Summary Basis of Decision for Pyzchiva and Pyzchiva 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 Pyzchiva and Pyzchiva I.V. is located below.

Recent Activity for Pyzchiva and Pyzchiva 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 Pyzchiva and Pyzchiva 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: 2025-02-18

Drug Identification Number (DIN):

  • DIN 02550520 (Pyzchiva I.V.) - 130 mg/26 mL (5 mg/mL), ustekinumab, solution, intravenous administration, single-use vial

  • DIN 02550539 (Pyzchiva) - 45 mg/0.5 mL, ustekinumab, solution, subcutaneous administration, pre-filled syringe

  • DIN 02550547 (Pyzchiva) - 90 mg/1 mL, ustekinumab, solution, subcutaneous administration, pre-filled syringe

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 290970

2024-10-01

Issued NOL 2024-12-16

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an extension of the shelf-life for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DINs 02550520, 02550547, 02550539) market notification

Not applicable

Date of first sale 2024-08-07

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

NDS # 278712

2023-09-08

Issued NOC 2024-08-07

NOC issued for the New Drug Submission.

NDS # 277532

2023-08-22

Issued NOC 2024-08-07

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

Date SBD Issued: 2025-02-18

The following information relates to the New Drug Submissions (NDS) for Pyzchiva and Pyzchiva I.V.

Ustekinumab

Drug Identification Number (DIN):

  • DIN 02550520 (Pyzchiva I.V.) - 130 mg/26 mL (5 mg/mL), ustekinumab, solution, intravenous administration, single-use vial

  • DIN 02550539 (Pyzchiva) - 45 mg/0.5 mL, ustekinumab, solution, subcutaneous administration, pre-filled syringe

  • DIN 02550547 (Pyzchiva) - 90 mg/1 mL, ustekinumab, solution, subcutaneous administration, pre-filled syringe

Samsung Bioepis Co., Ltd.

New Drug Submission Control Numbers: 277532, 278712

Submission Type: New Drug Submission

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

Date Filed: 2023-08-22

Authorization Date: 2024-08-07

On August 7, 2024, Health Canada issued two Notices of Compliance (NOCs) to Samsung Bioepis Co., Ltd. for Pyzchiva and Pyzchiva 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. Pyzchiva and Pyzchiva 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.

The sponsor submitted two NDSs for Pyzchiva and Pyzchiva I.V. Their contents differed solely in relation to the number of indications sought for the biosimilar drug. The NDS Control # 277532 requested authorization for the same indications and clinical uses that are currently authorized for Stelara and Stelara I.V. The NDS Control # 278712 was identical, but excluded the indication for the treatment of ulcerative colitis. Similarity between the biosimilars Pyzchiva and Pyzchiva 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 market authorizations of Pyzchiva and Pyzchiva I.V. were based on the quality (chemistry and manufacturing) packages submitted, as well as demonstrated similarity between the biosimilars and the reference biologic drugs. Similarity was established through data derived from comparative structural, functional, and clinical studies. Based on Health Canada’s review of both NDSs, the benefit-risk profiles of Pyzchiva and Pyzchiva I.V. are considered to be similar to the benefit-risk profiles of the reference biologic drugs, and are therefore considered favourable for the following indications:

Plaque Psoriasis (both NDSs)

  • Pyzchiva (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 (both NDSs)

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

Crohn’s Disease (both NDSs)

  • Pyzchiva/Pyzchiva 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.

Ulcerative Colitis (NDS # 277532 only)

  • Pyzchiva/Pyzchiva I.V. (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such therapies.

1 What was approved?

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

Plaque Psoriasis (both NDSs)

  • Pyzchiva (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 (both NDSs)

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

Crohn’s Disease (both NDSs)

  • Pyzchiva/Pyzchiva 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.

Ulcerative Colitis (NDS # 277532 only)

  • Pyzchiva/Pyzchiva I.V. (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such therapies.

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

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 or older) was not sufficient to determine whether they respond differently to Pyzchiva and Pyzchiva I.V. than younger patients.

