Summary Basis of Decision for Yuflyma

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 Yuflyma is located below.

Recent Activity for Yuflyma

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.

Summary Basis of Decision (SBD) for Yuflyma

Date SBD issued: 2022-04-14

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

Adalimumab

Drug Identification Number (DIN):

  • DIN 02523760 - 40 mg/0.4 mL adalimumab, solution, subcutaneous administration, single-dose prefilled syringe
  • DIN 02523779 - 40 mg/0.4 mL adalimumab, solution, subcutaneous administration, single-dose prefilled pen (auto-injector)

Celltrion Healthcare Co., Ltd.

New Drug Submission Control Number: 247265

On December 24, 2021, Health Canada issued a Notice of Compliance to Celltrion Healthcare Co., Ltd for Yuflyma, 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. Yuflyma 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. To be considered 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 and 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 Yuflyma and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within the submission, the sponsor requested the authorization of Yuflyma for all of the indications that are currently authorized for Humira. However, the available presentations of Yuflyma (prefilled syringe or prefilled pen [auto‑injector]) are designed to deliver a single 40 mg dose, and lower doses are required for some dosing regimens for pediatric patients. The indications approved for Yuflyma were therefore restricted to align with the available presentations.

The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar 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 Yuflyma 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, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, adult and adolescent hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

1 What was approved?

Yuflyma, 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. Yuflyma can be used alone or in combination with methotrexate or other disease‑modifying antirheumatic drugs (DMARDs).

When used as first‑line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Yuflyma should be given in combination with methotrexate.

Yuflyma 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 DMARDs. Yuflyma can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate. Adalimumab injection 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. Yuflyma can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in adult 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. Yuflyma 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.

Adult Ulcerative Colitis

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

Hidradenitis Suppurativa

  • Treatment of active moderate to severe hidradenitis suppurativa in adult and adolescent patients (12 to 17 years of age weighing ≥30 kg) 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, Yuflyma 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.

Pediatric Uveitis

  • Treatment of chronic non‑infectious anterior uveitis in pediatric patients from 2 years of age who have had an inadequate response to or are intolerant to conventional therapy, or in whom conventional therapy is inappropriate.

Treatment with Yuflyma (adalimumab injection) should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of the diseases indicated, and who are familiar with the efficacy and safety profile of adalimumab.

In pediatric patients (<18 years of age):

  • Adalimumab has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis less than 2 years of age, or in pediatric patients with a weight below 10 kg.
  • Clinical trials have not been conducted with adalimumab in adolescent patients with hidradenitis suppurativa. The dosage of Yuflyma in these patients has been determined based on pharmacokinetic/pharmacodynamic modelling and simulation.
  • Adalimumab has not been studied in pediatric patients with uveitis less than 2 years of age. Very limited data are available for pediatric patients with uveitis between 2 and <3 years of age.
  • The prefilled syringe and prefilled pen (auto‑injector) are not designed to deliver less than the full 40 mg dose contained in the packaging, and must not be used in pediatric patients who require a dose lower than 40 mg.

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

Yuflyma is a biosimilar to Humira. Both drugs contain the medicinal ingredient adalimumab, which is produced in Chinese hamster ovary cells using recombinant deoxyribonucleic acid (DNA) technology.

Similarity between Yuflyma and the reference biologic drug, Humira, has been established on the basis of comparative structural and functional studies, comparative non‑clinical studies, and clinical trials in patients with rheumatoid arthritis, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Yuflyma (40 mg/0.4 mL adalimumab) is presented as a sterile solution in a single dose prefilled syringe and a single dose prefilled pen. In addition to the medicinal ingredient, the solution contains acetic acid, glycine, polysorbate 80, sodium acetate trihydrate, and water for injection.

The use of Yuflyma is contraindicated in:

  • patients with known hypersensitivity to adalimumab or any components of Yuflyma,
  • patients with severe infections such as sepsis, tuberculosis and opportunistic infections, and
  • patients with moderate to severe heart failure (New York Heart Association class III/IV).

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

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

2 Why was Yuflyma approved?

Based on Health Canada's review, the benefit‑risk profile of Yuflyma is considered to be similar to that of the reference product, and is therefore considered favourable for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, adult and adolescent hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

Similarity between Yuflyma and the reference product, Humira, was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Humira is authorized and marketed in Canada for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis. The New Drug Submission (NDS) filed for Yuflyma requested authorization for all of the indications and clinical uses that are currently authorized for Humira. However, some dosing regimens for polyarticular juvenile idiopathic arthritis and the maintenance dose for pediatric Crohn’s disease require the administration of doses lower than 40 mg, which are unattainable with the available presentations of Yuflyma (a prefilled syringe or prefilled pen [auto‑injector]) that are not designed to deliver less than the full 40 mg dose contained in the packaging. The indications proposed for Yuflyma were therefore revised to align with the available presentations. Specifically, the indication for polyarticular juvenile idiopathic arthritis was limited to patients who require the full 40 mg dose, and the indication for pediatric Crohn’s disease was not approved. The other indications have been authorized on the basis of demonstrated similarity between Yuflyma and the reference biologic drug.

