Summary Basis of Decision for Steqeyma and Steqeyma I.V.

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.


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Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Steqeyma and Steqeyma I.V. is located below.

Recent Activity for Steqeyma and Steqeyma I.V.

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

The following table describes post-authorization activity for Steqeyma and Steqeyma I.V., products which contain the medicinal ingredient ustekinumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

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

Updated: 2025-02-10

Drug Identification Number (DIN):

  • DIN 02550245 (Steqeyma) - 45 mg/0.5mL, ustekinumab, solution, subcutaneous administration, single-use pre-filled syringe

  • DIN 02550253 (Steqeyma) - 90 mg/mL, ustekinumab, solution, subcutaneous administration, single-use pre-filled syringe

  • DIN 02550261 (Steqeyma I.V.) - 5 mg/mL, ustekinumab, solution, intravenous administration, single-use vial

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

Drug product (DINs 02550245, 02550253, 02550261) market notification

Not applicable

Date of first sale 2024-08-29

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

NDS # 274939

2023-06-30

Issued NOC 2024-07-30

NOC issued for the New Drug Submission.
Summary Basis of Decision (SBD) for Steqeyma and Steqeyma I.V.

Date SBD Issued: 2025-02-10

The following information relates to the New Drug Submission for Steqeyma and Steqeyma I.V.

Ustekinumab

Drug Identification Number (DIN):

  • DIN 02550245 (Steqeyma) - 45 mg/0.5mL, ustekinumab, solution, subcutaneous administration, single-use pre-filled syringe

  • DIN 02550253 (Steqeyma) - 90 mg/mL, ustekinumab, solution, subcutaneous administration, single-use pre-filled syringe

  • DIN 02550261 (Steqeyma I.V.) - 5 mg/mL, ustekinumab, solution, intravenous administration, single-use vial

Celltrion, Inc.

New Drug Submission Control Number: 274939

Submission Type: New Drug Submission

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): L04 Immunosuppressants

Date Filed: 2023-06-30

Authorization Date: 2024-07-30

On July 30, 2024, Health Canada issued a Notice of Compliance (NOC) to Celltrion, Inc. for Steqeyma and Steqeyma I.V., biosimilars of Stelara and Stelara I.V. (the reference biologic drugs). 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. Steqeyma and Steqeyma I.V. contain the medicinal ingredient ustekinumab, which has been demonstrated to be highly similar to ustekinumab contained in the reference biologic drugs Stelara and Stelara I.V.

Authorization of a drug as 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. The weight of evidence of similarity to the reference biologic drug is provided by the structural and functional studies, whereas 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, 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.

Similarity between the biosimilars Steqeyma and Steqeyma I.V. and the reference biologic drugs Stelara and Stelara I.V. was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. The sponsor requested the authorization of Steqeyma and Steqeyma I.V. for the same indications and clinical uses that are currently authorized for Stelara and Stelara I.V., with the exception of ulcerative colitis.

The market authorization of Steqeyma and Steqeyma I.V. was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilars and the reference biologic drugs. 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 Steqeyma and Steqeyma I.V. is considered to be similar to the benefit-risk profile of the reference biologic drugs, and is therefore considered favourable for the following indications:

Plaque Psoriasis

  • Steqeyma (ustekinumab) is indicated for the treatment of chronic moderate to severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy.

Psoriatic Arthritis

  • Steqeyma (ustekinumab) is indicated for the treatment of adult patients with active psoriatic arthritis. Steqeyma can be used alone or in combination with methotrexate (MTX).

Crohn’s Disease

  • Steqeyma/Steqeyma I.V. (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease, who have had an inadequate response, loss of response to, or were intolerant to either immunomodulators or one or more tumour necrosis factor-alpha (TNFα) antagonists, or have had an inadequate response, intolerance or demonstrated dependence on corticosteroids.

1 What was approved?

Steqeyma and Steqeyma I.V., selective immunomodulating agents, were authorized for the following indications:

Plaque Psoriasis

  • Steqeyma (ustekinumab) is indicated for the treatment of chronic moderate to severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy.

