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

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

Yesintek was evaluated for biosimilarity to Stelara through a comprehensive three-way comparative analytical assessment. The assessment used Stelara authorized in the European Union (herein referred to as EU-Stelara) as the designated reference biologic and Stelara authorized in the United States of America (herein referred to as US-Stelara) as a supportive comparator. 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 Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

The biosimilarity assessment included the comparison of physicochemical characterization (e.g., mass spectrometry, circular dichroism spectroscopy, differential scanning calorimetry, size-exclusion chromatography, capillary electrophoresis), glycosylation profiling, and functional bioassays such as interleukin 23 (IL-23) neutralization and neonatal fragment crystallizable receptor (FcRn) binding. Statistical evaluation was conducted using quality ranges (mean ± 3 standard deviations) and profile overlays to assess similarity. Minor differences were observed in lysine variants and glycosylation profiles, and these were determined to have no impact on biological activity. Overall, Yesintek demonstrated high similarity to EU-Stelara and US-Stelara in terms of structure, purity, potency, and biological function.

Further comparability assessments were conducted on the drug product presentations. The subcutaneous formats (prefilled syringe and vial) were evaluated using 46 quality attributes and were found to be analytically interchangeable. The intravenous format,was reviewed separately using 45 quality attributes due to formulation differences. Minor variations in charge heterogeneity and glycosylation were observed but deemed clinically insignificant. The analytical bridge between EU and US-sourced Stelara was successfully established, supporting the conclusion of biosimilarity across all presentations.

Characterization of the Drug Substance

Ustekinumab, the medicinal ingredient in Yesintek, is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to p40 protein subunit of IL-23 and IL-12. Binding of free IL-23 and IL-12 neutralizes IL-23- and IL-12-mediated cellular responses that are associated with immune-mediated human diseases.

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. 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).

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

The drug substance, ustekinumab, is produced using a Mouse myeloma cell line that is genetically engineered to express the protein. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of the drug substance involves inoculation of the content of one vial of working cell bank into a sterile shake flask, cell propagation in additional shake flasks, inoculum expansion in bioreactors, then growth at a larger scale in a production bioreactor that uses a fed-batch process. The culture is then collected and 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, formulated with excipients, filtered, dispensed into single-use bags and stored frozen.

The drug product for subcutaneous administration is supplied in a single-use prefilled syringe in two strengths (45 mg/0.5 mL and 90 mg/1 mL) or in a single-use vial (45 mg/0.5 mL). The manufacturing of this drug product begins with the thawing of the formulated drug substance, followed by pooling and mixing, pre-filtration (offline filtration) and sterile filtration, and aseptic filling into 1 mL syringes or 2R glass vials. The prefilled syringes and filled vials are stoppered, sealed, 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 and mixing, dilution to 5 mg/mL with intravenous spiking buffer, pre-filtration (offline filtration) and sterile filtration, and aseptic 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.

The critical process parameters and in-process controls of the drug substance, and the vial and prefilled syringe drug product manufacturing processes were established and validated. The results of process validation studies demonstrated that the processes are capable of consistently manufacturing drug substance and drug products that meet their respective specifications.

The materials used in the manufacture of the drug substance and drug product (including biological materials) are considered suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

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 processes, 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. Process performance and quality attributes criticality were appropriately defined, and were based on risk assessments, process characterization studies, and previous experience gained during development. The release/stability 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.

Yesintek 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 stability studies support the proposed shelf life of 36 months for the subcutaneous prefilled syringes when stored at 2 °C to 8 °C and protected from light. A shelf life of 24 months for both the subcutaneous vial and intravenous vial is deemed acceptable when stored at 2 °C to 8 °C and 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.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of all facilities and equipment involved in the production are considered suitable.

On-site evaluations of the facility involved in the manufacture and testing of the drug substance and drug product, as well as the facility responsible for packaging were not warranted since the facilities were recently inspected and received satisfactory ratings.

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 absence of adventitious microorganisms (bioburden, mycoplasma, and viruses) for which the appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Materials of biological origin are properly sourced and tested. The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens. A certification letter attesting to these claims was provided by the sponsor. The excipients used in the drug product formulation are not of animal or human origin.

For biosimilars, the degree of similarity to the reference biologic drug 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) demonstrated a high degree of similarity between Yesintek and Yesintek I.V. compared to Stelara and Stelara I.V., respectively. There were no residual uncertainties identified that needed to be resolved by additional comparative non-clinical in vivo pharmacodynamic, pharmacokinetic, and toxicology studies.