Pyzchiva and Pyzchiva I.V. are biosimilars of Stelara and Stelara I.V. The drugs contain the medicinal ingredient ustekinumab. Ustekinumab is a recombinant human immunoglobulin isotype class G subclass 1 kappa (IgG1κ) monoclonal antibody that belongs to the pharmacologic class of interleukin (IL)-23 and IL-12 antagonists. Ustekinumab binds to the p40 protein subunit of the IL-12 and IL-23 cytokines to neutralize IL-23- and IL-12-mediated signalling. Interleukin-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses. By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis through interruption of the T-helper (Th)1 and Th17 cytokine pathways, which have been implicated as contributors in the pathology of these diseases. Pyzchiva and Pyzchiva I.V. are produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell expression system.

Similarity between the biosimilars Pyzchiva and Pyzchiva I.V. and the reference biologic drugs Stelara and Stelara I.V. has been established on the basis of comparative structural and functional studies, a comparative pharmacokinetic study, and a clinical trial in patients with moderate to severe plaque psoriasis, in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Pyzchiva 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 histidine, histidine hydrochloride monohydrate, polysorbate 80, sucrose, and water for injection.

Pyzchiva 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 (5 mg/mL). In addition to the medicinal ingredient, the solution contains histidine, histidine hydrochloride monohydrate, methionine, disodium edetate, polysorbate 80, sucrose, and water for injection.

The use of Pyzchiva and Pyzchiva 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 products were approved for use under the conditions stated in their Product Monograph taking into consideration the potential risks associated with their administration. The Product Monograph for Pyzchiva and Pyzchiva 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 Pyzchiva and Pyzchiva I.V. approved?

Pyzchiva and Pyzchiva I.V. (hereafter referred to as Pyzchiva) are considered biosimilars of Stelara and Stelara I.V. (hereafter referred to as Stelara), the reference biologic drugs. Similarity between Pyzchiva 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, Pyzchiva and Stelara were judged highly similar in terms of quality attributes. Data from a Phase I pharmacokinetic study provided evidence of the pharmacokinetic similarity between Pyzchiva and Stelara in healthy adults. Further evidence of the clinical comparability of Pyzchiva and Stelara included the efficacy, safety, and immunogenicity results from a Phase III, randomized, double-blind, comparative study in adult subjects with moderate to severe plaque psoriasis. According to predefined equivalence margins, the study demonstrated similarity between Pyzchiva and Stelara in the primary efficacy endpoint of percent change from baseline in Psoriasis Area and Severity Index at 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 sponsor submitted two New Drug Submissions for Pyzchiva. Their contents differed solely in relation to the number of indications sought for the biosimilar drug. Based on Health Canada's review, Pyzchiva is considered favourable for the treatment of plaque psoriasis in adults, psoriatic arthritis in adults, Crohn’s disease in adults, and ulcerative colitis in adults. The indications have been authorized on the basis of demonstrated similarity between Pyzchiva and the reference biologic drug Stelara.

A Risk Management Plan (RMP) for Pyzchiva was submitted by Samsung Bioepis Co., Ltd. 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 Pyzchiva 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 Pyzchiva was accepted.

Overall, the therapeutic benefits of Pyzchiva 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 monitoring. Appropriate warnings and precautions are in place in the Product Monograph for Pyzchiva to address the identified safety concerns.

These New Drug Submissions comply with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted two Notices 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 Pyzchiva and Pyzchiva I.V.?

The sponsor submitted two New Drug Submissions (NDSs) for Pyzchiva and Pyzchiva I.V. (hereafter referred to as Pyzchiva). Their contents differed solely in relation to the number of indications sought for the biosimilar drugs.

The NDSs requested authorization of Pyzchiva for use in all five of the indications currently held by the reference biologic drugs Stelara and Stelara I.V. (hereafter referred to as Stelara), as follows:

  • plaque psoriasis in adults (both NDSs),

  • plaque psoriasis in pediatric patients 6 to 17 years of age (both NDSs),

  • psoriatic arthritis in adults (both NDSs),

  • Crohn’s disease in adults (both NDSs), and

  • ulcerative colitis in adults (NDS # 277532 only).