Adalimumab, the medicinal ingredient in Yuflyma, binds specifically to tumour necrosis factor (TNF) α, blocking its interaction with the cell surface TNF receptors p55 and p75. Tumour necrosis factor is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF play key roles in the pathogenesis of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and hidradenitis suppurativa.

The quality attributes of the biosimilar and the reference biologic drug were determined to be highly similar based on evidence from comparative structural and functional studies. A comparative efficacy, safety, and immunogenicity study in patients with rheumatoid arthritis provided the main clinical basis to support the biosimilarity (quality) assessment. The demonstration of similarity enables the biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug for the authorized indication.

Yuflyma has demonstrated a comparable safety profile with the reference product, Humira. Therefore, the Adverse Reactions section of the Yuflyma Product Monograph is based on the clinical experience with the reference biologic drug. As with Humira, the major identified safety concerns include hepatosplenic T‑cell lymphoma, infections, and pediatric malignancy. These risks have been listed in the Serious Warnings and Precautions box in the Yuflyma Product Monograph, as can be found in the Humira Product Monograph.

A Risk Management Plan (RMP) for Yuflyma was submitted by Celltrion Healthcare 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.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Yuflyma Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Yuflyma was accepted.

Overall, Yuflyma is considered to have a benefit‑risk profile comparable to that established for the reference biologic drug Humira. The approved indications for Yuflyma have been aligned with the available presentations. The benefits of Yuflyma are considered to outweigh the potential risks in the target patient populations. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Yuflyma Product Monograph to address the identified safety concerns and are based on the information presented in the labelling for the reference product Humira.

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 Yuflyma?

The review of the quality component of the New Drug Submission (NDS) for Yuflyma was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the European Medicines Agency (EMA) were used as an added reference, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Yuflyma NDS was made independently based on the Canadian review.

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

Submission Milestones: Yuflyma

Submission MilestoneDate
New Drug Submission filed2020-12-30
Screening
Screening Acceptance Letter issued2021-03-04
Review
Review of Risk Management Plan completed2021-11-29
Quality evaluation completed2021-12-09
Non-clinical evaluation completed2021-12-13
Labelling review completed2021-12-16
Clinical/medical evaluation completed2021-12-20
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate2021-12-24

4 What follow-up measures will the company take?

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

The onus is on the Yuflyma sponsor to monitor the post-market safety profile of this biosimilar 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 Yuflyma 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.

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

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.

At this time, no PAAT is available for Yuflyma. When available, the PAAT will be incorporated into this SBD.

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

As described above, the review of the quality component of the New Drug Submission for Yuflyma was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Yuflyma 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 with the reference biologic drug.

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

Comparative Structural and Functional Studies

The biosimilarity assessment for Yuflyma was based on a two‑way similarity study comparing Yuflyma and the reference product, Humira authorized in the European Union (EU‑Humira). The reference biologic drug is considered a suitable proxy for Canadian‑marketed Humira, as it meets the requirements for the use of non‑Canadian reference biologic drugs outlined in Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The results of the biosimilarity assessment indicate that Yuflyma is identical to EU‑Humira with respect to primary structure and higher order structure, and highly similar with respect to post‑translational modifications, purity, and potency. Furthermore, the degradation profiles of adalimumab in Yuflyma and EU‑Humira were comparable following exposure to accelerated and stressed conditions. Collectively, the results demonstrate that Yuflyma is highly similar to EU‑Humira and support the quality requirements for Yuflyma to be considered a biosimilar to the reference biologic drug.

Characterization of the Drug Substance

The drug substance, adalimumab, is a recombinant human immunoglobulin G1 (IgG1) type monoclonal antibody that consists of 1,330 amino acids and has a molecular weight of approximately 145 kDa. Adalimumab binds specifically to tumour necrosis factor (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 (TNFβ). Tumour necrosis factor is a naturally-occurring cytokine that is involved in normal inflammatory and immune responses.

Detailed characterization studies demonstrated that adalimumab, the medicinal ingredient in Yuflyma, consistently exhibits the desired characteristic structure and biological activity.

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

The drug substance, adalimumab, is produced using Chinese hamster ovary (CHO) cells that have been genetically engineered to express this protein. A culture of these cells is initiated from a single vial from a working cell bank and expanded through a fed‑batch process to reach commercial scale. When set criteria are reached, the cell culture medium is clarified, generating the cell‑free harvest material which contains the drug substance. The drug substance is purified through a series of chromatography and viral inactivation steps, concentrated, formulated, and filled. The adalimumab drug substance is stored at ‑75 °C ± 15 °C.

