study demonstrated pharmacokinetic comparability between Hyrimoz and Humira-EU; the point estimate for the Hyrimoz and Humira-EU geometric least square mean ratio for the maximum serum concentration (Cmax) and the 90% confidence intervals (CI) for the area under the serum concentration versus time curve (AUC) to the time of the last quantifiable concentration (AUCT) were within the comparability margins of 80.0% to 125.0%.

Study GP17-102 was a randomized, open-label, single-dose, parallel study conducted in 108 healthy adult male participants to support the authorization of the auto-injector presentation of Hyrimoz. In this study, a 40 mg subcutaneous dose of Hyrimoz delivered via auto-injector or prefilled syringe was shown to be bioequivalent; the point estimate for the auto-injector and prefilled syringe geometric least square mean ratio for Cmax and the 90% CI for AUCT were within the comparability margins of 80.0% to 125.0%.

Overall, these two comparative pharmacokinetic studies conducted in healthy male participants established comparable pharmacokinetics between Hyrimoz and Humira-EU, and between the auto-injector and prefilled syringe Hyrimoz presentations.

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

Comparative Clinical Efficacy and Safety

The comparative clinical efficacy, safety, and immunogenicity of Hyrimoz and its reference biologic drug, Humira, were evaluated in Study GP17-301, a pivotal Phase III, randomized, double-blind, multicenter study. Male and female adult patients (number of patients [n] = 465) were randomized in a 1:1 ratio to receive either Hyrimoz (n = 231) or Humira (Humira-EU [n = 44] or Humira-US [n = 190]). Eligible patients were ≥18 years of age (mean age: 46.3 years) with active, but clinically stable chronic plaque psoriasis involving a body surface area of ≥10%, a Psoriasis Area and Severity Index (PASI) score of ≥12 (indicating moderate to severe psoriasis), and an investigator global assessment of at least moderate severity (score ≥3), diagnosed at least 6 months before randomization. Hyrimoz and Humira were administered as subcutaneous injections with a loading dose of 80 mg on Day 1 and a dose of 40 mg every other week starting with Week 1 and up to Week 49. Stratification was based on body weight (<90 kg and ≥90 kg), prior systemic psoriasis therapy, and region (EU and US).

The primary objective of Study GP17-301 was to rule out any clinically meaningful differences between Hyrimoz and the reference biologic product, Humira. The primary efficacy endpoint was the difference in the PASI 75 (defined as a 75% reduction in PASI score) at Week 16. Therapeutic comparability was confirmed if the 95% CI (Humira-EU) and 90% CI (Humira-US) for the difference in the PASI 75 rates were contained within the predefined equivalence margin of -18% to 18%. The key secondary objective was the relative change from baseline in the continuous PASI score up to Week 16 in patients treated with Hyrimoz or Humira.

Results from the analyses of the primary efficacy endpoint demonstrated that the difference in the PASI 75 response rates at Week 16 fell within the predefined equivalence margin for both Humira-EU and Humira-US. Using the full analysis set, which consisted of all randomized patients to whom a study treatment was assigned, and based on the intent-to-treat principle, a difference of 2.2% (95% CI: -6.79%, 11.10%) and 5.1% (90% CI: -2.85%, 13.10%), respectively, against Humira-EU and Humira-US was demonstrated. The study also met its key secondary objective of overall mean percentage change from baseline in PASI score up to Week 16, supporting the conclusion of therapeutic comparability.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity, meaning the development of anti-drug antibodies (ADAs) which have the potential to neutralize the biological activity of the drug. The comparison of immunogenicity was determined by measuring the rate of ADA formation against Hyrimoz and Humira. The numbers and proportions of patients with positive ADA responses were comparable between Hyrimoz and Humira up to Week 17 (36.8% and 34.1%, respectively) and up to Week 51 (38.8% and 45.3%, respectively). Neutralizing antibodies were also comparable between Hyrimoz and Humira up to Week 17 (80.2% and 80.0%, respectively) and up to Week 51 (88.7% and 84.7%, respectively).

