Summary Basis of Decision for Wezlana/Wezlana I.V.

Wezlana/Wezlana I.V. (hereafter referred to as Wezlana) was developed as a biosimilar of the reference biologic drug, Stelara/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 according 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 three-way pairwise analytical assessment using Wezlana, Stelara authorized in the European Union (EU-Stelara), and Stelara authorized in the United States (US-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 studies demonstrate that Wezlana and Stelara have an identical primary amino acid sequence and similar physicochemical properties, higher-order structures, purity profiles, and potencies.

There were minor differences between Wezlana and Stelara, some of which were expected, given that Stelara is expressed in murine mouse myeloma Sp2/0 cell line, whereas Wezlana is expressed in a Chinese hamster ovary (CHO) cell line. The differences observed in glycosylation profiles and C-terminal lysine levels are directly attributed to the use of different expression cell lines. Unlike Stelara, Wezlana does not contain detectable levels of non-human glycans, such as N-glycolylneuraminic acid (NGNA)-containing glycans and alpha-galactosylated glycans. Wezlana contains N-acetylneuraminic acid (NANA)-containing glycans, which are absent in Stelara. Compared to Stelara, Wezlana has lower levels of C-terminal lysine and afucosylation, and higher levels of high-mannose glycans. While glycans can influence the effector function activities of a monoclonal antibody, ustekinumab does not induce effector functions. Hence, the biological activity of Wezlana and Stelara was very similar, notwithstanding the differences in binding to crystallizable fragment (Fc) gamma receptor IIIa (FcγRIIIa), which were attributed to the differences in afucosylation and mannose levels.

Overall, the observed differences between Wezlana and Stelara are well understood and are unlikely to be clinically meaningful. The biosimilarity assessment results support the conclusion that Wezlana is highly similar to Stelara.

Characterization of the Drug Substance

Ustekinumab is a fully human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to the p40 subunit of interleukin (IL)-12 and IL-23, thereby preventing these interleukins from binding to the IL-12 receptor β1 subunit of the IL-12 and IL-23 receptor complexes expressed on the surface of immune cells. The antibody is composed of two identical heavy chains and two identical light chains and has an approximate molecular weight of 148,079 to 149,660 Da.

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

Wezlana drug substance is produced using the mammalian CHO cell line that is genetically engineered to express ustekinumab. Briefly, the commercial manufacturing process of the drug substance consists of cell expansion steps, purification through a series of chromatography steps, viral inactivation and removal, formulation, and final filtration prior to filling into storage containers.

The manufacturing of the drug product includes thawing of the drug substance lots, formulation, bioburden reduction filtration, sterile filtration, aseptic filling and primary packaging, inspection, and storage at 2 °C to 8 °C.

Wezlana has the same formulations, dosage forms, presentations, and product strengths as Stelara. None of the non-medicinal ingredients (excipients) found in Wezlana is prohibited by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

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 the predefined specifications and quality attributes.

Control of the Drug Substance and Drug Product

Specifications for the drug substance and drug product were set using compendial guidelines, product and process knowledge, and statistical analyses of release and stability data. The established release and stability specifications for the drug substance and drug product are considered appropriate and in accordance with relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The analytical procedures used in the release and stability testing of the drug substance and drug product were adequately validated according to relevant ICH guidelines. Compendial methods were satisfactorily verified under conditions of use.

A risk assessment for the presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. No risk was identified of the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes. Accordingly, no confirmatory testing is required.

Wezlana is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale 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 satisfactory.

The stability data support the proposed shelf life of 36 months at -40 °C to -20 °C for the drug substance, 36 months at 2 °C to 8 °C for the prefilled syringe presentation of the drug product, when protected from light, and 24 months at 2 °C to 8 °C for the vial presentation of the drug product, when protected from light. In addition, the stability data support the storage, if necessary, of the prefilled syringes and 45 mg/0.5 mL vials at room temperature of up to 30 °C in the original carton and protected from light for a maximum single period of up to 30 days. If not used within 30 days of being stored at room temperature, the syringes and vials must be discarded. The drug product should not be frozen or shaken.