Psoriatic Arthritis

  • Steqeyma (ustekinumab) is indicated for the treatment of adult patients with active psoriatic arthritis. Steqeyma can be used alone or in combination with methotrexate (MTX).

Crohn’s Disease

  • Steqeyma/Steqeyma I.V. (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease, who have had an inadequate response, loss of response to, or were intolerant to either immunomodulators or one or more tumour necrosis factor-alpha (TNFα) antagonists, or have had an inadequate response, intolerance or demonstrated dependence on corticosteroids.

Health Canada has not authorized an indication for pediatric (less than 18 years of age) use.

No major age-related differences in clearance or volume of distribution were observed in clinical studies. Although no overall differences in safety and efficacy were observed between older and younger patients in clinical studies for the approved indications, the number of geriatric patients (65 years of age and older) studied is not sufficient to determine whether they respond to Steqeyma and Steqeyma I.V. differently than younger patients.

Steqeyma and Steqeyma I.V. are biosimilars of Stelara and Stelara I.V. The drugs contain the medicinal ingredient ustekinumab. Ustekinumab is a fully human immunoglobulin G1 kappa (IgG1қ) monoclonal antibody, a first-in-class agent that binds with specificity to the shared p40 protein subunit of human cytokines interleukin (IL)-12 and IL-23. By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in psoriasis, psoriatic arthritis, and Crohn’s disease through interruption of the T-helper (Th)1 and Th17 cytokine pathways, which have been implicated as contributors in the pathology of these diseases.

Similarity between the biosimilars Steqeyma and Steqeyma I.V. and the reference biologic drugs Stelara and Stelara I.V. has been established on the basis of comparative structural, functional, non-clinical, and clinical studies, in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Steqeyma is intended for subcutaneous administration. It is presented as a solution supplied in single-use prefilled syringes containing 45 mg of ustekinumab in 0.5 mL of solution or 90 mg of ustekinumab in 1 mL of solution. In addition to the medicinal ingredient, the solution contains L-histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, sucrose, and water for injection.

Steqeyma I.V. is intended for intravenous administration. It is presented as a solution supplied in a single-use vial containing 130 mg of ustekinumab in 26 mL of solution. In addition to the medicinal ingredient, the solution contains ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate, L-histidine, L-histidine monohydrochloride, monohydrate, L-methionine, polysorbate 80, sucrose, and water for injection.

The use of Steqeyma and Steqeyma I.V. is contraindicated in:

  • patients who are hypersensitive to ustekinumab or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

  • patients with severe infections such as sepsis, tuberculosis, and opportunistic infections.

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 Product Monograph for Steqeyma and Steqeyma I.V. 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 were Steqeyma and Steqeyma I.V. approved?

Steqeyma and Steqeyma I.V. (hereafter referred to as Steqeyma) are considered biosimilars of Stelara and Stelara I.V. (hereafter referred to as Stelara), the reference biologic drugs. Similarity between Steqeyma and Stelara was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Based on the comparative structural and functional studies submitted, Steqeyma and Stelara were judged highly similar in terms of quality attributes. Data from two Phase I pharmacokinetic studies (Study CT-P43 1.1 and Study CT-P43 1.2) provided evidence of the pharmacokinetic similarity between Steqeyma and Stelara in healthy adults. Further evidence of the clinical comparability of Steqeyma and Stelara included efficacy, safety, and immunogenicity results of a Phase III, randomized, double-blind, comparative study (Study CT-P43 3.1) in adult patients with moderate to severe chronic plaque psoriasis. According to predefined equivalence margins, the study demonstrated similarity between Steqeyma and Stelara in the primary efficacy endpoint of percent improvement in the Psoriasis Area and Severity Index from baseline to Week 12. No clinically meaningful differences were identified in the results of the comparative safety or immunogenicity assessment.

In Canada, Stelara is authorized for the treatment of plaque psoriasis in adults, plaque psoriasis in pediatric patients 6 to 17 years of age, psoriatic arthritis in adults, Crohn’s disease in adults, and ulcerative colitis in adults.

