Summary Basis of Decision for Stoboclo

Stoboclo (denosumab, also known as CT-P41) was developed as a biosimilar of the reference biologic drug, Prolia. 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

The drug substance, denosumab (CT-P41), was developed as a biosimilar of the reference denosumab marketed by Amgen Canada Inc. as two drug products which differ only in the denosumab strength, container closure, and indication: Prolia (denosumab 60 mg/mL supplied in a pre-filled syringe) and Xgeva (denosumab 120 mg/1.7 mL [70 mg/mL] supplied in a single-use vial). Celltrion Inc. submitted to Health Canada the New Drug Submission (NDS) for Stoboclo, an intended biosimilar of Prolia, in parallel with the NDS for Osenvelt (Control No. 278930), an intended biosimilar of Xgeva.

Comprehensive biosimilarity assessment studies using side-by-side and independent testing demonstrated analytical and functional biosimilarity between CT-P41 and the reference biologic products authorized in the United States (herein referred to as US-Prolia and US-Xgeva). The biosimilarity assessment primarily comprised a two-way assessment of CT-P41 (60 mg/mL in a pre-filled syringe) and US-Prolia. A second supportive two-way assessment compared CT-P41 (120 mg/1.7 mL in a single-use vial) and US-Xgeva. For the purpose of this drug submission, Health Canada considers US-Xgeva and US-Prolia as suitable proxies for the Canadian reference product, because they met the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

The results of the biosimilarity assessment demonstrate that CT-P41 is highly similar to US-Xgeva and US-Prolia with respect to sequence, higher order structure, glycans, charge and size variants, post translational modifications, potency, target binding, thermal stability, and impurity and degradation profiles. The protein content for each CT-P41 drug product (60 mg/mL in a pre-filled syringe and 120 mg/1.7 mL in a single-use vial) corresponds to US-Prolia and US-Xgeva, respectively. Minor differences observed in some post-translational modifications and in glycosylation profiles are not expected to have any impact on the clinical efficacy, pharmacokinetics, or safety of Stoboclo, and do not preclude a determination of biosimilarity.

Characterization of the Drug Substance

Denosumab (CT-P41) is a fully human immunoglobulin G2 (IgG2) monoclonal antibody with affinity and specificity for the receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL). The monoclonal antibody heterotetramer 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 144 kDa.

Detailed characterization studies were performed to provide assurance that the drug substance consistently exhibits the desired characteristic structure and biological activity.

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

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 is produced using a mammalian Chinese hamster ovary cell line that is genetically engineered to express the protein. A single vial of working cell bank is thawed and expanded, then used to inoculate the fed-batch production bioreactor. This is followed by depth filtration, column chromatography, viral inactivation and removal, and ultrafiltration/diafiltration. Next, the drug substance is formulated and filtered prior to filling, then stored frozen.

The drug product is formulated for subcutaneous administration as a sterile liquid solution and is available in a pre-filled syringe. The manufacturing process consists of drug substance pooling, mixing, and dilution to target protein concentration with formulation buffer, bioburden reduction filtration, sterile filtration, aseptic filling, and visual inspection. The syringes are then labelled, assembled with a plunger, finger flange, and safety guard, and packaged in a carton at room temperature. 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 denosumab with the excipients is supported by the stability data provided.

Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review. The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

A comprehensive control strategy for the drug substance and drug product has been developed which includes control of materials, in-process controls of product quality attributes, control of process parameters, release and stability specifications, and facility and equipment controls. The in-process and specification acceptance criteria were suitably justified and ensure the safety, identity, strength, potency and purity of the drug substance and drug product. The in-house analytical methods were validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and compendial methods complied with pharmacopeia standards. A two-tier reference standard program has been established, and the in-house analytical methods were appropriately validated.

Stoboclo 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 proposed 48-month shelf life at 2 °C to 8 °C for Stoboclo is considered acceptable, with a single short-term storage period of up to 30 days when stored at 25°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

Based on a risk assessment score determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

Adventitious Agents Safety Evaluation

The drug substance 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) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Raw materials of animal and recombinant deoxyribonucleic acid origin used in the manufacturing process are adequately tested to ensure absence of adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.

Denosumab (also known as CT-P41) is the medicinal ingredient in Stoboclo. The non-clinical program consists of a 4-week repeat dose study (Study 1878-035) where CT-P41, Prolia authorized in the United States (US-Prolia), and vehicle control were administered to cynomolgus monkeys (3 males and 3 females per group). The study demonstrated that 4 weekly subcutaneous injections of 10 mg/kg of CT-P41 or US-Prolia were well tolerated and resulted in no apparent differences in toxicokinetic profiles. Test article-related changes were limited to an increased incidence of watery feces. However, this was not considered to be adverse as there was no impact on body weight. Hypocalcemia was reported in 2 out of 6 monkeys from each of the CT-P41 and US-Prolia groups, consistent with the mechanism of action of denosumab. However, there were no associated histopathological changes or clinical signs (weakness or muscle twitching, spasms or seizures) observed. The presence of anti-drug antibodies was not detected in any of the animals treated with CT-P41 or US-Prolia.

The non-clinical database submitted for Stoboclo was 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.

In view of the intended use of Stoboclo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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 CT-P41), the medicinal ingredient in Stoboclo, was developed by Celltrion Inc. as a biosimilar of the reference denosumab marketed by Amgen Canada Inc. as two drug products which differ only in the denosumab strength, container closure, and indication: Prolia (denosumab 60 mg/mL supplied in a pre-filled syringe) and Xgeva (denosumab 120 mg/1.7 mL [70 mg/mL] supplied in a single-use vial). Celltrion Inc. submitted to Health Canada the New Drug Submission (NDS) for Stoboclo, an intended biosimilar of Prolia in parallel with the NDS for Osenvelt (Control No. 278930), an intended biosimilar of Xgeva.

