Summary Basis of Decision for Ogivri

The demonstration of similarity between the biosimilar and its reference biologic drug derived from comparative structural, functional, non-clinical and clinical studies enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The degree of similarity at the quality level determines 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 Pharmacokinetic and Pharmacodynamic Studies

Trastuzumab, the medicinal ingredient in Ogivri and Herceptin, is a humanized recombinant immunoglobulin G1 (IgG1) antibody directed against the human epidermal growth factor receptor 2 (HER2). The HER2 protein, which promotes cell growth, is overexpressed in approximately 25%-30% of cases of primary breast cancer. The binding of trastuzumab to HER2 inhibits ligand-independent HER2 signalling, which in turn inhibits the proliferation of cells overexpressing HER2. Additionally, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC).

Two Phase I studies were conducted to compare the pharmacokinetics and bioavailability of Ogivri to those of EU-Herceptin and US-Herceptin. The subjects in both studies were healthy male volunteers. In both studies, each subject received a single 8 mg/kg intravenous infusion of his assigned drug.

MYL-Her-1001 was a two-way crossover study comparing Ogivri to EU-Herceptin, with 22 patients initially randomized and dosed, and 19 patients completing the study. MYL-Her-1002 had a three-way parallel design, in which 42 subjects received Ogivri, 41 subjects received EU-Herceptin, and 37 subjects received US-Herceptin.

The outcomes of both studies indicated that following intravenous administration, systemic exposure to trastuzumab from Ogivri, EU-Herceptin, and US-Herceptin are within the acceptable clinical limits of ±20%. The pharmacokinetic profile of Ogivri is consistent with those of EU-Herceptin and US-Herceptin based on the results of both studies.

The 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 Ogivri Product Monograph, approved by Health Canada and available through the Drug Product Database.

Comparative Clinical Efficacy and Safety

The comparative study MYL-Her-3001 compared Ogivri to its reference product, Herceptin, with respect to clinical efficacy and safety. EU-Herceptin was the official reference biologic drugused in this study, and is hereafter referred to as Herceptin. Additionally, the study BM200-CT3-001-11 was filed as a supportive study. Immunogenicity was also examined, and is addressed in the Comparative Immunogenicity section.

MYL-Her-3001

Study MYL-Her-3001 was conducted in female patients with untreated HER2-positive metastatic breast cancer. Five hundred patients were initially randomized in the study, and 493 patients were treated.

The study was organized into two parts. In Part 1, patients were randomized in a 1:1 ratio to be treated with either Ogivri or Herceptin, and received an initial loading dose of 8 mg/kg of their assigned treatment by intravenous infusion. Maintenance doses of 6 mg/kg were administered every three weeks, along with a taxane (either 80 mg/m² paclitaxel every week, or 75 mg/m² docetaxel every three weeks). Treatment continued for a minimum of eight cycles (24 weeks). Patients who received a minimum of eight cycles of treatment and had stable disease, a partial response, or a complete response following the treatment in Part 1 (as opposed to progressive disease) continued on to Part 2. These patients received 6 mg/kg of either Ogivri or Herceptin as a single agent, every three weeks. Treatment continued until disease progression, unacceptable toxicity, or death. Randomization was stratified based on the timing of tumour progression (≥2 years or <2 years), estrogen receptor/progesterone receptor (ER/PgR) status, and the type of taxane received (paclitaxel or docetaxel).

The primary efficacy endpoint was objective response rate (ORR), determined independently by central review at Week 24 according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1). In the intent-to-treat population and using a non-responder approach, the ORR was determined to be 69.6% in the Ogivri treatment arm and 64.0% in the Herceptin treatment arm. The risk ratio of the ORR was 1.09 (95% confidence interval [CI]: 0.954, 1.237). The two-sided 95% CI was contained within the pre-defined interval of 0.81 to 1.24.

