Summary Basis of Decision for Jubbonti

Jubbonti (denosumab, also known as GP2411) was developed as a biosimilar of Prolia (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 Jubbonti, an intended biosimilar of Prolia, in parallel with the NDS for Wyost (Control No. 267788), an intended biosimilar of Xgeva.

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 (the latter was the only reference drug product used in Study CGP24112301, described in the Clinical Basis for Decision section), 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 Jubbonti, 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

Jubbonti 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 Jubbonti 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.

Jubbonti 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 Jubbonti and Prolia. 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 Jubbonti 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.

A double-blind, randomized, parallel-group, active-controlled study (CGP24112301) compared the pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity of Jubbonti (GP2411) and EU-Prolia in 527 women with postmenopausal osteoporosis. The study had two treatment periods: TP1 (Day 1 to Week 52) and TP2 (Week 52 to Week 78). On Day 1, subjects were randomized in a ratio of 1:1 to receive two doses of Jubbonti (255 patients) or EU-Prolia (257 patients) during TP1. At Week 52 (the beginning of TP2), all subjects in the Jubbonti groups continued treatment with a third dose of Jubbonti, whereas subjects in the EU-Prolia group were rerandomized in a ratio of 1:1 to either continue with a third dose of EU-Prolia or switch to Jubbonti.

Of note, the establishing of a scientific bridge between US-Prolia (the non-Canadian reference drug product that, for the purpose of this submission, Health Canada declared a suitable proxy for Prolia approved in Canada) and EU-Prolia (the only reference drug product used in Study CGP24112301) is elaborated in the Quality Basis for Decision section.

Comparative Pharmacokinetics and Pharmacodynamics

Study CGP24112301 demonstrated similarity between Jubbonti and EU-Prolia in terms of the pharmacokinetic and pharmacodynamic parameters evaluated in women with postmenopausal osteoporosis.

The point estimates of the geometric mean ratios (Jubbonti/EU-Prolia) of the maximum concentration observed (C_max) and the 90% confidence intervals (CIs) of the geometric mean ratios (Jubbonti/EU-Prolia) of the area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC_0-t) after the first dose of 60 mg were within the prespecified comparative bioavailability standards of 80.0% to 125.0%, as set out in the Health Canada’s Guidance Document: Comparative Bioavailability Standards: Formulations Used for Systemic Effects (2018).

Pharmacodynamic markers evaluated were collagen type I C-terminal telopeptide (CTX), a marker of bone resorption, and procollagen type I N-terminal propeptide (PINP), a marker of bone formation. The 95% CI for the ratio (Jubbonti/EU-Prolia) of geometric means for the area under the effect-time curve (AUEC) of percent change from baseline in serum concentrations of CTX after the first dose of 60 mg were contained within the prespecified equivalence limits of 0.80 to 1.25. The CTX and PINP serum concentrations and their associated percent change from baseline by visit were comparable across treatment groups in TP1 and in TP2.

Comparative Efficacy, Safety, and Immunogenicity

The primary efficacy endpoint of Study CGP24112301 was the percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 52. Jubbonti and EU-Prolia showed similar efficacy in the treatment of women with postmenopausal osteoporosis. The 95% CI for the difference between the Jubbonti group and the EU-Prolia group in means of the percent change from baseline in LS-BMD at Week 52 was fully contained within the prespecified equivalence margins of -1.45% to 1.45%. Additional secondary efficacy endpoints were suggestive of similarity.

Jubbonti was well tolerated during the period of up to 78 weeks. The types, incidence, and severity of adverse events were generally consistent with those observed for EU-Prolia.

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). In Study CGP24112301, the incidences of ADAs and neutralizing ADAs were similar in both treatment groups overall. Throughout TP1, the incidence of treatment-emergent ADAs was 35.4% in the Jubbonti group and 40.9% in the EU-Prolia group. Anti-drug antibody titres were very low across treatment groups throughout the study. The incidence of neutralizing ADAs was similar in both treatment groups. Among the patients who developed treatment-emergent ADAs, neutralizing ADAs were found in 1.1% of patients treated with Jubbonti and in 0.4% of patients treated with EU-Prolia.

Compared with TP1, in TP2 there was no increase in the incidence of ADAs or the values of ADA titres. After switching from EU-Prolia to Jubbonti, there was no increase in ADA titres, persistent ADA responses or the incidence of neutralizing ADAs. The detected ADAs did not affect the pharmacodynamic, pharmacokinetic, efficacy, or safety parameters evaluated.

Overall, the results of Study CGP24112301 suggest 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 Jubbonti is considered to be comparable to that which has been established for the reference biologic drug Prolia. The identified safety concerns are appropriately addressed in the Warnings and Precautions section of the Jubbonti Product Monograph, as they are in the Product Monograph for Prolia.

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

Indications

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

Similarity between Jubbonti and Prolia 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 women with postmenopausal osteoporosis. 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 Jubbonti. The rationale referred to 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, Jubbonti was authorized for all of the indications currently held by Prolia, as follows:

• Treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Jubbonti reduces the incidence of vertebral, nonvertebral, and hip fractures.

• Treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.

• Treatment to increase bone mass in men with nonmetastatic prostate cancer receiving androgen-deprivation therapy, who are at high risk for fracture.

• Treatment to increase bone mass in women with nonmetastatic breast cancer receiving adjuvant aromatase-inhibitor therapy, who have low bone mass and are at high risk for fracture.

• Treatment to increase bone mass in women and men at high risk for fracture due to sustained systemic glucocorticoid therapy.

• Treatment to increase bone mass in women and men at high risk for fracture who are starting or have recently started long-term glucocorticoid therapy.