The New Drug Submission filed for Steqeyma requested authorization for the same indications and clinical uses that are currently authorized for Stelara, with the exception of ulcerative colitis. Based on Health Canada's review, Steqeyma is considered favourable for the treatment of plaque psoriasis in adults, psoriatic arthritis in adults, and Crohn’s disease in adults. The indications have been authorized on the basis of demonstrated similarity between Steqeyma and the reference biologic drug.

A Risk Management Plan (RMP) for Steqeyma was submitted by Celltrion, Inc. to Health Canada. 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. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Product Monograph for Steqeyma met 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 Steqeyma was accepted.

Overall, the therapeutic benefits of Steqeyma for the authorized indications are expected to be similar to the known benefits of the reference biologic drug Stelara and are considered to outweigh the potential risks. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Product Monograph for Steqeyma 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 Steqeyma and Steqeyma I.V.?

The review of the quality component of the New Drug Submission (NDS) for Steqeyma and Steqeyma I.V. (hereafter referred to as Steqeyma) was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the European Medicines Agency, the United States Food and Drug Administration, and Australia's Therapeutic Goods Administration were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Steqeyma NDS was made independently based on the Canadian review.

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

Submission Milestones: Steqeyma, Steqeyma I.V.

Submission Milestone

Date

New Drug Submission filed

2023-06-30

Screening

Screening Acceptance Letter issued

2023-08-21

Review

Two requests were granted to pause review clock (extensions to respond to clarification requests)

44 days in total

Review of Risk Management Plan completed

2024-04-29

Quality evaluation completed

2024-05-30

Non-clinical evaluation completed

2024-07-26

Clinical/medical evaluation completed

2024-07-26

Labelling review completed

2024-07-26

Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate

2024-07-30
4 What follow-up measures will the company take?

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

The onus is on the sponsor to monitor the post-market safety information of Steqeyma and Steqeyma I.V. (hereafter referred to as Steqeyma) as well as the Product Monograph of the reference biologic drugs Stelara and Stelara I.V. for safety signals that could impact the safety profile of Steqeyma, and make safety updates to the Product Monograph for Steqeyma as appropriate. New safety issues that are first identified with Steqeyma, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both Steqeyma and the reference biologic drug. For more information, refer to the Biosimilar Biologic Drugs in Canada: Fact Sheet.

5 What post-authorization activity has taken place for Steqeyma and Steqeyma I.V.?

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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 Steqeyma and Steqeyma I.V. 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?

Refer to the What steps led to the approval of Steqeyma and Steqeyma I.V.? section for more information about the review process for this submission.

7.1 Quality Basis for Decision

Steqeyma and Steqeyma I.V. (hereafter referred to as Steqeyma) were developed as biosimilars of the reference biologic drugs, Stelara and Stelara I.V. (hereafter referred to as Stelara). The weight of evidence of similarity between a biosimilar and the reference biologic drug 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.

Comparative Structural and Functional Studies

The biosimilarity evaluation was conducted as a head-to-head analytical assessment using Steqeyma and Stelara authorized in the European Union (EU-Stelara). Health Canada considers EU-Stelara a suitable proxy for Stelara authorized in Canada as it meets all of the requirements for a non-Canadian reference biologic drug set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The results of the biosimilarity assessment demonstrated that Steqeyma is highly similar to Stelara with respect to primary and higher order structure, size heterogeneity, and mechanism of action. No new impurities were observed in Steqeyma that were not present in Stelara. Differences were mainly observed in the levels of C-terminal lysine and sialic acid, such that Stelara has higher levels of the sialic acid N-glycolylneuraminic acid (NGNA). Additional characterization studies were performed to demonstrate that the observed differences would not have an impact on the pharmacokinetics or efficacy of the medicinal ingredient ustekinumab. The relative binding affinity for the crystallizable fragment gamma (Fcγ) receptor was slightly lower for Steqeyma; however, this is unlikely to be clinically meaningful given the lack of effector function of ustekinumab. Comparative accelerated, stressed, and forced degradation studies showed that the stability indicating attributes and the stability profiles are similar between Steqeyma and Stelara.

Overall, the results of the biosimilarity assessment support the conclusion that Steqeyma is highly similar to Stelara.

