Summary Basis of Decision for Adheroza

Adheroza (trastuzumab, referred to as HLX02) was developed as a biosimilar of Herceptin (trastuzumab), the reference biologic drug. The weight of evidence of similarity between a proposed 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

Comparative structural and functional studies were conducted to compare the physicochemical and biological properties of Adheroza and Herceptin authorized in the European Union (herein referred to as EU-Herceptin). For the purpose of this drug submission, Health Canada considered EU-Herceptin a suitable proxy for Herceptin 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.

The results of the biosimilarity studies demonstrate that the primary and higher-order structures of Adheroza and EU-Herceptin are highly similar and consistent with the expected results for an immunoglobulin G (IgG) molecule. The purity profiles were also highly similar between Adheroza and the reference drug, and there were no new impurities detected in Adheroza. The analysis of N-linked glycosylation demonstrated similarity in the type and abundance of the glycoform variants. Minor differences observed in sialylation and afucosylation are not expected to be clinically relevant, which is further supported by the results of the biological activity studies. Comparison of functional and receptor-binding assays demonstrated comparable biological activity and immunological characteristics between Adheroza and EU-Herceptin. Highly similar results obtained from the human epidermal growth factor receptor 2 (HER2)-binding, anti-proliferation, and antibody-dependent cell-mediated cytotoxicity assays support a comparable mechanism of action. Forced degradation studies indicate that Adheroza and EU-Herceptin have highly similar degradation pathways.

Taken together, these results suggest that Adheroza is highly similar to EU-Herceptin and support the quality requirements for Adheroza to be considered a biosimilar of Herceptin.

Characterization of the Drug Substance

The medicinal ingredient in Adheroza, trastuzumab (HLX02), is a humanized immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is directed against the extracellular domain of HER2. Trastuzumab binds to the HER2 protein on the surface of cancer cells and inhibits their proliferation and survival.

Detailed characterization studies were performed to provide assurance that trastuzumab (HLX02) 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. In addition, 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. The risk of the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes is considered negligible or low; therefore, no confirmatory testing is required.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Adheroza drug substance is produced using a mammalian expression system (a Chinese hamster ovary [CHO] cell line that is genetically engineered to express the protein).

The upstream manufacturing process of the drug substance includes thawing of a single vial of the working cell bank, a series of cell expansion steps, cell culture in a production bioreactor, and depth filtration of the cell culture harvest. In the downstream process, the protein in the clarified cell culture fluid is purified through chromatography steps, virus inactivation, and virus filtration. An ultrafiltration/diafiltration step is used to concentrate the protein and place it in the formulation buffer. The formulated drug substance is then subjected to bioburden reduction filtration, filled into containers, and stored at -40±5 °C.

The drug product manufacturing process consists of thawing, mixing, and sterilizing filtration of the drug substance, followed by filling into glass vials, lyophilization, capping, visual inspection, and labelling. The lyophilized drug product is stored at 2 °C to 8 °C.

Adheroza is provided in two strengths: 150 mg of trastuzumab per vial and 420 mg of trastuzumab per vial. None of the non-medicinal ingredients (excipients) found in Adheroza are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of trastuzumab with the excipients is supported by the stability data provided.

The control strategy for the drug substance and drug product manufacturing processes was established based on risk assessments, process characterization studies, and historical data. Operating ranges of the process parameters and acceptance criteria of the in-process controls were appropriately justified. 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 methods used in the release and stability testing of the drug substance and drug product were successfully validated according to relevant guidelines.

Adheroza 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 48 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

A thorough review of the documentation and the associated information from the United States Food and Drug Administration and the European Medicines Agency suggested that an on-site evaluation of the drug substance and drug product manufacturing sites or other risk mitigation strategies were not warranted to support the review of the submission.

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

Adequate control measures are incorporated in the manufacturing process of Adheroza to prevent contamination and maintain microbial control.

No raw materials of human or animal origin are directly used in the manufacturing process other than the CHO-derived cell line. Relevant information was provided to demonstrate the safety of animal-derived materials used during the cell line development with respect to the risks of introduction of transmissible spongiform encephalopathy agents.