The compatibility of the drug product with the container closure system was demonstrated through stability studies and a comprehensive extractables and leachables study.

Facilities and Equipment

Based on a risk assessment performed by Health Canada, on-site evaluations for the drug substance and drug product manufacturing sites were not deemed necessary.

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured. The manufacturing sites are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. In-process testing is performed to monitor for bioburden, endotoxins, mycoplasma, and viruses. Purification process steps designed to inactivate and remove any potential viral contaminants from the cell culture process are adequately validated.

No animal-derived materials are used in the manufacturing process other than the CHO cell banks, puromycin dihydrochloride (a media additive for the cell banks), and tallow derivatives (which are in compliance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products [EMA/410/01 rev. 3]). The risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered negligible.

The excipients used in the drug product formulation are not of animal or human origin.

The non-clinical data submitted for Wezlana 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. For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty. Where similarity is well established by structural and functional studies, and where extensive in vitro mechanistic studies are indicative of similarity, in vivo non-clinical studies may not be necessary.

The results from the analytical similarity assessment (including the in vitro biological activity studies) demonstrated a high degree of similarity between Wezlana and Stelara. There were no residual uncertainties identified that needed to be resolved by additional comparative non-clinical in vivo pharmacology, pharmacokinetic, toxicokinetic, or toxicology studies.

For more information, refer to the Wezlana/Wezlana I.V. Product Monograph, approved by Health Canada and available through the Drug Product Database.

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.

Comparative Pharmacokinetics

The pharmacokinetic similarity of Wezlana, Stelara authorized in the European Union (EU-Stelara), and Stelara authorized in the United States (US-Stelara) was demonstrated in a Phase I, randomized, double-blind, single-dose, three-arm, parallel-group study (Study 20190230). For the purpose of this drug submission, Health Canada considered EU-Stelara a suitable proxy for Stelara authorized in Canada, as it met all of the requirements for a non-Canadian reference biologic drug stipulated in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Study 20190230 was conducted in 238 healthy adult male and female subjects randomized in a 1:1:1 ratio to receive Wezlana, EU-Stelara, or US-Stelara as a single subcutaneous dose of 90 mg on Day 1 of the study. Serum samples collected up to Day 112 post dose were used to assess the area under the concentration versus time curve from time 0 to the last quantifiable concentration (AUC_last) as well as the maximum concentration (C_max) of both Wezlana and EU-Stelara. Pharmacokinetic parameters were estimated by a non-compartmental analysis. The geometric least squares mean ratio between Wezlana and EU-Stelara for C_max was 0.96, and the 90% confidence interval (CI) of the geometric least squares mean ratio between Wezlana and EU-Stelara for AUC_last was 0.87 to 1.05. Both ratios were contained within the prespecified comparative pharmacokinetic biosimilarity margins of 80.0% to 125.0%, as per Health Canada’s Guidance Document: Comparative Bioavailability Standards: Formulations Used for Systemic Effects (2018).

Comparative Efficacy, Safety, and Immunogenicity

The efficacy, safety, and immunogenicity of Wezlana in comparison to the reference drug, EU-Stelara, were assessed in Study 20190232 in adult patients with moderate-to-severe plaque psoriasis.

Study 20190232 was a randomized, double-blind, active-controlled study. Enrolled patients were randomized in a 1:1 ratio to receive Wezlana (281 patients) or EU-Stelara (282 patients). Randomization was stratified by prior use of biologic treatment for psoriasis (yes versus no), by baseline body weight (less than or equal to 100 kg versus greater than 100 kg), and by geographic region (North America versus Europe). Patients received a dose of 45 mg (those with body weight of less than or equal to 100 kg) or 90 mg (those with body weight of greater than 100 kg) of Wezlana or EU-Stelara, administered subcutaneously on Day 1 (Week 0), Week 4, and Week 16. At Week 28, patients who had an improvement of at least 75% with respect to the baseline Psoriasis Area and Severity Index (PASI 75 or better response) in the Wezlana treatment arm continued receiving Wezlana, whereas patients with PASI 75 or better response in the EU-Stelara treatment arm were rerandomized in a 1:1 ratio to continue receiving EU-Stelara or to switch to Wezlana. Patients were treated at Week 28 and Week 40 and followed up to Week 52.