Characterization of the Drug Substance

Ustekinumab is a fully human immunoglobulin G1 kappa (IgG1қ) monoclonal antibody that binds with high affinity to p40, a subunit of both interleukin (IL)-12 and IL-23. Binding of free IL-12 and IL-23 neutralizes IL-12- and IL-23-mediated cellular responses that are associated with immune-mediated human diseases.

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

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established and acceptable limits.

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

Ustekinumab is manufactured in Chinese hamster ovary cells. The manufacturing process begins with the thawing of a working cell bank vial followed by cell expansion and inoculation of a bioreactor. The harvested cell culture fluid is clarified via depth filtration and purified through a series of chromatography, viral inactivation and removal, and ultrafiltration/diafiltration steps. The drug substance is formulated and filtered prior to being filled into bottles and stored.

The drug product for subcutaneous administration is supplied in single-use pre-filled syringes. Manufacturing of this drug product begins with the thawing of the formulated drug substance. Equilibrated drug substance is then filtered, pooled, mixed, sterile filtered, aseptically filled into 1-mL glass syringes, stoppered, visually inspected, labelled, assembled with the safety device, and stored. The only difference between the 45 mg/0.5 mL and 90 mg/1 mL strengths is the fill volume of the pre-filled syringes.

The drug product for intravenous administration is supplied in a single-use vial. Manufacturing of this drug product includes formulation buffer preparation and formulation steps. The formulated bulk is then filtered into a filtrate tank, sterile filtered, aseptically filled into vials, capped, visually inspected, and stored.

Controls of critical steps of the drug substance and drug product manufacturing processes were established during manufacturing development and were based on a risk assessment and process characterization. Process validation conducted at commercial scale demonstrated that the manufacturing processes are capable of consistently manufacturing drug substance and drug product that meet predefined specifications and quality attributes.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by 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 in-process and release specification acceptance criteria were suitably justified and ensure safety, identity, strength, potency, and purity. The in-house analytical methods were validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and compendial methods complied with pharmacopeia standards. All drug substance batches met predefined specifications.

The drug product release and stability specifications were established based on ICH guidelines, product and process knowledge, attribute criticality, and non-clinical and clinical experience. All drug product batches met release and stability acceptance criteria.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

Steqeyma 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.

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 drug product stability studies support the proposed shelf life of 36 months when stored at 2 °C to 8 °C with protection from light, including a single period up to 31 days at room temperature (up to 30 °C), for the pre-filled syringe and vial presentations.

The in-use stability and microbial challenge studies support an in-use shelf life of the diluted infusion solution of up to 48 hours when stored at 2 °C to 8 °C, or up to 8 hours when stored at room temperature (up to 25°C).

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.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

Based on a risk assessment score determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure absence of adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

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

7.2 Non-Clinical Basis for Decision

For biosimilars, the degree of similarity to the reference product 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 package consisted of one comparative four-week repeat-dose toxicity study comparing the toxicology and toxicokinetics of Steqeyma to those of Stelara authorized in the European Union (EU-Stelara) in healthy cynomolgus monkeys. The results of this study demonstrated no adverse effects associated with either Steqeyma or EU-Stelara. Additionally, there were no clear differences between Steqeyma and EU-Stelara in the toxicity endpoints assessed. Systemic exposure was also generally comparable between Steqeyma and EU-Stelara.

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

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. Within this submission, Steqeyma and Steqeyma I.V. (hereafter referred to as Steqeyma) were developed as biosimilars of the reference biologic drugs, Stelara and Stelara I.V. (hereafter referred to as Stelara).

Comparative Pharmacokinetics and Pharmacodynamics

The pharmacokinetic similarity of Steqeyma, Stelara authorized in the European Union (EU-Stelara), and Stelara authorized in the United States (US-Stelara) was demonstrated in Study CT-P43 1.1, a Phase I, randomized, double-blind, single-dose, three-arm, parallel-group study in healthy adult male subjects.