Extensive testing of the master cell bank, working cell bank, and unprocessed bulk is conducted to confirm that the cell substrate and starting materials for the drug substance manufacturing process are free of detectable adventitious agents (bacteria, fungi, mycoplasma, and viruses). The cell culture process includes in-process tests to monitor for bioburden, endotoxins, mycoplasma, and viruses. Scaled-down viral clearance studies demonstrate that the downstream purification process is capable of inactivating or removing model viruses with a broad range of biochemical and biophysical properties.

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.

Nevertheless, the sponsor conducted comparative in vivo pharmacodynamic, pharmacokinetic, and toxicity studies to demonstrate the similarity between Adheroza (trastuzumab, also referred to as HLX02) and Herceptin.

Trastuzumab (HLX02) and Herceptin exhibited similar inhibitory effects on transplanted tumours (in xenograft animal models), showed comparable cross-reactivity in animal and human tissues, and had similar pharmacokinetic and toxicokinetic profiles.

Overall, the non-clinical findings are supportive of similarity between Adheroza and Herceptin.

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 Adheroza, Herceptin authorized in the European Union (herein referred to as EU-Herceptin), and Herceptin authorized in the United States (herein referred to as US-Herceptin) was demonstrated in the Phase I study HLX02-HV01 (Part 2) in healthy male subjects. For the purpose of this drug submission, Health Canada considered EU-Herceptin a suitable proxy for Herceptin 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.

In Part 2 of the HLX02-HV01 study, 111 healthy male subjects were randomized to receive a single dose of 6 mg/kg of the assigned drug, administered by intravenous infusion for 90 minutes. For each of the three pairwise comparisons (Adheroza versus US-Herceptin, Adheroza versus EU-Herceptin, and US-Herceptin versus EU-Herceptin), 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). Specifically, for the pharmacokinetic comparison of Adheroza versus EU-Herceptin, the ratio of geometric means for the C_max was 97.8% and the 90% CI of the relative mean for the AUC_last was 80.4% to 91.1%.

Comparative Efficacy

The comparative efficacy of Adheroza and EU-Herceptin was evaluated in a Phase III, double-blind, randomized, multicentre study (HLX02-BC01) conducted in patients with human epidermal growth factor receptor 2 (HER2)-positive, recurrent or previously untreated metastatic breast cancer. Patients were randomized (1:1) to receive Adheroza (324 patients) or EU-Herceptin (325 patients) in combination with docetaxel. Adheroza or EU-Herceptin was administered intravenously as a loading dose of 8 mg/kg on Day 1, Cycle 1, followed by a dose of 6 mg/kg once every three weeks for up to a maximum of 12 months. Stratification of patients was based on the cancer hormone receptor status (estrogen receptor and progesterone receptor status), prior neoadjuvant or adjuvant therapy with Herceptin, and ethnicity (Asian and non-Asian).

The primary efficacy endpoint of the study was the overall response rate up to Week 24 (ORR_Wk24), calculated as the proportion of patients with a best response of complete response or partial response from first assessment up to Week 24. The ORR_Wk24 was determined based on a central imaging review of tumour response according to the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. Equivalence with respect to the primary efficacy endpoint could be declared if the two-sided 95% CI of the risk difference in the ORR_Wk24 between the two treatments (Adheroza treatment group minus EU-Herceptin treatment group) was fully contained within the prespecified equivalence margins of -13.5% to 13.5%.

In the intention-to-treat population, the ORR_Wk24 was 71.3% in the Adheroza treatment group and 71.4% in the Herceptin treatment group, and the risk difference for the ORR_Wk24 was -0.1% (95% CI: -7.0%, 6.9%). The 95% CI of the risk difference for the ORR_Wk24 was fully contained within the prespecified equivalence margins of -13.5% to 13.5%. Supportive results were provided by a supplementary post hoc analysis, which showed that the risk ratio for ORR_Wk24 between the two groups (Adheroza treatment group versus EU-Herceptin treatment group) was 0.999 and its 95% CI of 0.91 to 1.10 was fully contained within the predefined equivalence boundaries of 0.808 to 1.237.