For the purpose of this drug submission, Health Canada considers Prolia authorized in the United States (US-Prolia) and Xgeva authorized in the United States (US-Xgeva) as suitable proxies for the Canadian reference product, because they met the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Comparative Pharmacokinetics and Pharmacodynamics

The pivotal, Phase I, randomized, double-blind, two-arm, parallel-group, single-dose study (CT-P41 1.2) was conducted in healthy male subjects to evaluate the pharmacokinetics, pharmacodynamics, immunogenicity, and safety of CT-P41 and US-Prolia.

Study CT-P41 1.2 was powered to demonstrate pharmacokinetic similarity between CT-P41 and US-Prolia with respect to exposure as measured by area under the concentration versus time curve to the time of the last quantifiable concentration (AUC_0-last) and maximum concentration (C_max), and their associated 90% confidence intervals (CIs). The ratios of geometric means between CT-P41 and US-Prolia and their associated 90% CIs for AUC_0-last and C_max were 106.9% (90% CI: 99.9% to 114.3%) and 101.1% (90% CI: 95.2% to 107.3%), respectively. These results confirmed the comparative bioavailability between CT-P41 and reference product, as the estimated pharmacokinetic parameters fell within the comparative pharmacokinetic bioavailability margins of 80.0% to 125.0%.

Additionally, the pharmacodynamic similarity between CT-P41 and US-Prolia was investigated by comparing the area under the effect curve (AUEC) response profiles (% change from baseline) and their associated 95% CIs for the biomarkers serum type 1 C-telopeptide (s-CTX) and procollagen type 1 N-terminal propeptide (P1NP). The ratios of geometric means between CT-P41 and US-Prolia and their associated 95% CIs for the AUEC of s-CTX and P1NP were 101.4% (95% CI: 97.2% to 105.7%) and 93.4% (95% CI: 83.6% to 104.3%), respectively. These results confirmed the comparative pharmacodynamics between CT-P41 and the reference product.

The incidence of anti-drug antibodies was similar between the two arms and neutralizing antibodies were low in both arms of the study, which therefore precluded definitive conclusions from being made on the impact of immunogenicity on the pharmacokinetics or pharmacodynamics of CT-P41. However, based on the limited data available, there did not appear to be any discernible impacts of the presence of anti-drug antibodies or neutralizing antibodies on the primary pharmacokinetic and pharmacodynamic parameters of CT-P41. Thus it is also unlikely that immunogenicity will have a meaningful clinical impact. Lastly, the occurrence of treatment emergent adverse events and other safety assessments between CT-P41 and US-Prolia were comparable, suggesting a similar safety profile with no new safety findings reported.

Comparative Clinical Efficacy and Safety

There were no clinically meaningful differences between CT-P41 and US-Prolia in terms of pharmacokinetics, pharmacodynamics, efficacy, and safety in a comparative study (CT-P41 3.1) conducted in postmenopausal women with osteoporosis.

Study CT-P41 3.1 met the outcome criteria for the primary efficacy endpoint as the 95% CI of the difference in the mean percent change from baseline in bone mineral density for the lumbar spine, measured by dual-energy X-ray absorptiometry, between groups fell within an equivalence margin of ±1.503% (-0.139 [95% CI: -0.826 to 0.548]). Additionally, the means (standard deviation [SD]) for the AUEC of s-CTX over the initial 6 months were similar between CT-P41 (14,603.57 [2,869.79] day*% inhibition) and US-Prolia (14,871.27 [2,158.18] day*% inhibition). The geometric mean AUEC of s-CTX over the initial 6 months was also similar for CT-P41 (14,059.26 day*% inhibition) and US-Prolia (14,658.90 day*% inhibition). The mean (SD) AUEC of P1NP over the initial 6 months were similar between CT-P41 (9,178.42 [2,601.08] day*% inhibition) and US-Prolia (9,307.54 [2,207.93] day*% inhibition), but the geometric mean AUEC of P1NP for US-Prolia (8,856.24 day*% inhibition) was slightly higher than CT-P41 (7,669.45 day*% inhibition), the differences of which were attributed to artifact by the sponsor. Given that the differences in the geometric mean AUEC for P1NP are about 10%, it is not considered to be clinically meaningful.

Furthermore, the pharmacokinetics of the CT-P41 and US-Prolia arms were generally similar in the target population of postmenopausal women with osteoporosis. These results support the comparability of the primary clinical outcomes and the pharmacodynamic outcomes reported by the sponsor.

In study CT-P41 3.1, no new safety signals were identified in postmenopausal women with osteoporosis and the overall safety profile of CT-P41was consistent with the known safety profile of the reference biologic drug Prolia. The identified safety concerns are appropriately addressed in the Warnings and Precautions section of the Product Monograph for Stoboclo, as they are in the Product Monograph for Prolia.

Indications

Stoboclo is considered to be biosimilar to Prolia, the reference biologic drug. Prolia is authorized and marketed in Canada for several indications and clinical uses.

Similarity between Stoboclo 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 submitted 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 Stoboclo. The rationale was based on the totality of evidence from analytical and functional characterization studies; the similarity in the pathophysiological progression of diseases treated by denosumab; and the mechanism of action of denosumab, which is similar across all authorized indications. No clinically meaningful differences in terms of pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity were observed between Stoboclo and the reference biologic drug.

Upon review of the evidence submitted, Stoboclo 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, Stoboclo 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.