Summary Basis of Decision for Vegzelma

As described above, the review of the quality component of the New Drug Submission for Vegzelma was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Vegzelma was developed as a biosimilar to the reference biologic drug Avastin. For biosimilars, the weight of evidence 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

A biosimilarity assessment was performed using Avastin sourced from the European Union (Avastin‑EU) as the non-Canadian reference biologic drug. Avastin‑EU is considered a suitable proxy for the Canadian-approved Avastin, as it meets all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The results of the biosimilarity assessment demonstrated that Vegzelma is highly similar to Avastin‑EU with respect to primary structure, higher order structure, size heterogeneity, and potency. Minor differences in glycan peaks, post-translational modification for N‑ and C‑terminal residues, and levels of methionine oxidation did not have an impact on potency and are unlikely to be clinically meaningful.

Comparative stability and forced degradation studies under stressed conditions demonstrated that Vegzelma and Avastin‑EU have similar degradation pathways.

Overall, the results of the biosimilarity assessment support the conclusion that Vegzelma is biosimilar to Avastin.

Characterization of the Drug Substance

The drug substance, bevacizumab, is a recombinant humanized immunoglobulin G1 monoclonal antibody directed against vascular endothelial growth factor (VEGF).

Bevacizumab has a molecular weight of approximately 149 kDa and is composed of two heavy chains and two light chains. The fragment antigen-binding region of bevacizumab neutralizes VEGF-mediated activity by binding to and inhibiting the interaction of VEGF with its cognate receptors, VEGFR1 and VEGFR2.

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

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

The Vegzelma drug substance is manufactured in Chinese hamster ovary cells at a commercial scale. The commercial process consists of cell expansion, purification through a series of chromatography steps, viral inactivation and removal, and final filtration ahead of filling into storage bags. All drug substance batches were manufactured at the commercial site and using the commercial process.

Controls of critical steps of the drug substance manufacturing process 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 process is capable of consistently manufacturing drug substance with the desired product quality.

The Vegzelma drug product is a sterile, single-dose, ready-to-use, preservative-free solution, filled in Type I glass vials. Vegzelma is supplied as two presentations for intravenous administration: 100 mg/4 mL and 400 mg/16 mL. Both presentations are manufactured using the same process, with the only differences being fill volume and vial size. The manufacturing process of the drug product consists of thawing and mixing of the drug substance, dilution with formulation buffer to a target protein concentration, bioburden reduction, and sterile filtration followed by filling, stoppering, capping, labelling, and packaging.

Controls of critical steps of the drug product manufacturing process were established during manufacturing development and were based on a risk assessment and process characterization. Process validation, conducted at the commercial scale, demonstrates that the manufacturing process is capable of consistently producing drug product with the desired product quality.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The proposed release and stability specifications for the drug substance were suitably justified. The in-house analytical methods were validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and compendial methods complied with pharmacopeial standards. All drug substance batches met the release and stability acceptance criteria.

The proposed release and stability specifications for the drug product were set based on ICH guidelines, manufacturing experience, and batch release and stability testing. All drug product batches met the release and stability acceptance criteria.

Vegzelma 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 drug product stability studies support the proposed shelf life of 30 months for the 100 mg/mL presentation and 48 months for the 400 mg/mL presentation when the drug product is stored at 2 ºC to 8 ºC.

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 risk assessment scores determined by Health Canada, on-site evaluations were not deemed necessary for the drug substance or drug product manufacturing facilities.

Adventitious Agents Safety Evaluation

Raw materials of biological origin used during the generation of the cell substrate were adequately tested to ensure freedom from adventitious agents. No materials of animal or human origin were used in the drug substance processes or in the final product formulation. Certification letters attesting to these claims were provided by the sponsor.

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.

In the pivotal comparative repeat-dose toxicology study, cynomolgus monkeys were administered Vegzelma (herein referred to as CT-P16) or reference bevacizumab sourced from the European Union (Avastin‑EU). Monkeys were administered doses of 10 or 50 mg/kg body weight two times per week by intravenous injection for four weeks. An additional group of monkeys were administered the vehicle control (0.9% sodium chloride). A few monkeys administered CT-P16 or Avastin‑EU developed red discolored feces which was likely the result of gastrointestinal hemorrhage. In the electrocardiogram assessment, increased PR intervals were noted in male monkeys who were administered either CT-P16 or Avastin‑EU; however, these changes were within the normal range established for cynomolgus monkeys. No injection site reactions or anti-drug antibodies were reported in the study animals. Toxicokinetic parameters were similar between animals who were administered CT-P16 or Avastin‑EU. Overall, no unique toxicities were reported for animals that were given CT-P16 when compared to animals given the reference bevacizumab.

