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

Otulfi and Otulfi I.V. (hereafter referred to as Otulfi) 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 Otulfi and Stelara authorized in the European Union (EU-licensed Stelara). Health Canada considers EU-licensed 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. Stelara authorized in the United States of America (US-licensed Stelara) was used as supportive data.

The results of the biosimilarity assessment demonstrated that Otufli is identical to Stelara with respect to primary structure and is highly similar with regards to higher order structures, purity, and biological activities. Differences between Otulfi and Stelara were observed for some quality attributes, including significant differences in levels of C‑terminal lysine and the types and levels of charged sialic acid containing glycans; this is largely due to the use of different cell lines in the production of Otulfi (Chinese Hamster Ovary[CHO] cell line) compared to Stelara (Sp2/0 mouse myeloma cell line). Minor differences in levels of free thiols, size variants, and some post-translational modifications were also noted. Overall, these differences did not impact biological activities or translate into clinically meaningful differences. Additionally, forced degradation and stability studies demonstrated similar degradation profiles between Otulfi and Stelara (EU and US). Overall, the results of the biosimilarity assessment support the conclusion that Otulfi 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)-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.

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, formulated with excipients, filtered, dispensed into bottles, 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, bioburden reduction, sterile filtration, and aseptic filling into 1 mL syringes. 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, 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 pre-filled 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.

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.

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).

Otulfi and Otulfi I.V. 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 protected from light for the pre-filled syringe and vial presentations. If needed, the pre-filled syringe may be stored at room temperature (up to 30 °C) for a single period of up to 30 days within the product expiry date. Furthermore, if necessary, the diluted Otulfi I.V. infusion solution may be stored for up to eight hours at room temperature.

The compatibility of the two drug product presentations with their respective container closure systems 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 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, an on-site evaluation of the drug substance and the vial and pre-filled syringe drug product manufacturing facilities was 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 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.

No raw materials of animal origin are used during drug substance or drug product manufacturing.

For biosimilars, non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.

The non-clinical package for Otulfi and Otulfi I.V. consisted of one in vivo comparative pharmacokinetic study comparing the pharmacokinetics of FYB202 (ustekinumab in Otulfi and Otulfi I.V.) to those of EU-licensed Stelara and US-licensed Stelara in minipigs. In this study, the pharmacokinetics of FYB202 in the Stelara vehicle formulation were generally comparable to those of EU-licensed Stelara and US-licensed Stelara following a single subcutaneous dose of 0.9 mg/kg body weight.

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

Comparative Pharmacokinetics and Pharmacodynamics

Ustekinumab, the drug substance in both Otulfi/Otulfi I.V. and Stelara/Stelara I.V., is a recombinant human immunoglobulin isotype class G subclass 1 kappa monoclonal antibody that belongs to the pharmacologic class of interleukin‑23 (IL‑23) and interleukin‑12 (IL‑12) antagonists. Ustekinumab binds to the p40 protein subunit of the IL‑23 and IL‑12 cytokines to neutralize IL‑23- and IL‑12- mediated signalling. Interleukin‑23 and IL‑12 are naturally occurring cytokines that are involved in inflammatory and immune responses.

Phase I Studies

Study FYB202‑01‑01 was the first comparative Phase I pharmacokinetic study conducted in healthy subjects. This study failed to establish pharmacokinetic similarity between Otulfi and Stelara due to slightly higher than acceptable ustekinumab exposure associated with the proposed biosimilar compared to the reference product Stelara. Based upon the findings from a root cause analysis, the sponsor implemented design changes for the second comparative pharmacokinetic study, FYB202‑01‑02, including increasing sample size and amending the drug substance set point for protein concentration and drug product fill volume for Otulfi.

Study FYB202-01-02 was the second Phase I pharmacokinetic study conducted in healthy subjects. This study was a randomized, double‑blind, three‑arm, parallel‑group, single‑dose study evaluating Otulfi, EU-licensed Stelara, and US-licensed Stelara in 478 healthy adult subjects. The pivotal objective of the study was to evaluate pharmacokinetic similarity between Otulfi, EU-licensed Stelara, and US-licensed Stelara. Each subject received a single 45 mg subcutaneous injection of either Otulfi, EU-licensed Stelara, or US-licensed Stelara, and serum samples were collected up to Day 112. A non-compartmental analysis was used to estimate pharmacokinetic parameters, with statistical assessment of pharmacokinetic parameters performed using an analysis of variance without covariates. The point estimate for the Otulfi and EU-licensed Stelara geometric least square mean ratio for the maximum concentration and the 90% confidence intervals for the area under the concentration versus time curve to the time of the last quantifiable concentration were within Health Canada’s prespecified comparative pharmacokinetic biosimilarity margin of 80.0% to 125.0%, as per Health Canada’s Guidance Document: Comparative Bioavailability Standards: Formulations Used for Systemic Effects (2018). As a result, Study FYB202‑01‑02 established similar pharmacokinetics between Otulfi and the declared proxy to the Canadian reference biologic drug, EU-licensed Stelara.