Upon finalization of the review, Health Canada issued a Notices of Compliance for both of the submissions on August 7, 2024. Four of the five indications sought were authorized by Health Canada. The fifth indication that was requested, plaque psoriasis in pediatric patients 6 to 17 years of age, was not authorized by Health Canada. This is because, as per the Product Monograph for Stelara, pediatric patients with plaque psoriasis weighing less than 60 kg are dosed subcutaneously from a vial presentation of Stelara. Since the vial presentation is not available for Pyzchiva, this indication was not authorized by Health Canada.

The review of the NDSs for Pyzchiva was based on a critical assessment of the data packages submitted to Health Canada. The reviews completed by the European Medicines Agency were used as an added reference for the review of the quality component, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decisions on the Pyzchiva NDSs were 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: Pyzchiva, Pyzchiva I.V.

Submission Milestone

Date

New Drug Submission filed for Control # 277532

2023-08-22

New Drug Submission filed for Control # 278712

2023-09-08

Screening

Screening Acceptance Letters issued

2023-10-12

Review

Review of Risk Management Plan completed

2024-03-26

Quality evaluation completed

2024-07-26

Non-clinical evaluation completed

2024-08-01

Clinical/medical evaluation completed

2024-08-01

Labelling review completed

2024-08-06

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

2024-08-07
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 Pyzchiva and Pyzchiva I.V. (hereafter referred to as Pyzchiva) 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 Pyzchiva, and make safety updates to the Product Monograph for Pyzchiva as appropriate. New safety issues that are first identified with Pyzchiva, the reference biologic drugs, or other biologics that share a common medicinal ingredient may or may not have relevance to both Pyzchiva and the reference biologic drugs. For more information, refer to the Biosimilar Biologic Drugs in Canada: Fact Sheet.

5 What post-authorization activity has taken place for Pyzchiva and Pyzchiva 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 Pyzchiva and Pyzchiva 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 Pyzchiva and Pyzchiva I.V.? section for more information about the review process for these submissions.

7.1 Quality Basis for Decision

Pyzchiva and Pyzchiva I.V. (hereafter referred to as Pyzchiva) 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 to the reference biologic drug.

Comparative Structural and Functional Studies

The biosimilarity evaluation was conducted as a head-to-head analytical assessment using Pyzchiva 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 Pyzchiva is identical to Stelara with respect to primary structure and is highly similar with regards to higher order structure, purity, and biological activities. Owing to differences in the cell line used to manufacture Pyzchiva (Chinese hamster ovary cells [CHO]) and Stelara (Sp2/0 mouse myeloma), differences in the type and content of charged glycan species were observed. Specifically, N-acetylneuraminic acid was present in Pyzchiva and N-glycolylneuraminic acid was present in EU-Stelara. These differences are not expected to translate into clinically meaningful differences. Cation-exchange high-performance liquid chromatography demonstrated that Pyzchiva has lower levels of acidic and basic peaks and higher levels of main peak as compared to EU-Stelara. These variations were attributed to differences in C-terminal variants (lysine clipping and α-amidation of proline). These variants are known to have no expected impact on the safety and efficacy of Pyzchiva. The biological activities were highly similar between lots of Pyzchiva and EU-Stelara. Comparative forced degradation studies using different stress conditions generated similar degradation profiles for Pyzchiva and EU-Stelara, further supporting the similarity of the two products. Some differences in rates of degradation were noted but were attributed to differences in the Pyzchiva and EU-Stelara formulations.

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

Characterization of the Drug Substance

Ustekinumab is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to the shared p40 protein subunit of 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

The ustekinumab drug substance manufacturing process begins with the thawing of a CHO-derived working cell bank. The culture is expanded and the collected harvest is then purified using a series of chromatography steps and ultrafiltration. Potential viruses are inactivated and removed through low pH inactivation and viral filtration steps. The drug substance is then diafiltered into a formulation buffer, filtered, dispensed into bags, and stored.

