Summary Basis of Decision for Wyost

Wyost (denosumab, also known as GP2411) was developed as a biosimilar of Xgeva (denosumab), the reference biologic drug. 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 drug substance, denosumab (GP2411), was developed as a biosimilar of the reference denosumab marketed by Amgen Canada Inc. as two drug products which differ only in the denosumab concentration, container closure, and indications: Prolia (denosumab 60 mg/mL supplied in a prefilled syringe) and Xgeva (denosumab 120 mg/1.7 mL [70 mg/mL] supplied in a single-use vial). Sandoz Canada Inc. submitted to Health Canada the New Drug Submission (NDS) for Wyost, an intended biosimilar of Xgeva in parallel with the NDS for Jubbonti (Control No. 271806), an intended biosimilar of Prolia.

The sponsor conducted comprehensive biosimilarity assessment studies using an array of comparative structural analyses and functional assays to demonstrate analytical and functional biosimilarity between GP2411 and the reference biologic products approved in the European Union (herein referred to as EU-Prolia and EU-Xgeva) and the United States (herein referred to as US-Prolia and US-Xgeva). US-Prolia and US-Xgeva were considered suitable proxies for Prolia and Xgeva authorized in Canada, because they met the requirements for a non-Canadian reference biologic drug set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The comparative analytical and functional assessments of GP2411, EU-Prolia, US-Prolia, EU-Xgeva, and US-Xgeva, together with the results of a three-way pharmacokinetic and pharmacodynamic comparison of GP2411, US-Xgeva, and EU-Xgeva in healthy adults contributed to establishing a scientific bridge between US-Prolia and EU-Prolia, as well as between US-Xgeva and EU-Xgeva.

The results of the biosimilarity studies demonstrate that GP2411 and Prolia/Xgeva are identical with respect to the primary structure and highly similar in terms of the higher-order structure, purity and impurities, biological activities, and drug product-related attributes. In addition, the data demonstrate that GP2411 and Prolia/Xgeva specifically and selectively bind the target, receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), and confirm that GP2411 and Prolia/Xgeva do not induce antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated phagocytosis, or complement-dependent cytotoxicity. Minor differences in the levels of immunoglobulin G2 A (IgG2A) isoform, charge variants, deamidation, and glycation were observed between GP2411 and Prolia/Xgeva; however, these analytical differences have no impact on the biological activity of denosumab and are unlikely to be clinically meaningful. Slightly higher levels of high-mannose glycans were observed in GP2411 compared to the reference products, but the differences are not expected to be clinically meaningful. Comparative forced degradation studies conducted under different stress conditions generated highly similar degradation profiles for GP2411 and Prolia/Xgeva, thereby further supporting similarity of the products. Taken together, these results suggest that GP2411 is highly similar to Prolia/Xgeva and support the quality requirements for GP2411 to be considered a biosimilar of Prolia/Xgeva.

Characterization of the Drug Substance

Denosumab (GP2411), the medicinal ingredient in Wyost, is a fully human IgG2 monoclonal antibody with affinity and specificity for RANKL. The monoclonal antibody consists of two heavy chains of the gamma 2 subclass (containing 447 amino acids per chain) and two light chains of the kappa subclass (containing 215 amino acids per chain). Its approximate molecular weight is 145 kDa.

Detailed characterization studies were performed to provide assurance that denosumab 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

Wyost drug substance is produced using a mammalian Chinese hamster ovary cell line that is genetically engineered to express the protein.

A single vial of the working cell bank is thawed and used as the starting inoculum. After a series of expansion steps, the cells are transferred to the production bioreactor. The bulk harvest is clarified by centrifugation and depth filtration. Subsequently, the drug substance is purified from the clarified harvest through a series of chromatography steps, viral inactivation and viral filtration steps. This is followed by an ultrafiltration/diafiltration step to concentrate the protein to the target value and bring the protein solution into the formulation buffer. After final filtration and filling into containers, the drug substance is stored at or below -60 °C.

The drug product manufacturing process consists of thawing of the drug substance, manufacture of the excipient dilution solution, manufacture of the bulk drug product solution (including compounding and microbial filtration), followed by sterile filtration, aseptic filling, assembly, visual inspection, labelling, secondary packaging, and storage at 2 °C to 8 °C. None of the non-medicinal ingredients (excipients) in Wyost 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.

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 the intended 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

The release and stability specifications for the drug substance and drug product were appropriately set and justified. Analytical procedures used in the release and stability testing of the drug substance and drug product were validated according to relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Compendial methods were in compliance with pharmacopeia standards.

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.

Wyost 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 shelf life of 36 months at 2 °C to 8 °C for the drug product, when protected from light, is considered acceptable.

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

Facilities and Equipment

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary. During the review, in lieu of the recommended on-site evaluation of the drug substance manufacturing facility, Health Canada considered the United States Food and Drug Administration (FDA)’s inspection observations (cited in the FDA Form 483) and the corresponding corrective and preventive actions.

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. Both sites involved in production 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 raw materials of animal or human origin are used in the manufacturing process of the drug substance. Other materials used 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.

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) demonstrated a high degree of similarity between Wyost and Xgeva. There were no residual uncertainties identified that needed to be resolved by additional comparative non-clinical in vivo pharmacodynamic, pharmacokinetic, and toxicology studies.

For more information, refer to the Wyost 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.

Denosumab (also known as GP2411), the medicinal ingredient in Wyost, was developed by Sandoz Canada Inc. as a biosimilar of the reference denosumab marketed by Amgen Canada Inc. as two drug products which differ only in the denosumab concentrations, container closures, and indications: Prolia (denosumab 60 mg/mL supplied in a prefilled syringe) and Xgeva (denosumab 120 mg/1.7 mL [70 mg/mL] supplied in a single-use vial). Sandoz Canada Inc. submitted to Health Canada the New Drug Submission (NDS) for Wyost, an intended biosimilar of Xgeva, in parallel with the NDS for Jubbonti (Control No. 271806), an intended biosimilar of Prolia.