Manufacturing of the drug product, Yuflyma, begins with pooling of the formulated drug substance, followed by sterile filtration, aseptic filling into syringes, and visual inspection. The syringes are then further assembled into either a prefilled syringe with a safety guard or a prefilled pen (auto‑injector).

Process validation was conducted using batches of the drug substance and drug product manufactured at commercial scale at the proposed manufacturing sites. When executed within defined process parameter ranges, the processes consistently produce drug substance or drug product that meets predefined acceptance criteria. The results were well within the acceptance criteria, reflecting consistency in the manufacturing processes.

None of the non‑medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of adalimumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

An integrated control strategy has been implemented for the manufacturing of the drug substance and drug product. Raw and starting materials were tested to ensure their suitability for use. In‑process tests have been incorporated into the manufacturing process, and the drug substance and drug product are evaluated through release and stability specifications and continuous process verification.

Yuflyma is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. Through Health Canada's lot release testing and evaluation program, final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use, and the results support the consistency of the manufacturing process.

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 Yuflyma of 33 months at 5 °C ± 3 °C or 30 days at 25 °C ± 2 °C is considered acceptable. The product must be protected from light.

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

Although an on‑site evaluation (OSE) was recommended for the drug substance manufacturing facility, it was not feasible to conduct an OSE during the review cycle due to travel limitations resulting from the coronavirus disease 2019 (COVID‑19) pandemic. The risk of not performing an OSE was assessed in the review and mitigated appropriately.

Based on a risk assessment score determined by Health Canada, an OSE was not recommended or conducted for the drug product manufacturing facility.

Adventitious Agents Safety Evaluation

The master and working cell banks were extensively characterized and confirmed to be free of adventitious agents (mycoplasma, bacteria, fungi, and viruses).

Viral clearance capability is built into multiple steps of the drug substance purification process. Under worst‑case settings, the proposed strategy was found to be capable of consistently reducing viral contamination to levels below the acceptable limits.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) agents or other human pathogens.

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 information submitted for Yuflyma 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 data package consisted of one comparative 28‑day repeat‑dose toxicity study conducted in cynomolgus monkeys. The results of this study demonstrated general comparability between a 50 mg/mL formulation of Yuflyma with the reference biologic drug, Humira authorized in the European Union (EU‑Humira; 50 mg/mL), with respect to elicited effects and immunogenicity. No unique toxicities were observed with this formulation of Yuflyma.

The results of the comparative non‑clinical study as well as the potential risks to humans have been included in the Yuflyma Product Monograph. Considering the intended use of Yuflyma, there are no toxicological issues within this submission which preclude authorization of the product.

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

7.3 Clinical basis for decision

The purpose of the clinical program for a biosimilar is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the 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.

Adalimumab, the medicinal ingredient in Yuflyma, binds specifically to tumour necrosis factor (TNF) α, blocking its interaction with the cell surface TNF receptors p55 and p75. Tumour necrosis factor is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF play key roles in the pathogenesis of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and hidradenitis suppurativa.

Comparative Pharmacokinetic and Pharmacodynamic Studies

The pharmacokinetics of Yuflyma, Humira authorized in the European Union (EU‑Humira), and Humira authorized in the United States (US‑Humira) was evaluated in Study CT‑P17 1.1, which was conducted in healthy adult subjects. The designated Canadian reference product is EU‑Humira, and therefore the review focused on the comparison between Yuflyma and EU‑Humira. Each subject received a single 40 mg subcutaneous dose of one of the three versions of adalimumab: Yuflyma, EU‑Humira, or US‑Humira. Serum samples were collected at a suitable frequency up to Day 71, and pharmacokinetic parameters were estimated using a non‑compartmental analysis method. The point estimate for the geometric least squares mean ratio for the maximum serum concentration (Cmax) for Yuflyma and EU‑Humira was within the comparability margins of 80.0% and 125.0%, as was the 90% confidence interval (CI) for the area under the concentration‑time curve (AUC) to the time of the last quantifiable concentration (AUCT). Pharmacokinetic comparability was therefore demonstrated between Yuflyma and EU‑Humira.

Study CT‑P17 1.3 compared the administration of Yuflyma using the prefilled pen presentation versus the prefilled syringe in healthy adult subjects. A 40 mg subcutaneous dose of Yuflyma was delivered to subjects using either a prefilled pen or a prefilled syringe. The point estimate for the prefilled pen and prefilled syringe geometric least squares mean ratio for the Cmax was within the comparability margins of 80.0% to 125.0%. However, the upper bound of the 90% CI for the AUCT (96.0, 143.8) exceeded these margins, and pharmacokinetic comparability between the two presentations of Yuflyma was not established in this study. However, additional components (quality, clinical efficacy and safety, and post‑market data) were assessed along with the pharmacokinetic data, which collectively supported the authorization of the prefilled pen presentation.