The safety data support the comparability of safety. There was one death due to suicide reported in the Hyrimoz group; this event was not considered by the investigator to be related to study treatment. The proportion of patients reported with adverse events (AEs) was comparable between Hyrimoz (50.2%) and Humira (52.6%), with no major differences. Infections and infestations, gastrointestinal disorders, general disorders and injection site conditions, musculoskeletal, and connective tissue disorders were the most commonly affected primary system organ classes. The proportion of patients with AEs considered related to the study drug was similar between Hyrimoz and Humira. Further, the AE profile of ADA-positive patients was found to be similar to that of ADA-negative patients. The impact of the development of an ADA response on the clinical benefit-risk of Hyrimoz was comparable to that of the reference biologic drug, Humira.

Hyrimoz demonstrated a comparable safety profile to the reference product, Humira. Therefore, the Adverse Reactions section of the biosimilar product monograph is based on the clinical experience with the reference biologic drug. As with Humira, a Serious Warnings and Precautions box describing reports of hepatosplenic T-cell lymphoma, infections, and pediatric malignancies in patients treated with TNF-blockers has been included in the Hyrimoz Product Monograph.

A Risk Management Plan (RMP) for Hyrimoz was submitted by Sandoz Canada Incorporated 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.

Overall, the efficacy and safety profile of Hyrimoz is considered to be comparable to that which has been established for the reference biologic drug, Humira. Appropriate warnings and precautions are in place in the approved Hyrimoz Product Monograph to address the identified safety concerns, as they are in the Humira Product Monograph.

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

Indications

Hyrimoz is considered to be biosimilar to Humira, the reference biologic drug. Humira is currently authorized in Canada for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, and uveitis.

Within this drug submission, the sponsor requested the authorization of Hyrimoz for all of the indications that are currently authorized for Humira. However, the available Hyrimoz presentations (prefilled syringe and prefilled auto-injector) did not include a formulation capable of delivering less than the full 40 mg dose of adalimumab required for some polyarticular juvenile idiopathic arthritis dosing regimens and for the 20 mg maintenance dose for pediatric Crohn’s disease. Therefore, recommended indications were modified to align with the available presentations of Hyrimoz. Specifically, the pediatric Crohn’s disease indication was not recommended, and the polyarticular juvenile idiopathic arthritis dosing was limited to patients who require the full 40 mg dose.

Similarity between Hyrimoz and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor’s submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication. The indications have been authorized on the basis of demonstrated similarity between Hyrimoz and the reference biologic drug in structural, functional, non-clinical, pharmacokinetic/pharmacodynamic, and clinical studies, and the pathophysiological mechanisms of the diseases and conditions involved and the safety profile, dosage regimen, and clinical experience with the reference biologic drug.

Indication

To ensure safe and effective use of the product, Health Canada authorized Hyrimoz for the following indications:

Rheumatoid Arthritis

  • Reducing the signs and symptoms, inducing major clinical response and clinical remission, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Hyrimoz can be used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs.

When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Hyrimoz should be given in combination with methotrexate. Hyrimoz can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is contraindicated.

Polyarticular Juvenile Idiopathic Arthritis

  • In combination with methotrexate, reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients, 2 years of age and older who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs. Hyrimoz can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate (see Hyrimoz Product Monograph). Adalimumab has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis aged less than 2 years.

Psoriatic Arthritis

  • Reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis patients. Hyrimoz can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in patients with active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Adult Crohn’s Disease

  • Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants. Hyrimoz is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Ulcerative Colitis

  • Treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy including corticosteroids and/or azathioprine or 6-mercaptopurine or who are intolerant to such therapies. The efficacy of adalimumab in patients who have lost response to or were intolerant to tumour necrosis factor blockers has not been established.

Hidradenitis Suppurativa

  • Treatment of active moderate to severe hidradenitis suppurativa in adult patients, who have not responded to conventional therapy (including systemic antibiotics).

Plaque Psoriasis

  • Treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Hyrimoz should be used after phototherapy has been shown to be ineffective or inappropriate.

Adult Uveitis

  • Treatment of non-infectious uveitis (intermediate, posterior and panuveitis) in adult patients with inadequate response to corticosteroids or as corticosteroid sparing treatment in corticosteroid-dependent patients.

 

 

 

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