No comparative in vivo pharmacodynamic studies were conducted with CT-P16.

The non-clinical database submitted for Vegzelma was in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The results of the comparative non-clinical studies, as well as the potential risks to humans, have been included in the Vegzelma Product Monograph. In view of the intended use of Vegzelma, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Vegzelma 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.

The authorization of Vegzelma was based primarily on data submitted from the pivotal clinical study CT‑P16 3.1. During the review of these data, no clinically meaningful differences in efficacy, safety, and immunogenicity were observed. These results, in combination with the non-clinical and comparative pharmacokinetic results, support the demonstration of similarity between Vegzelma and the reference biologic drug.

Comparative Pharmacokinetic and Pharmacodynamic Studies

In study CT‑P16 1.1, the similarity of the pharmacokinetic metrics associated with absorption (i.e., maximum serum concentration [C_max], area under the concentration-time curve [AUC] from time zero to infinity [AUC_0-inf], and AUC from time zero to the last quantifiable concentration [AUC_T]) were compared between Vegzelma and the reference bevacizumab sourced from the European Union (Avastin‑EU). Study CT‑P16 1.1 was a randomized, double-blind, three-arm, parallel-group, single-dose (5 mg/kg) Phase I study conducted in healthy Asian male subjects. The specificity of this population reduced the variability associated with the estimates of the pharmacokinetic parameters, and hence refined the precision of the comparison. The sponsor’s analysis used a covariance (analysis of covariance) model with the two covariates: body weight (<70 kg versus ≥70 kg) and study site. Health Canada reached the same conclusion as the sponsor by using a general linear model without covariance. For comparisons of Vegzelma to Avastin‑EU, the 90% confidence intervals [CIs] for the test-to-reference ratios of AUC_T, AUC_0-inf, and C_max were within the pre-specified interval of 80% to 125%. In the context of an intravenous infusion, absorption is not an issue since bioavailability is complete and to the same extent for both drugs. Thus, the analysis can only suggest that the amount of test drug delivered to the patient will be within ±20% (on the log scale) of the amount expected of the reference drug, at a CI of 90%.

Comparative bioavailability studies indicated there are no clinically meaningful differences between the biosimilar and the reference biologic drug.

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

Comparative Clinical Efficacy and Safety

The comparative clinical efficacy and safety of Vegzelma and its reference biologic drug (Avastin‑EU) were evaluated in study CT‑P16 3.1, a global, randomized, double-blind, active-controlled, parallel-group, Phase III study comparing Vegzelma plus chemotherapy (carboplatin and paclitaxel) and Avastin‑EU plus chemotherapy (carboplatin and paclitaxel) in patients with metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC). Patients with NSCLC are considered a sensitive population to detect clinically meaningful differences between treatment groups in the evaluation of the objective response rate (ORR). The study had two distinct phases: an induction treatment period (up to 18 weeks) with bevacizumab plus chemotherapy (carboplatin and paclitaxel), followed by a maintenance treatment period with bevacizumab monotherapy.

Patients were randomized by country, sex, disease status, and Eastern Cooperative Oncology Group (ECOG) performance status. The mean age was 61.4 years, and the majority of patients were male (64.6%) and current or former smokers (68.8%). The inclusion and exclusion criteria were representative of the target NSCLC population. In total, 689 patients were randomized (1:1) to receive 15 mg/kg of either Vegzelma (345 patients) or Avastin‑EU (344 patients) by intravenous infusion on Day 1 of every 3‑week cycle. Both were administered in combination with paclitaxel 200 mg/m² and carboplatin with a target AUC of 6 mg/ml per minute by intravenous infusion on Day 1 of every 3‑week cycle for at least 4 cycles (up to 6 cycles) of the induction treatment period. Eligible patients continued to receive either Vegzelma or Avastin‑EU every 3 weeks as monotherapy until disease progression or unacceptable toxicity occurred. Tumour assessments were conducted every 2 cycles (6 weeks), as assessed by independent central review and according to the Response Evaluation Criteria in Solid Tumours (RECIST) guidelines (version 1.1) in the intent-to-treat population.

The primary endpoint was ORR at the end of the induction study period (18 weeks of treatment). The reported ORR was 42.4% in the Vegzelma arm and 42.1% in the Avastin‑EU arm. The risk ratio of ORR for the Vegzelma arm to Avastin‑EU arm was 1.01 (95% CI: 0.85, 1.20), which was fully contained within the pre-specified acceptance interval of 0.74 to 1.36. Tipping point analyses conducted under missing-not-at-random scenarios supported the robustness of the primary analysis.