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.

Yesintek and Yesintek I.V. (herein referred to as Yesintek) are proposed biosimilar drugs to the reference biologic drugs Stelara and Stelara I.V (herein referred to as Stelara). The sponsor sought approval for all indications and presentations of Stelara, based on the demonstrated biosimilarity between the two products.

The New Drug Submission for Yesintek included two main clinical studies: a Phase I comparative bioavailability study conducted in healthy subjects (study BM12H-NHV-01-G-01) and a Phase III clinical study conducted in subjects with moderate to sever plaque psoriasis (study BM12H-PSO-03-G-02). In both studies, Stelara authorized in the European Union (EU-Stelara) served as the reference biologic. Additionally, Stelara authorized in the United States of America (US-Stelara) was included as a supportive comparator in the Phase I study.

Comparative Pharmacokinetics and Pharmacodynamics

Yesintek and Stelara both contain the medicinal ingredient ustekinumab, which is a recombinant humanized monoclonal antibody of the immunoglobulin G1κ subclass. The antibody binds with specificity to the p40 protein subunit shared by interleukin 12 (IL‑12) and IL-23 cytokines, thereby blocking their interaction with the cell-surface IL-12 receptor beta-1 subunit (IL-12Rβ1) and inhibiting downstream receptor signaling. Interleukin-12 and IL-23 play a role in the pathophysiology of psoriatic inflammatory diseases, including psoriatic arthritis and Crohn’s disease. By binding to the p40 subunit shared by IL-12 and IL-23, ustekinumab may exert its clinical effects in these conditions by disrupting the Th1 and Th17 cytokine pathways, which are implicated in the pathology of these diseases.

Phase I Study

Study BM12H-NHV-01-G-01 was a Phase I, randomized, double-blind, three-arm, parallel group, single-dose comparative bioavailability study conducted in healthy subjects to evaluate the pharmacokinetics, safety, tolerability, and immunogenicity of Yesintek.

In this study, 258 subjects were randomized in a 1:1:1 ratio to receive a single 45 mg subcutaneous dose of either Yesintek (86 subjects), EU-Stelara (85 subjects) or US-Stelara (87 subjects). The primary pharmacokinetic parameters were the area under the concentration-time curve from time zero extrapolated to infinity (AUC_0-inf) and the maximum observed concentration (C_max). The ratio of the area under the curve from time zero to the last measurable concentration (AUC_0-t) to the total area under the curve (AUC_T) was assessed as a secondary endpoint.

The study demonstrated that Yesintek is pharmacokinetically similar to EU-Stelara. The results met Health Canada’s comparative bioavailability standards, as both the relative mean maximum observed serum concentration (C_max) of Yesintek to the reference product and the 90% confidence interval (CI) for the relative mean AUC to the last measurable concentration (AUC_T) fell within the predefined comparative biosimilarity margins of 80% to 125%.

Furthermore, no consistent imbalance in safety was observed between Yesintek and EU-Stelara (and US-Stelara) across the Phase I study. The immunogenicity profiles were consistent between treatment groups and did not raise any safety concerns.

In conclusion, the clinical pharmacology data derived from the Phase I study support pharmacokinetic similarity between Yesintek and EU-Stelara (and US-Stelara) in healthy subjects.

Comparative Clinical Efficacy and Safety

Further evidence of the clinical similarity of Yesintek and Stelara was obtained from the results of a supportive Phase III, randomized, active-controlled, double-blind study, BM12H-PSO-03-G-02. This study evaluated the efficacy, pharmacokinetics, safety, and immunogenicity of subcutaneous injections of Yesintek or EU-Stelara (45 mg) administered at baseline, Week 4, and every 12 weeks thereafter over a 52 period, in adults with moderate to severe chronic plaque psoriasis. Upon enrollment, subjects were randomly assigned to one of the two treatment groups in a 1:1 ratio where 191 patients received Yesintek and 193 patients received EU-Stelara.

The primary efficacy endpoint was the mean percentage change from baseline in the Psoriasis Area Severity Index (PASI) score at Week 12. Equivalent efficacy was established if the 90% and 95% CIs for the treatment difference (Yesintek, EU-Stelara) were within predefined equivalence margins of ±10% and ±13%, respectively.