The primary efficacy endpoint of the study was the percent improvement in PASI from baseline to Week 12. Clinical similarity of the primary endpoint was evaluated by comparing the two-sided 95% CI of the mean difference of PASI percent improvement from baseline to Week 12 between Wezlana and EU-Stelara with the prespecified similarity margins of -10% to 10%. The mean (standard deviation) percent improvement in PASI from baseline to Week 12 based on multiple imputation was 81.46% (20.058%) in the Wezlana group and 81.45% (20.004%) in the EU-Stelara group. The point estimate of the mean difference of PASI percent improvement from baseline to Week 12 between Wezlana and EU-Stelara was 0.14% with a two-sided 95% CI of -3.16% to 3.43%, which was within the prespecified similarity margins of -10% to 10%. Therefore, the study provided a demonstration of no clinically meaningful differences between Wezlana and EU-Stelara in the primary efficacy endpoint of PASI percent improvement from baseline to Week 12. Secondary efficacy endpoints were suggestive of similarity; however, these endpoints were not assessed with the same rigour as the primary efficacy endpoint.

Based on the clinical data submitted, Wezlana demonstrated a comparable safety profile with that established for Stelara. Wezlana was well tolerated over 12 weeks and up to 52 weeks. The incidence of adverse events was generally consistent with that observed for Stelara, with few serious adverse events, adverse events of special interest, or discontinuations of treatment due to adverse events. No deaths were reported and no new safety signals have been identified in the Wezlana-treated patients.

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 both clinical studies, the incidence of ADAs was lower in patients dosed with Wezlana compared to the patients who received EU-Stelara. In the comparative pharmacokinetic study in healthy subjects (Study 20190230), 13 of the 78 subjects (16.7%) who received Wezlana tested positive for ADAs at any time point throughout the study, compared with 30 of the 80 subjects (37.5%) who received EU-Stelara. In the comparative clinical efficacy and safety study (Study 20190232), at Week 28, the incidence of ADAs was 18.6% in the Wezlana treatment arm compared with 37.1% in the EU-Stelara treatment arm. Similarly, the incidence of neutralizing ADAs at Week 28 was lower in the Wezlana treatment arm (8.6%) than that observed in the EU-Stelara treatment arm (17.9%). The sponsor attributed this imbalance to the lack of non-human glycans in Wezlana (see Comparative Structural and Functional Studies); however, no clinical data are available to support this statement. Consistent with the information on immunogenicity provided in the Stelara Product Monograph, ADA-positive subjects had consistently lower exposure to ustekinumab than ADA-negative subjects in the Wezlana and Stelara treatment arms. In both treatment arms, a small but not clinically meaningful decrease in efficacy was observed in ADA-positive subjects when compared to ADA-negative subjects. No consistent impact of ADAs on the safety profile of Wezlana was observed.

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 Wezlana/Wezlana I.V. Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Stelara. The Adverse Reactions section of the Wezlana/Wezlana I.V. Product Monograph is based on the clinical experience with Stelara.

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

Indications

Within this drug submission, the sponsor requested the authorization of Wezlana/Wezlana I.V. for all of the indications granted for the reference biologic drug, Stelara/Stelara I.V. In Canada, Stelara/Stelara I.V. 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 disease in adults, and ulcerative colitis in adults.

Similarity between Wezlana/Wezlana I.V. and Stelara/Stelara I.V. 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, and therefore clinical trials are not required to support each of the sought indications. 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 Wezlana/Wezlana I.V. 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.

Upon review of the evidence submitted, Wezlana/Wezlana I.V. was authorized for all of the indications currently held by Stelara/Stelara I.V., as follows:

Plaque psoriasis

Wezlana is indicated for:

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

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

Psoriatic arthritis

Wezlana is indicated for the treatment of adult patients with active psoriatic arthritis. Wezlana can be used alone or in combination with methotrexate.

Crohn disease

Wezlana/Wezlana I.V. is indicated for the treatment of adult patients with moderately to severely active Crohn 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

Wezlana/Wezlana I.V. 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.