Comparative Clinical Efficacy and Safety

The efficacy, safety, and immunogenicity of Otulfi in comparison to the reference drug, EU-licensed Stelara, were evaluated in Study FYB202‑301 in adult subjects with moderate to severe plaque psoriasis. Study FYB202‑301 was a confirmatory, Phase III, randomized, double‑blind, active‑controlled, multicentre clinical study conducted in adult subjects with moderate to severe plaque psoriasis.

A total of 392 subjects were randomized 1:1 to receive subcutaneous injections of either Otulfi or Stelara 45 mg at Weeks 0 and 4 and at 12-week intervals thereafter (Weeks 16, 28, and 40). The end-of-study visit took place at Week 52. Randomization was stratified by prior inadequate response or intolerance to a systemic biological treatment in the opinion of the investigator. Of the subjects enrolled, 197 subjects received Otulfi and 195 subjects received Stelara.

At Week 28, after receiving treatment at Week 0, 4 and 16, the subjects were assessed for Psoriasis Area and Severity Index (PASI) response. Subjects not achieving a 75% or greater improvement from baseline in PASI score (PASI 75) at Week 28 were considered non-responders. For recruitment planning, it was estimated that 30% of the subjects would be non-responders. Non-responders were discontinued from study intervention, but were to be followed until end-of-study and underwent all study-related assessments.

Before the Week 28 administration of study intervention, the responding subjects were re-randomized in a blinded fashion. Subjects initially randomized to the Stelara treatment group were re-randomized in a 1:1 ratio, so that 50% of the subjects in the original Stelara treatment group received Otulfi and 50% continued with Stelara. Subjects originally randomized to Otulfi continued with Otulfi. Treatment was given until Week 40 and the last assessment was conducted at Week 52.

Final study results showed that at Week 12, the two-sided 95% confidence interval for the geometric least squares (LS) mean difference in the percent improvement in PASI score from baseline to Week 12 means between Otulfi and Stelara was within the pre-defined equivalence margin (i.e., [-11 to 11]). Supportive secondary efficacy endpoints were also suggestive of similarity; however, these endpoints were not assessed with the same rigor as the primary efficacy endpoint.

The safety profile of Otulfi was consistent with that of Stelara. Otulfi was well-tolerated over 52 weeks, with an incidence of adverse events generally consistent with those observed for Stelara, with few serious adverse events and some adverse events of special interest, or discontinuations due to adverse events.

Overall, the safety profile of Otulfi 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 Otulfi, as they are in the Product Monograph for Stelara.

The intravenous formulation of Otulfi and Otulfi I.V., has not been investigated in the submitted clinical trials. As such, the approval of Otulfi I.V. relies upon an extrapolation approach based on a favourable benefit-risk profile for the Otulfi subcutaneous formulation from the clinical perspective, in addition to the satisfactory review of Otulfi I.V. based on the Chemistry and Manufacturing (Quality) review. This extrapolation approach has been utilized previously for the preceding ustekinumab biosimilars approved in Canada.

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). Across the two clinical studies, FYB202-01-02 and FYB202‑301, the incidence of anti-drug antibodies was lower in subjects dosed with Otulfi compared to those dosed with EU-licensed Stelara. In the comparative pharmacokinetic FYB202-01-02 study, a total of 32/164 (19.5%) subjects in the Otulfi arm were anti-drug antibody positive at any timepoint throughout the study, compared with 69/163 (42.3%) subjects for EU-licensed Stelara. In the comparative clinical efficacy and safety FYB202-03-01 study at Week 28, the incidence of anti-drug antibodies for the Otulfi arm was 12.4% compared with 19.4% for the EU-licensed Stelara arm. Therefore, across both clinical studies, anti-drug antibody incidence was lower in subjects dosed with Otulfi compared to EU-licensed Stelara. The higher anti-drug antibody incidence associated with EU-licensed Stelara compared to Otulfi was expected, as this has been observed with the previous ustekinumab biosimilars authorized in Canada. Like Otulfi and Otulfi I.V., the previous ustekinumab biosimilars are manufactured using Chinese hamster ovary cells, while Stelara is manufactured using a potentially more immunogenic murine cell line (Sp2/0 mouse myeloma). This observation was not deemed clinically significant from a clinical efficacy or safety perspective. Consistent with the labelling in the Product Monograph for Stelara, anti-drug antibody positive subjects had slightly lower exposure than anti-drug antibody negative subjects, which was consistent between the Otulfi and Stelara treatment arms.

Indications

Otulfi 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.

Similarity between Otulfi 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 Otulfi. 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

• Otulfi (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

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

Crohn’s Disease

• Otulfi/Otulfi 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

• Otulfi/Otulfi 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.