Comparative Safety and Immunogenicity

Comparative safety and immunogenicity data for Adheroza and Herceptin were provided from the Phase III study (HLX02-BC01) in patients with HER2-positive, recurrent or previously untreated metastatic breast cancer and the Phase I study (HLX02-HV01) in healthy subjects.

In both studies, there were no new safety signals identified in the Adheroza treatment groups compared with the known safety profile of Herceptin. Overall, no clinically meaningful differences in the safety profile were observed between Adheroza and Herceptin.

In the Phase I study, no anti-drug antibodies (ADAs) were detected in any treatment group following a single intravenous dose of the assigned drug (Adheroza, EU-Herceptin, or US-Herceptin). In the Phase III study, two (0.6%) patients in each treatment arm (Adheroza and EU-Herceptin), developed treatment-emergent ADAs and neutralizing ADAs, which was consistent with the known low immunogenicity of Herceptin. There were no clinically meaningful differences between Adheroza and Herceptin in terms of immunogenicity.

Based on the provided data, the safety and immunogenicity profiles of Adheroza are considered to be comparable to those of the reference biologic drug Herceptin. As with Herceptin, appropriate warnings and precautions are in place in the Adheroza Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box has been included in the Product Monograph for Adheroza, as is found in the Product Monograph for Herceptin. It highlights the risk of medication errors between Adheroza (trastuzumab) and Kadcyla (trastuzumab emtansine) and the risks of cardiotoxicity, serious infusion reactions and pulmonary toxicity, and embryo-fetal toxicity. The Adverse Reactions section of the Adheroza Product Monograph is based on the clinical experience with Herceptin.

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

Indications

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

Similarity between Adheroza and Herceptin 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.

Considering the totality of evidence submitted, including comparative structural and functional, non-clinical, and clinical studies, Health Canada authorized Adheroza for the same indications held by Herceptin (including relevant caveat statements), as follows:

Early Breast Cancer

Adheroza (trastuzumab) is indicated for the treatment of patients with early-stage breast cancer with Eastern Cooperative Oncology Group (ECOG) 0-1 status, whose tumours overexpress HER2,

• following surgery and after chemotherapy,

• following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel,

• in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

For detailed information on the inclusion criteria for the clinical trials of trastuzumab in early breast cancer according to the TNM (Tumour, Node, Metastasis) classification system, see Part II: 14.1 Clinical Trials by Indication section of the Adheroza Product Monograph.

Based on the analysis of the HERA trial, the benefit of the adjuvant treatment with trastuzumab for low-risk patients not given adjuvant chemotherapy is unknown.

The comparative efficacy and safety between different chemotherapy regimens (i.e., concurrent versus sequential, anthracycline containing versus non-anthracycline containing) were not studied.

Metastatic Breast Cancer

Adheroza is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2.

The benefits of treatment with Adheroza in patients who do not overexpress HER2 (HER2 overexpression 0 as defined by a validated immunohistochemical [IHC] assay) or who exhibit lower-level overexpression (HER2 overexpression 1+ as defined by a validated IHC assay and the subgroup of patients with HER2 overexpression 2+ as defined by a validated IHC assay that corresponds to 1+ scoring by the investigative clinical trial assay) are unclear (see Warnings and Precautions: Selection of Patients / Diagnostic Tests section of the Adheroza Product Monograph).

Adheroza can be used in combination with pertuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. For information on the use of Adheroza in combination with pertuzumab and docetaxel, consult the Product Monograph for pertuzumab.

Metastatic Gastric Cancer

Adheroza in combination with capecitabine or intravenous 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who have not received prior anticancer treatment for their metastatic disease.

Adheroza should only be administered to patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by IHC2+ confirmed by fluorescent in situ hybridization (FISH+), or IHC3+ as determined by an accurate and validated assay.