Study CT-P43 1.1 consisted of two parts. Part 1 (pilot study) was designed to collect preliminary safety data in 30 subjects who were randomized in a 1:1 ratio to receive a single dose (45 mg) of Steqeyma or EU-Stelara. Part 2 (comparative pharmacokinetic study) enrolled 241 subjects who were randomized in a 1:1:1 ratio to receive a single dose (45 mg) of Steqeyma, EU-Stelara, or US-Stelara. The primary objective of the study was to demonstrate the pharmacokinetic similarity of Steqeyma compared with EU-Stelara or US-Stelara. Serum pharmacokinetic sampling times up to Day 127 post dose were deemed suitable for assessment of the area under the concentration versus time curve to the time of the last quantifiable concentration (AUClast) as well as the maximum concentration (Cmax) of both Steqeyma and EU-Stelara.

A non-compartmental analysis was used to estimate the pharmacokinetic parameters, with a statistical assessment of the pharmacokinetic parameters performed using an analysis of variance (ANOVA) without covariates. The geometric least squares (LS) mean ratio between Steqeyma and EU-Stelara for Cmax was 118.56, which fell within the prespecified comparative pharmacokinetic biosimilarity standard of 80.0% to 125.0%, as per Health Canada’s Guidance Document: Comparative Bioavailability Standards: Formulations Used for Systemic Effects (2018). However, the 90% confidence interval (CI) of the geometric LS mean ratio between Steqeyma and EU-Stelara for AUClast fell outside of this margin, ranging from 114.97 to 137.56. Post-hoc root cause analyses suggested that three main factors (protein content, immunogenicity, and increased and variable clearance related with increased body weight) played a role in this finding, and that repeat analyses controlling for these aspects brought the upper bound of the 90% CI closer to the upper limit of 125%, compared to the original unadjusted results.

The Sponsor subsequently planned Study CT-P43 1.2, a Phase I, randomized, double-blind, single-dose, three-arm, parallel-group study in healthy Japanese male subjects. Study CT-P43 1.2 enrolled a larger and more homogeneous population in a sensitive setting such that potential variability was minimized. Batches of Steqeyma with similar protein content to commercially available EU-Stelara batches used in Study CT-P43 1.2 were selected. A total of 331 subjects were enrolled in Study CT-P43 1.2 and randomized in a 1:1:1 ratio to receive a single dose (45 mg) of Steqeyma, EU-Stelara, or US-Stelara. The primary objective of the study was to demonstrate the pharmacokinetic similarity of Steqeyma compared with EU-Stelara or US-Stelara. Serum pharmacokinetic sampling times up to Day 113 post dose were deemed suitable for the assessment of AUClast and Cmax for both Steqeyma and EU-Stelara.

The geometric LS mean ratio between Steqeyma and EU-Stelara for Cmax was 103.09. The 90% CI of the geometric LS mean ratio between Steqeyma and EU-Stelara for AUClast was 99.83 to 116.00, which was within Health Canada’s prespecified comparative pharmacokinetic biosimilarity standard of 80.0% to 125.0%.

In addition, pooled post-hoc analysis of Study CT-P43 1.1 Part 2 and Study CT-P43 1.2 suggested that the 90% CIs for the ratio of geometric LS means of AUClast and Cmax of Steqeyma versus EU-Stelara were all contained within the equivalence margin of 80% to 125%. The 90% CI of the geometric LS mean ratio between Steqeyma and EU-Stelara for AUClast was 108.78 to 122.06. The geometric LS mean ratio between Steqeyma and EU-Stelara for Cmax was 109.68.

Comparative Clinical Efficacy and Safety

The comparative clinical efficacy, safety, and immunogenicity of Steqeyma and its reference biologic drug, EU-Stelara, were assessed in Study CT-P43 3.1, a Phase III, randomized, active-controlled, blinded, multicentre study. The primary objective of the study was to demonstrate comparability between Steqeyma and EU-Stelara as determined by the mean percent improvement in the Psoriasis Area and Severity Index (PASI). The study also sought to evaluate the overall safety and immunogenicity of Steqeyma up to Week 52.

Enrolled male and female patients (aged 18 to 80 years) had moderate to severe chronic plaque psoriasis for at least 24 weeks before the first administration of study drug. The active treatment period for comparison (Treatment Period I) was 16 weeks. The primary efficacy assessment and comparison was performed at Week 12.