The safety analysis was based on data from 247 patients in the Ogivri treatment arm, 246 patients in the Herceptin treatment arm, and 42 patients who received a second-line treatment for metastatic breast cancer. At least one treatment-emergent adverse event (TEAE) was reported in 98.0% of Ogivri-treated patients, and in 97.2% of Herceptin-treated patients. The most common TEAEs reported in either treatment arm (in ≥15% of patients) were anemia, leukopenia, neutropenia, diarrhea, nausea, asthenia, fatigue, peripheral edema, and alopecia. The proportions of patients with Grade ≥3 TEAEs and serious TEAEs were comparable between the two treatment arms. Grade ≥3 TEAEs were reported in 65.6% of patients in the Ogivri treatment arm, and in 65.9% of patients in the Herceptin treatment arm. Serious TEAEs were reported in 39.3% of patients in the Ogivri treatment arm, and in 37.0% of patients in the Herceptin treatment arm. However, the proportion of TEAEs determined to be related to treatment was higher in the Ogivri treatment arm (41.7%) than in the Herceptin treatment arm (35.8%). Patients with TEAEs leading to discontinuation of trastuzumab were similar in both arms, 4% for Ogivri and 6.5% for Herceptin. Cardiac disorders were more frequently reported in the Ogivri treatment arm (11.3%) than in the Herceptin treatment arm (8.5%), including cases of cardiac failure (2.4% and 0.4% for Ogivri and Herceptin treatment arms, respectively). The values reported in the safety analysis are within the range of historical data with trastuzumab, and these differences between the two treatment arms are not expected to be clinically meaningful.

The safety data obtained in Parts 1 and 2 of the study were consistent, and the safety profiles of the two products are considered comparable.

BM200-CT3-001-11

The supportive study BM200-CT3-001-11 was a double-blind, randomized study that compared Herceptin and Bmab-200. Bmab-200 contains the same medicinal ingredient as Ogivri and Herceptin (trastuzumab), but has a different formulation than the one intended for commercial use. Both Herceptin and Bmab-200 were administered in combination with docetaxel to patients with HER2-positive metastatic breast cancer. In both treatment arms, patients received an 8 mg/kg loading dose of their assigned treatment (either Herceptin or Bmab-200), followed by maintenance doses of 6 mg/kg administered every three weeks. Treatment continued for eight cycles, for a total for 24 weeks.

The results of the supportive study were of limited value due to the use of a different product formulation and differences in the study design, endpoints, and objectives compared to the study MYL-Her-3001.

The safety analysis included data from 134 patients. The safety endpoints were comparable between the Bmab-200 and Herceptin treatment arms, and no new signals were identified for Bmab-200.

As with Herceptin, one of the main safety concerns for Ogivri is the risk of medication error. Trastuzumab, the medicinal ingredient in both Ogivri and Herceptin, may be confused with trastuzumab emtansine. Patients and healthcare providers are advised to check the vial labels to confirm that the drug is trastuzumab (and not trastuzumab emtansine). Ogivri and Herceptin should also be prescribed using both the trade name and the non-proprietary name. The other major safety concerns for Ogivri (and Herceptin) are cardiotoxicity, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity. These risks are addressed in a Serious Warnings and Precautions box in the Ogivri and Herceptin Product Monographs.

Overall, the safety profile of Ogivri is considered to be comparable to that of the reference biologic drug, Herceptin.

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

Comparative Immunogenicity

Treatment with any therapeutic protein is naturally accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs]). The immunogenicity of Ogivri was compared to that of Herceptin in Study MYL-Her-3001, and also examined in Study BM200-CT3-001-11. Both studies are described in detail in the Comparative Clinical Efficacy and Safety section.

At least one binding anti-drug antibody (ADA) was detected in nine patients (3.9%) in the Ogivri treatment arm and ten patients (4.4%) in the Herceptin treatment arm, regardless of baseline results. Neutralizing antibodies were detected in one patient (0.4%) in the Ogivri treatment arm, and in three patients (1.3%) in the Herceptin treatment arm. During Part 2 of the study, in which Ogivri and Herceptin were administered as single agents, positive ADAs were detected in three patients treated with Ogivri and in one patient treated with Herceptin. No clinically meaningful differences in immunogenicity were identified in this study between the biosimilar and the reference biologic drug.

The immunogenicity endpoints examined in the supportive study, BM200-CT3-001-11, were comparable between the Bmab-200 and Herceptin treatment arms.

Indications

Ogivri is considered to be biosimilar to Herceptin, the reference biologic drug. Herceptin is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Herceptin is authorized are early breast cancer, metastatic breast cancer, and metastatic gastric cancer.

Within this drug submission, the sponsor requested the authorization of Ogivri for all but one of the indications that are currently authorized for Herceptin. The indication of Herceptin in combination with pertuzumab and docetaxel, for untreated HER2-positive metastatic breast cancer was not requested in the submission filed for Ogivri.

Similarity between Ogivri and Herceptin 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 biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized, and therefore clinical trials are not required to support each indication.

The indications have been authorized based on demonstrated similarity between Ogivri and Herceptin with respect to structural and functional, non-clinical and clinical studies. In addition, a scientific rationale taking into consideration the mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug Herceptin, was provided and was considered in line with Health Canada's biosimilar guidance document.