The analyses of secondary efficacy endpoints (progression-free survival and overall survival) and respective comparative analyses were supportive of the results of the primary comparative efficacy analysis.

No clinically meaningful differences in the safety profile of Vegzelma and Avastin‑EU were observed. The majority of patients (96.2% in the Vegzelma arm and 92.4 % in the Avastin‑EU arm) reported at least one treatment emergent adverse event (TEAE) throughout the whole study period. The incidences of grade 3 or higher TEAEs, TEAEs leading to study drug discontinuation, serious TEAEs, and TEAEs leading to death were comparable between the treatment arms. Numerical differences in the incidences of blood, lymphatics, and nervous system events were noted; however, these imbalances were not considered clinically meaningful. Overall, the safety profile observed in this study was consistent with the known profile for the reference biologic drug.

As with Avastin, appropriate warnings and precautions are in place in the approved Vegzelma Product Monograph to address the identified safety concerns, including a Serious Warnings and Precautions box describing the risk of eye disorders, gastrointestinal perforations, wound healing complications, and hemorrhage.

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

Comparative Immunogenicity

The comparative immunogenicity of Vegzelma and the reference biologic drug (Avastin‑EU) were also evaluated in study CT-P16 3.1. The overall incidence of post-dose anti-drug antibodies was similar between the Vegzelma arm (14.2%) and the Avastin‑EU arm (16.0%). The incidence of anti-drug antibodies was usually transient in nature, with most positive anti-drug antibody test results occurring at one or two time points. Most of these patients had negative neutralizing antibody test results. The incidence of neutralizing antibodies was comparable between the Vegzelma arm (14.3%) and the Avastin‑EU arm (12.7%). There was no clear correlation between anti-drug antibody status and ORR or TEAEs, thus no conclusions can be made regarding anti-drug antibody status on the safety or efficacy of Vegzelma.

Indications

Similarity between Vegzelma and the reference biologic drug, Avastin, was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication.

Within this drug submission, the sponsor requested the authorization of Vegzelma for all of the indications that are currently authorized for Avastin. The indications have been authorized on the basis of demonstrated similarity between Vegzelma and the reference biologic drug, in structural, analytical, functional, non-clinical, pharmacokinetic, pharmacodynamic, and clinical comparisons.

Based on the evidence submitted, Vegzelma has been authorized for the same indications currently held by the reference drug, Avastin, as follows:

Metastatic Colorectal Cancer (mCRC)

Vegzelma in combination with fluoropyrimidine-based chemotherapy is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.

Consideration should be given to current standard of care guidelines for colorectal cancer.

See the Drug-Drug Interactions section of the Vegzelma Product Monograph for further information on the use of Vegzelma in combination with irinotecan.

Please refer to the Product Monographs for irinotecan, 5‑fluorouracil, and leucovorin for additional information on these products, and specifically the Dosage and Administration sections for guidance on dose adjustments.

Locally Advanced, Metastatic or Recurrent Non-Small Cell Lung Cancer (NSCLC)

Vegzelma, in combination with a carboplatin/paclitaxel chemotherapy regimen, is indicated for treatment of patients with unresectable advanced, metastatic, or recurrent non-squamous NSCLC.

Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

Vegzelma, in combination with carboplatin and gemcitabine, is indicated for the treatment of patients with first recurrence platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer. These patients should not have received prior vascular endothelial growth factor (VEGF)-targeted therapy including Vegzelma.

The effectiveness of bevacizumab in platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer is based on an improvement of progression-free survival in patients who had first recurrence after 6 months of platinum-based chemotherapy. No overall survival benefit was demonstrated with bevacizumab.

Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

Vegzelma in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin is indicated for the treatment of patients with recurrent, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens. These patients should not have received prior VEGF-targeted therapy including Vegzelma.

The effectiveness of bevacizumab in platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer is based on a study in patients with disease progression within less than 6 months from the most recent platinum-based chemotherapy, with a minimum of four platinum therapy cycles completed. A statistically significant improvement in progression-free survival was seen. No overall survival benefit was demonstrated with bevacizumab.

Malignant Glioma (World Health Organization Grade IV) - Glioblastoma

Vegzelma, in combination with lomustine, is indicated for the treatment of patients with glioblastoma after relapse or disease progression, following prior therapy.

The efficacy of bevacizumab in relapsed glioblastoma is based on an improvement in progression-free survival, while an improvement in overall survival was not demonstrated in study EORTC 26101.