For the primary efficacy assessment, patients received either Steqeyma or EU-Stelara (45 mg) administered subcutaneously at Weeks 0, 4, 16, 28, and 40 based on the patient’s baseline body weight. Patients weighing more than 100 kg were provided with a 90 mg dose of Steqeyma or EU-Stelara; however, they were not evaluated in the primary efficacy analysis. The primary endpoint for the evaluation of efficacy was the mean percent improvement from baseline in PASI score at Week 12. The predefined equivalence margin was -15% to 15% using a 95% CI of the difference between Steqeyma and EU-Stelara at Week 12.

For the primary analysis, 574 patients were screened and 509 patients were randomized in a 1:1 ratio to receive either Steqeyma (number of patients [n] = 256) or EU-Stelara (n = 253). The majority of patients were male (65.6%) and White (90.6%), with a mean age of 42.4 years (Standard Deviation [SD]: 12.81), and an average weight of 85.36 kg (average body mass index of 28.41 kg/m2). The average age since plaque-psoriasis diagnosis was 16.69 years (SD: 11.899). Patients were recruited in 34 centers from Poland (74.1%), Ukraine (14.3%), Korea (9.4%), and Estonia (2.2%). Baseline characteristics were comparable between the Steqeyma and EU-Stelara groups.

At Week 12, the primary efficacy analysis was conducted on patients who had received a 45 mg dose of study drug and who had never received a 90 mg dose of study drug. The results demonstrated an estimate of treatment difference of 0.94 (95% CI:-2.29 to 4.16) between Steqeyma and EU-Stelara as assessed by the PASI score from baseline. The difference was entirely contained within the predefined equivalence margin of -15% to 15%. The study met its primary objective. Secondary and sensitivity analyses supported the primary analysis and the Sponsor’s claim of lack of clinically meaningful difference in terms of efficacy as evaluated by the difference in PASI response at Week 12 between Steqeyma and EU-Stelara.

At the end of Treatment Period I (primary analysis), 255 (99.6%) patients in the Steqeyma group and 249 (98.4%) patients in the EU-Stelara group received two doses of investigational product. There were a total of 268 treatment-emergent adverse events (TEAEs) that were reported in 170 (33.4%) patients: 95 (37.1%) patients in the Steqeyma group and 75 (29.6%) patients in the EU-Stelara group. Of these, TEAEs considered to be related to the study drug were reported in 33 (6.5%) patients: 18 (7%) patients in the Steqeyma group and 15 (5.9%) patients in the EU-Stelara group. The most frequently reported TEAE by preferred term in both groups was coronavirus disease 2019 (COVID-19), reported in 11 (4.3%) patients in the Steqeyma group and 12 (4.7%) patients in the EU-Stelara group. Infections and infestations were the most frequently reported System Organ Class, occurring in 66 (13.0%) patients: 34 (13.3%) patients in the Steqeyma group and 32 (12.6%) patients in the EU-Stelara group.

Treatment Period II for further evaluation began at Week 16 and ran until Week 40. During Treatment Period II, patients receiving EU-Stelara were re-randomized in a 1:1 ratio to receive either Steqeyma or EU-Stelara. Patients receiving Steqeyma continued treatment with Steqeyma.