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

Comparative Clinical Efficacy, Safety and Immunogenicity

The Phase III study CT‑P17 3.1 compared Yuflyma to its reference product, EU‑Humira (hereafter referred to as Humira), with respect to efficacy, safety, and immunogenicity. The study had a total duration of 58 weeks. The patients enrolled in this study were 18 to 75 years of age. Prior to the first administration of the study drug, patients had a diagnosis of active rheumatoid arthritis for at least 24 weeks and were receiving methotrexate for at least 4 weeks. Doses of either Yuflyma or Humira (40 mg each) were administered subcutaneously via pre‑filled syringe to patients with moderate to severe active rheumatoid arthritis every other week, in combination with methotrexate.

The primary efficacy endpoint was clinical response according to the American College of Rheumatology (ACR) 20% improvement (ACR20) criteria at Week 24. The primary analysis at Week 24 included 648 patients randomized to either the Yuflyma or Humira treatment group (324 patients per group). The proportion of patients who achieved a clinical response according to ACR20 criteria was 82.72% in each of the two treatment groups (268 out of 324 patients). Therapeutic equivalence between Yuflyma and Humira was demonstrated, as the 95% CI of the treatment difference between the two groups (‑5.94%, 5.94%) fell entirely within the predefined equivalence margin (‑15%, 15%). The mean change from baseline in the ACR component scores was also comparable between the Yuflyma and Humira treatment groups, which was supported by sensitivity analyses. No clinically meaningful differences were observed between Yuflyma and Humira with respect to efficacy.

Treatment‑emergent adverse events (TEAEs) were reported at similar proportions between the two treatment groups. In total, 989 TEAEs were reported in 367 (56.6%) of the 648 patients included in the primary analysis. Treatment‑emergent adverse events considered to be related to the study drug were reported in 197 patients (30.4%). Severe TEAEs were reported in 12 (3.7%) of the 324 patients in the Yuflyma group and 19 (5.9%) of the 324 patients in the Humira group. Seven patients (2.2%) in the Yuflyma group and 10 patients (3.1%) in the Humira group discontinued treatment due to TEAEs.

At Week 24, 93 patients (28.7%) in the Yuflyma group and 116 patients (35.8%) in the Humira group were positive for anti‑drug antibodies (ADAs). At the same time point, 83 patients (25.6%) with positive ADA results in the Yuflyma group and 103 patients (31.8%) with positive ADA results in the Humira group were also positive for neutralizing antibodies. The impact of the ADAs on the clinical efficacy and safety of Yuflyma was consistent with the information generated for the reference product, Humira.

As with Humira, the major identified safety concerns for Yuflyma include hepatosplenic T‑cell lymphoma, infections, and pediatric malignancy. These risks are highlighted in a Serious Warnings and Precautions box in the Yuflyma and Humira Product Monographs.

Overall, the clinical evidence indicates no clinically meaningful differences in efficacy and safety between Simlandi and Humira.

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

Indications

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

Within this drug submission, the sponsor requested the authorization of Yuflyma for all of the indications that are currently authorized for Humira. However, some dosing regimens for polyarticular juvenile idiopathic arthritis and the maintenance dose for pediatric Crohn’s disease require the administration of doses lower than 40 mg. The available presentations of Yuflyma (a prefilled syringe or prefilled pen [auto‑injector]) are not designed to deliver less than the full 40 mg dose contained in the packaging. The indications proposed for Yuflyma were therefore restricted to align with the available presentations. Specifically, the indication for polyarticular juvenile idiopathic arthritis was limited to patients who require the full 40 mg dose, and the indication for pediatric Crohn’s disease was not approved.

Similarity between Yuflyma 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 Yuflyma and the reference biologic drug, in structural and functional studies, mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, and clinical experience with the reference biologic drug.

To support the safe and effective use of the product, Health Canada approved Yuflyma 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. Yuflyma can be used alone or in combination with methotrexate or other disease‑modifying anti‑rheumatic drugs (DMARDs).

When used as first‑line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Yuflyma should be given in combination with methotrexate.

Yuflyma 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 DMARDs. Yuflyma can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate. Adalimumab injection 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. Yuflyma can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in adult 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. Yuflyma 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.

Adult Ulcerative Colitis

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

Hidradenitis Suppurativa

  • Treatment of active moderate to severe hidradenitis suppurativa in adult and adolescent patients (12 to 17 years of age weighing ≥30 kg) 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, Yuflyma 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.

Pediatric Uveitis

  • Treatment of chronic non‑infectious anterior uveitis in pediatric patients from 2 years of age who have had an inadequate response to or are intolerant to conventional therapy, or in whom conventional therapy is inappropriate.

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