The drug product for subcutaneous administration is supplied in a single-use pre-filled syringe in two strengths (45 mg/0.5 mL and 90 mg/1 mL). Manufacturing of this drug product begins with the thawing of the formulated drug substance, followed by pooling of the drug substance, filtration, and sterile filling into syringes. A plunger is inserted and the pre-filled syringes are visually inspected and stored.

The drug product for intravenous administration is supplied in a single-use vial (130 mg/26 mL). Manufacturing of this drug product begins with the thawing of the formulated drug substance, followed by pooling of the drug substance, filtration, and sterile filling into vials. The vial process also includes a compounding step to dilute the drug substance and to reach the final target protein concentration. The vials are stoppered, sealed, visually inspected, and stored.

In-process controls and lot release tests for the drug substance and drug product were established and validated.

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 safety and quality of all materials used in the manufacturing process, including cellular substrates and raw materials, were appropriately demonstrated. The drug substance and drug product manufacturing processes are controlled by process parameters and in-process controls/tests with defined operating ranges and action limits/acceptance criteria. Performance and quality attribute criticality was appropriately defined, and was based on risk assessments, process characterization studies, and previous experience gained during development. The analytical methods were appropriately validated or complied with relevant pharmacopeia standards.

Overall, the control strategy is considered suitable for the drug substance and drug product over the lifetime of the product.

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).

Pyzchiva 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 proposed shelf lives of 18 months for the Pyzchiva vial and 24 months for the Pyzchiva pre-filled syringes are considered acceptable when stored at 2 °C to 8 °C and protected from light.

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

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

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

No raw materials of animal or human origin are used during the drug substance or drug product manufacturing, or during the generation of the cell substrates.

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. According to the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs, where similarity is well established by structural and functional studies, and where extensive in vitro mechanistic studies are indicative of similarity, non-clinical in vivo studies may not be necessary.

The results from the analytical similarity assessment (see Comparative Structural and Functional Studies above) demonstrated a high degree of similarity between the biosimilars Pyzchiva and Pyzchiva I.V. (hereafter referred to as Pyzchiva) and the reference biologic drugs Stelara and Stelara I.V. (hereafter referred to as Stelara). There were no residual uncertainties identified that needed to be resolved by additional comparative non-clinical in vivo pharmacodynamic, pharmacokinetic, and toxicology studies.

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

Comparative Pharmacokinetics and Pharmacodynamics

Study SB17-1001 was a Phase I, randomized, double-blind, single-dose, three-arm, parallel-group study. A total of 201 healthy adult subjects were randomized in a 1:1:1: ratio (67 subjects per group) to receive a single 45 mg subcutaneous dose of either Pyzchiva, Stelara authorized in the European Union (EU-Stelara), or Stelara authorized in the United States (US-Stelara). The primary objective was to demonstrate the pharmacokinetic similarity between Pyzchiva and EU-Stelara in healthy subjects.

Serum pharmacokinetic sampling times up to Day 99 post dose were deemed suitable for the 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 Pyzchiva and EU-Stelara.

Non-compartmental analysis was used to estimate the pharmacokinetic parameters, with statistical assessment of the pharmacokinetic parameters performed using an analysis of variance (ANOVA) without covariates. The geometric least squares (LS) mean ratio between Pyzchiva and EU-Stelara for Cmax was 0.90, and the 90% confidence interval (CI) of the geometric LS mean ratio between Pyzchiva and EU-Stelara for AUClast was 0.90 to 1.07. Both geometric ratios were 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).

Comparative Clinical Efficacy and Safety

The efficacy, safety, and immunogenicity of Pyzchiva in comparison to the reference drug, EU-Stelara, were assessed in Study SB17-3001 in adult subjects with moderate to severe plaque psoriasis.