There were 594 TEAEs reported in 277 (54.4%) patients: 135 (53.4%), 64 (51.2%), and 75 (60.5%) patients in the Steqeyma, EU-Stelara, and EU-Stelara-to-Steqeyma groups, respectively. Treatment-emergent adverse events considered to be related to the study drug by the investigator were reported in 60 (11.8%) patients: 27 (10.7%), 13 (10.4%), and 20 (16.1%) patients in the Steqeyma, EU-Stelara, and EU-Stelara-to-Steqeyma groups, respectively. Treatment-emergent adverse events leading to study drug discontinuation were reported in 7 (1.4%) patients: 5 (2.0%), 1 (0.8%), and 1 (0.8%) patients in the Steqeyma, EU-Stelara, and EU-Stelara-to-Steqeyma groups, respectively. Infections and infestations was the most frequently reported System Organ Class in the Steqeyma (67 [26.5%]), EU-Stelara (33 [26.4%]), and EU-Stelara-to-Steqeyma (41 [33.1%]) groups. There was one report of malignancy [breast cancer] in the Steqeyma group. There were no reports of malignancy in the EU-Stelara or EU-Stelara-to-Steqeyma groups. There was a single report of myocardial infarction leading to death in one patient in the Steqeyma group that was considered unrelated to study drug.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Across the three clinical studies, the incidence of ADAs was lower in participants dosed with Steqeyma compared with EU-Stelara. In the comparative pharmacology Study CT-P43 1.1, 13 (16.3%) subjects in the Steqeyma group were ADA positive at any timepoint throughout the study, compared with 24 (29.3%) subjects in the EU-Stelara group. In Study CT-P43 1.2, 18 (16.2%) subjects in the Steqeyma group were ADA positive at any timepoint throughout the study, compared with 48 (44.4%) subjects in the EU-Stelara group. In the comparative clinical efficacy and safety Study CT-P43 3.1, 7 (1.4%) patients were ADA positive at baseline (none of which were neutralizing antibodies): 4 (1.6%) patients in the Steqeyma group and 3 (1.2%) patients in the EU-Stelara group. At the Week 12 assessment, there were 78 (15.3%) patients who were ADA positive, including 21 (8.2%) patients in the Steqeyma group and 57 (22.5%) patients in the EU-Stelara group. Of these, 8 (3.1%) patients in the Steqeyma group and 24 (9.5%) patients in the EU-Stelara group were also positive for neutralizing antibodies. Based on subgroup analyses of efficacy performed at Week 12, ADA positivity was associated with higher clearance and lower serum drug concentrations for the 45 mg and 90 mg doses at various timepoints. In terms of safety, ADA-positive subgroups had a higher percentage of patients with at least one TEAE compared with all ADA-negative subgroups. Anti-drug antibody positivity was also associated with TEAEs related to study drug compared to ADA-negative subgroups. The ADA-positive subgroups were also associated with a lower efficacy response; however, this was consistent amongst treatment groups and is consistent with prior experience with the Canadian reference product.

Overall, the clinical data submitted indicate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. Appropriate warnings and precautions are in place in the approved Product Monograph for Steqeyma to address the identified safety concerns, as is found in the Product Monograph for Stelara. The Adverse Reactions section of the Product Monograph for Steqeyma is based on the clinical experience with Stelara.

Indications

Steqeyma is considered to be biosimilar to Stelara, the reference biologic drug. Stelara is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Stelara is authorized are plaque psoriasis in adults, plaque psoriasis in pediatric patients 6 to 17 years of age, psoriatic arthritis in adults, Crohn’s disease in adults, and ulcerative colitis in adults.

Within this drug submission, the sponsor requested the authorization of Steqeyma for all of the indications that are currently authorized for Stelara, with the exception of ulcerative colitis.

As per the Product Monograph for Stelara, pediatric patients with plaque psoriasis and weighing less than 60 kg are dosed subcutaneously from a vial presentation. Since the vial presentation for this use is not available for Steqeyma, the pediatric indication (less than 18 years of age) was not authorized by Health Canada.

Similarity between Steqeyma and Stelara was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. 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 Steqeyma and the reference biologic drug, in comparative structural, functional, non-clinical, and clinical studies.

Indication

To ensure safe and effective use of the product, Health Canada approved the following indications:

Plaque Psoriasis

  • Steqeyma (ustekinumab) is indicated for the treatment of chronic moderate to severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy.

Psoriatic Arthritis

  • Steqeyma (ustekinumab) is indicated for the treatment of adult patients with active psoriatic arthritis. Steqeyma can be used alone or in combination with methotrexate (MTX).

Crohn’s Disease

  • Steqeyma/Steqeyma I.V. (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease, who have had an inadequate response, loss of response to, or were intolerant to either immunomodulators or one or more tumour necrosis factor-alpha (TNFα) antagonists, or have had an inadequate response, intolerance or demonstrated dependence on corticosteroids.

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