The PASI is a quantitative scoring system used to assess the severity of psoriatic lesions based on body surface area involvement, plaque characteristics, and treatment response. Four body regions, head, upper limbs, trunk, and lower limbs are evaluated separately for erythema, induration (thickness), and scaling. For each region, the degree of involvement is scored from 0 (no involvement) to 6 (90 to 100% involvement). The total score for erythema, thickness, and scaling is multiplied by the degree of involvement for that region and then by a region-specific constant. The sum of all regional scores yields a PASI score ranging from 0 (no disease) to 72 (maximal disease), with higher scores indicating more severe disease. Change from baseline in PASI score indicates response to therapy.

The study results from BM12H-PSO-03-G-02 showed that Yesintek demonstrated comparability to EU-Stelara with respect to the percentage improvement in PASI scores at Week 12. The least square mean difference between treatments was 0.6800% (90% CI, -1.27 to 2.63; 95% CI, -1.64 to 3.00). Equivalence of the treatments was established as the 90% CI was contained entirely within the predefined margin of ±10% and the 95% CI was contained entirely within the predefined margin of ±13%. Therefore, the efficacy data evaluated in this study supports the establishment of biosimilarity between Yesintek and the reference biologic drug EU‑Stelara, demonstrating no clinically meaningful differences in subjects with plaque psoriasis.

The serum trough concentration and immunogenicity profile measured in this Phase III study did not result in any treatment related differences between Yesintek and EU-Stelara. The immunogenicity profiles were consistent between treatment groups and did not raise any safety concerns.

The safety profile of Yesintek was consistent with that observed for EU-Stelara. The overall incidence of adverse events was consistent between both treatment groups. No clinically meaningful imbalances were observed for severity of adverse events, serious adverse events, adverse events of special interest, or discontinuations due to adverse events. No deaths occurred among subjects in either treatment group.

Across all indications, the most common adverse reactions with Yesintek (occurring in more than 5% of patients) were nasopharyngitis and headache. Most events were considered to be mild and did not necessitate drug discontinuation. In some clinical studies, serious bacterial, fungal, and viral infections were observed in subjects receiving Yesintek. Serious infections requiring hospitalization occurred in the psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis development programs. In the psoriasis and psoriatic arthritis programs serious infections included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis and sepsis. In the Crohn’s disease program, serious infections included anal abscess, gastroenteritis, pneumonia and sepsis. Other clinically important infections included listeria meningitis and ophthalmic herpes which were each reported in one patient.

As with Stelara, safety concerns of interest associated with the use of Yesintek include: serious systemic hypersensitivity reactions; potential risks of serious infections (including mycobacterial and salmonella infections); malignancy; cardiovascular events; and venous thromboembolism. The sponsor will conduct routine pharmacovigilance activities for all risks associated with Yesintek, including the use of specific follow-up questionnaires for the safety concerns of interest.

Currently, there are no available data on the long-term safety of Yesintek in adults with moderately to severely active ulcerative colitis or Crohn’s disease. In addition, there are no data on its long-term safety or potential impact on the growth and development of pediatric patients aged 6 years and older with psoriasis.

Yesintek has demonstrated a comparable safety profile to that of the reference biologic drug, Stelara. Therefore, the Adverse Reactions section of the Product Monograph for Yesintek is based on the clinical experience with Stelara.

Comparative Immunogenicity

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies, which have the potential to neutralize the biological activity of the drug). In both the Phase I and Phase III studies, no consistent imbalance in immunogenicity was observed between Yesintek and EU-Stelara. There was no clinically meaningful impact of anti-drug antibodies on pharmacokinetic, efficacy, or safety of either Yesintek or EU-Stelara.

Indications

Within this drug submission, the sponsor requested the authorization of Yesintek for the indications granted for Stelara, the reference biologic drug.

Similarity between Yesintek and Stelara was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. The demonstration of similarity between a proposed biosimilar and its reference biologic drug enables the sponsor's submission for the proposed biosimilar to rely on the safety and efficacy information already generated for the reference biologic drug.

Upon review of the evidence submitted, including results of structural, functional, clinical pharmacokinetic, immunogenicity, efficacy, and safety comparisons, Health Canada authorized Yesintek for the same indication held by Stelara, as follows:

Plaque Psoriasis

• Yesintek (ustekinumab) is indicated for:

  • treatment of chronic moderate to severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy.

  • treatment of chronic moderate to severe plaque psoriasis in pediatric patients (6-17 years of age) who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

Psoriatic Arthritis

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

Crohn’s Disease

• Yesintek/Yesintek 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 antagonists, or have had an inadequate response, intolerance or demonstrated dependence on corticosteroids.

Ulcerative Colitis

• Yesintek/Yesintek 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.