Study SB17-3001 was a confirmatory, Phase III, randomized, double-blind, multicentre clinical study. A total of 503 subjects were randomized to receive a 45 mg subcutaneous dose of Pyzchiva (number of subjects [n] = 232) or EU-Stelara (n = 232) at Week 0, Week 4, and every 12 weeks up to Week 40. A dose of 90 mg was used in subjects with a body weight greater than 100 kg during the study. At Week 28, the EU-Stelara treatment group was re-randomized in a 1:1 ratio to switch to Pyzchiva or to continue treatment with EU-Stelara until Week 40. Subjects that received Pyzchiva continued to receive Pyzchiva until Week 40. The last assessment was conducted at Week 52.

Of the 503 subjects who were randomized, 481 (95.6%) completed 28 weeks of the study and 466 (96.9%) completed 52 weeks of the study. The primary endpoint was the percent change (improvement) from baseline in Psoriasis Area and Severity Index (PASI) at Week 12. The secondary objective was the assessment of the safety and immunogenicity of Pyzchiva compared with EU-Stelara.

The primary endpoint was met and the clinical similarity of Pyzchiva to EU-Stelara was established based on pre-defined criteria. The two-sided 95% CI of the LS mean difference of percent change from baseline in PASI at Week 12 was entirely contained within the pre-defined equivalence margin of ‑15% to 15%. A similar analysis was performed for the Full Analysis Set (FAS; all randomized subjects who received study drug and who had an efficacy assessment) to support the primary analysis.

More specifically, the percent change from baseline in PASI at Week 12 was equivalent between the Pyzchiva and EU-Stelara treatment groups in the per-protocol set (PPS; all FAS subjects who weighed 100 kg or less, received 45 mg of study drug at Week 0 and Week 4, and had a PASI assessment result at baseline and at Week 12). The adjusted LS mean difference at Week 12 was ‑ || .0.6 (standard error [SE]: 1.62) and the 95% CI of the adjusted treatment difference was ‑3.780 to 2.579, which was entirely contained within the pre-defined equivalence margin of ‑15% to 15%, thus supporting a demonstration of no clinically meaningful differences between Pyzchiva and Stelara.

Additionally, the two-sided 90% CI of the LS mean difference between the two treatment groups was estimated at Week 12 for both the FAS and the PPS, with a narrower pre-defined equivalence margin of -10% to 10% as a sensitivity analysis. The LS mean difference was ‑0.6 (SE: 1.62, 90% CI [‑3.267, 2.066]) for the PPS, and ‑0.7 (SE: 1.60, 90% CI [‑3.329, 1.948]) for the FAS, which were all within the pre-specified margin of ‑10% to 10%.

The results of the clinical efficacy study indicated there are no clinically meaningful differences between Pyzchiva and the reference biologic drug Stelara.

During Study SB17-3001, there were no notable differences observed between treatment groups in the incidence of reported serious treatment-emergent adverse events (TEAEs), TEAEs that led to discontinuation from study treatment, or TEAEs of special interest. No serious TEAEs and TEAEs leading to discontinuation deemed related to study treatment were reported during the study. There were no deaths reported in the study and no new safety signals were identified. Pyzchiva was well-tolerated over 12 weeks and up to 52 weeks.

Overall, the safety profile of Pyzchiva is considered to be comparable to that which has been established for the reference biologic drug Stelara. The identified safety concerns are appropriately addressed in the Product Monograph for Pyzchiva, as they are in the Product Monograph for Stelara.

Comparative Immunogenicity

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 two clinical studies, the incidence of ADAs was lower in subjects dosed with Pyzchiva compared to those dosed with EU-Stelara. In the comparative pharmacology Study SB17-1001, the overall incidence of subjects with post-dose ADAs to ustekinumab was 18/67 (26.9%), 23/67 (34.3%), and 23/67 (34.3%) in the Pyzchiva, EU-Stelara, and US-Stelara treatment groups, respectively. The incidence of subjects with neutralizing antibodies (NAbs) at each timepoint was lower in the Pyzchiva treatment group compared to that in the EU-Stelara or US-Stelara treatment groups, except at Day 29. The incidence of subjects with NAbs at Day 99 was 5/14 (35.7%), 12/19 (63.2%), and 11/19 (57.9%) in the Pyzchiva, EU-Stelara, and US-Stelara treatment groups, respectively.