Comparative Pharmacokinetics and Pharmacodynamics

The pharmacokinetics, pharmacodynamics, safety, and immunogenicity of Wyost, Xgeva authorized in the European Union (EU-Xgeva), and Xgeva authorized in the United States (US-Xgeva) were evaluated in a comparative Phase I, randomized, double-blind, single-dose, three-arm, parallel-group study (CGP24112101). For the purpose of this drug submission, Health Canada considered US-Xgeva a suitable proxy for Xgeva 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 CGP24112101 was conducted in healthy adult male subjects who were randomized in a 1:1:1 ratio to receive GP2411, EU-Xgeva or US-Xgeva as a single subtherapeutic dose of 35 mg, administered subcutaneously on Day 1 of the study. Serum samples collected up to 39 weeks after dosing were available from 493 subjects.

For each of the three pairwise comparisons (Wyost versus EU-Xgeva, Wyost versus US-Xgeva, and EU-Xgeva versus US-Xgeva), the ratio of geometric means for the maximum concentration observed (C_max) and the 90% confidence interval (CI) of the ratio of geometric means for the area under the concentration-time curve (AUC) from the time of dosing to the time of the last quantifiable concentration (AUC_last) were within the comparative pharmacokinetic bioavailability margins of 80.0% to 125.0%, as set out in Health Canada’s Guidance Document: Comparative Bioavailability Standards: Formulations Used for Systemic Effects (2018).

Study CGP24112101 evaluated the pharmacodynamic marker C-terminal telopeptide of type I collagen (CTX), which is a marker of bone resorption. Treatment with denosumab rapidly reduces the serum concentration of CTX within 6 hours of subcutaneous administration by up to 70% from baseline, with reductions of more than 80% from baseline occurring by 3 days after subcutaneous administration of 6 mg to 210 mg of denosumab to postmenopausal women.

Study CGP24112101 demonstrated that the 95% CIs of the ratios (GP2411 versus EU-Xgeva, GP2411 versus US-Xgeva, and EU-Xgeva versus US-Xgeva) of geometric means for the area under the effect-time curve (AUEC) of percent change from baseline in serum concentrations of CTX after a single subcutaneous dose of 35 mg were contained within the prespecified equivalence limits of 80.0% to 125.0%, thereby supporting pharmacodynamic similarity of the products.

Comparative Efficacy, Safety and Immunogenicity

There were no clinically meaningful differences between GP2411 and the reference denosumab product EU-Prolia in terms of pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity in a comparative study (CGP24112301) conducted in postmenopausal women with osteoporosis, one of the target patient populations for Jubbonti and Prolia. In line with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs, an acceptable scientific justification provided by the sponsor substantiated the request for authorization of indications relating to patient populations that were not directly studied in the clinical development program for GP2411. The justification drew upon the demonstrated structural and functional similarity between the biosimilar and the reference drug products, the common mechanism of action of denosumab across all indications, and the comparable pharmacokinetic, safety, and immunogenicity profiles of the reference denosumab (Prolia and Xgeva) across approved indications and patient populations. No additional comparative clinical study was deemed necessary to compare the efficacy of GP2411 and the reference drug products in any other indication held by Prolia or Xgeva.

In Study CGP24112101, there were no new safety signals identified in healthy male subjects who received a single subcutaneous dose of Wyost.

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). The incidence of ADAs reported in Study CGP24112101 was higher in each of the three treatment groups than the overall ADA incidence of less than 1% reported in historical studies with Xgeva. This finding is considered to be due to the high sensitivity of the ADA assay used in Study CGP24112101 (6 ng/mL). All detected ADAs had concentrations within the range of 6 ng/mL to 20 ng/mL. Of note, ADA concentrations higher than 100 ng/mL are considered clinically relevant. Furthermore, the sponsor provided an integrated immunogenicity analysis which explored the impact of immunogenicity findings reported in Study CGP24112101 and Study CGP24112301 on the pharmacokinetic and pharmacodynamic parameters evaluated. In both studies, there was no impact of ADAs or neutralizing ADAs on the pharmacokinetics or safety of GP2411, US-Xgeva, EU-Xgeva, and EU-Prolia.

Overall, the provided data indicate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug in terms of efficacy, safety, and immunogenicity. The safety profile of Wyost is considered to be comparable to that which has been established for the reference biologic drug Xgeva. The known risks of Xgeva have been appropriately addressed in the Wyost Product Monograph, which retains the information presented in the Xgeva Product Monograph, including contraindications, a Serious Warnings and Precautions box, a Warnings and Precautions section, and an Adverse Reactions section.

For more information, refer to the Wyost Product Monograph, approved by Health Canada and available through the Drug Product Database.

Indications

Within this drug submission, the sponsor requested the authorization of Wyost for all of the indications granted for Xgeva, the reference biologic drug.

Similarity between Wyost and Xgeva 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. An acceptable scientific rationale was provided by the sponsor for requesting the authorization of indications that were not directly studied in the clinical development program for Wyost. The rationale addressed the common mechanism of action of denosumab across all indications and the comparable pharmacokinetic, safety, and immunogenicity profiles of denosumab across approved indications and patient populations.

Upon review of the evidence submitted, Wyost was authorized for all of the indications currently held by Xgeva, as follows:

• Reducing the risk of developing skeletal-related events in patients with multiple myeloma and in patients with bone metastases from breast cancer, prostate cancer, non-small cell lung cancer, and other solid tumours.

• Treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

• Treatment of hypercalcemia of malignancy that is refractory to intravenous bisphosphonate.