In the comparative clinical efficacy and safety Study SB17-3001, the incidence of ADAs tended to be lower by visit and overall status in the Pyzchiva treatment group compared to the EU-Stelara treatment group. The overall incidence of ADA-positive subjects up to Week 28 was 33/249 (13.3%) in the Pyzchiva treatment group and 100/254 (39.4%) in the Stelara Overall treatment group (EU-Stelara + Pyzchiva, EU-Stelara + EU-Stelara). Overall, of the subjects who received Pyzchiva, EU-Stelara, or both during the study period (defined as Safety Set 1), the incidence of ADA-positive subjects up to Week 52 was 41/249 (16.5%) in the Pyzchiva treatment group and 105/254 (41.3%) in the EU-Stelara Overall treatment group. The titer distribution for ADAs was comparable between the treatment groups and the majority of ADA titers were low. Within treatment groups, the serum concentration of ustekinumab was lower in subjects with overall ADA-positive results compared to subjects with overall ADA-negative results, which is consistent with what has been reported for the Canadian reference biologic drug. The proportions of subjects with any TEAEs in the overall ADA-positive and ADA-negative subgroups were comparable between the Pyzchiva and the EU-Stelara treatment groups.

The Sponsor attributes the differences in the incidence of ADAs and NAbs to the lack of non-human glycan on the protein backbone of Pyzchiva; however, no direct clinical data was available to support this statement at the time of authorization. In alignment with the labelling in the Product Monograph for Stelara, ADA-positive subjects had a lower exposure to ustekinumab than ADA-negative subjects, which was consistent between the Pyzchiva and EU-Stelara treatment groups. There was no observed consistent impact of ADAs on the safety of Pyzchiva.

Indications

Pyzchiva 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.

The sponsor submitted two New Drug Submissions (NDSs) for Pyzchiva. The NDS under Control # 277532 requested authorization for the same five indications and clinical uses that are currently authorized for Stelara. The NDS under Control # 278712 was identical, but excluded the indication for the treatment of ulcerative colitis.

Upon finalization of the review, Health Canada issued a Notices of Compliance for both of the submissions on August 7, 2024. Four of the five indications sought were authorized by Health Canada. The fifth indication that was requested, plaque psoriasis in pediatric patients 6 to 17 years of age, was not authorized by Health Canada. This is because, as per the Product Monograph for Stelara, pediatric patients with plaque psoriasis weighing less than 60 kg are dosed subcutaneously from a vial presentation of Stelara. Since the vial presentation is not available for Pyzchiva, this indication was not authorized by Health Canada.

Similarity between Pyzchiva 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 sponsor provided data from a comparative clinical trial conducted in adult patients with moderate-to-severe plaque psoriasis. In addition, the sponsor provided an acceptable scientific rationale for requesting the authorization of indications that were not directly studied in the clinical development program for Pyzchiva. The rationale addressed each of the critical points for extrapolation of data including the mechanism of action of ustekinumab across all indications, the pharmacokinetics and biodistribution of the product in different patient populations, and the safety and immunogenicity profiles of ustekinumab across indications. The primary focus of the scientific justification was on the similarity demonstrated through comparative physicochemical and functional assessments, and clinical pharmacokinetic, efficacy, safety, and immunogenicity comparisons.

Indications

Plaque Psoriasis (both NDSs)

  • Pyzchiva (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 (both NDSs)

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

Crohn’s Disease (both NDSs)

  • Pyzchiva/Pyzchiva 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.

Ulcerative Colitis (NDS # 277532 only)

  • Pyzchiva/Pyzchiva I.V. (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such therapies.

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