Summary Basis of Decision for Vyloy

Clinical Pharmacology

The clinical pharmacology of zolbetuximab was evaluated in nine clinical studies in patients with advanced adenocarcinoma of the stomach, esophagus, or gastroesophageal junction with Claudin (CLDN) 18.2-positive tumours. In these studies, zolbetuximab exhibited dose-proportional pharmacokinetics at doses ranging from 33 mg/m² to 1,000 mg/m². When administered a loading dose of 800 mg/m², followed by subsequent doses of 600 mg/m² every 3 weeks, steady state was achieved by 24 weeks. Steady state is expected to be achieved by 22 weeks when zolbetuximab is administered as loading dose of 800 mg/m², followed by 400 mg/m² every 2 weeks. Additionally, zolbetuximab was further characterised using a population pharmacokinetic analysis, which showed that the pharmacokinetics of zolbetuximab can be described by a two-compartment disposition model with linear- and time-dependent clearance components. No clinically relevant differences in exposure were identified according to patient characteristics, including age, body surface area, sex, race, mild or moderate renal impairment, or mild hepatic impairment. The effect of severe renal impairment and moderate to severe hepatic impairment on the pharmacokinetics of zolbetuximab are unknown due to limited data.

Analyses of the exposure-response for efficacy and safety were also conducted, however given that the majority of the data were from one dosage (i.e., 800 mg/m² followed by subsequent doses 600 mg/m² once every 3 weeks), no inference on the exposure-response for efficacy and safety could be made.

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

Clinical Efficacy

The clinical efficacy of Vyloy was evaluated based on data from two pivotal Phase III studies, SPOTLIGHT and GLOW. Both studies were randomized, double-blind, placebo-controlled, multicentre studies conducted in patients who had CLDN 18.2-positive (≥75% of tumour cells with moderate to strong membranous CLDN 18.2 staining as determined by central immunohistochemical testing), human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. In both studies, the primary efficacy endpoint was progression-free survival (PFS), as assessed by an independent review committee, and the key secondary endpoint was overall survival (OS).

In the SPOTLIGHT study, 565 patients were randomized (1:1) to receive Vyloy in combination with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy or placebo plus mFOLFOX6 chemotherapy. The median patient age was 61 years (range: 20 to 86 years). Of these, 62% were male, 53% were Caucasian, and 38% were Asian. Patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (43%) or 1 (57%). The median time from diagnosis was 56 days (range: 2 to 5,366 days). Vyloy was administered intravenously as a single loading dose of 800 mg/m² on Day 1 of Cycle 1, followed by subsequent doses of 600 mg/m² every 3 weeks in combination with up to 12 treatments (4 cycles) of mFOLFOX6 (oxaliplatin 85 mg/m², folinic acid [leucovorin or local equivalent] 400 mg/m², fluorouracil 400 mg/m² given as a bolus, and fluorouracil 2,400 mg/m² given as a continuous infusion) administered every 2 weeks.

The study demonstrated statistically significant and clinically meaningful improvements in PFS and OS in patients who received Vyloy plus mFOLFOX6 compared with those who received placebo plus mFOLFOX6. In the intention-to-treat population, the median PFS was 10.6 months in the Vyloy treatment arm compared to 8.7 months in the placebo treatment arm, with a hazard ratio of 0.75 (95% confidence interval [CI]: 0.60, 0.94). The median OS was 18.2 months in the Vyloy treatment arm compared to 15.5 months in the placebo treatment arm, with a hazard ratio of 0.75 (95% CI: 0.60, 0.94).

In the GLOW study, 507 patients were randomized (1:1) to receive Vyloy in combination with oxaliplatin and capecitabine (CAPOX) chemotherapy or placebo plus CAPOX chemotherapy. The median patient age was 60 years (range: 21 to 83 years). Of these, 62% were male, 63% were Asian, and 37% were Caucasian. Patients had a baseline ECOG performance status of 0 (43%) or 1 (57%). The median time from diagnosis was 44 days (range: 2 to 6,010 days). Vyloy was administered intravenously as a single loading dose of 800 mg/m² on Day 1 of Cycle 1, followed by subsequent doses of 600 mg/m² every 3 weeks in combination with up to 8 treatments (8 cycles) of CAPOX administered on Day 1 (oxaliplatin 130 mg/m²) and on Days 1 to 14 (capecitabine 1,000 mg/m²) of a 3-week cycle.

The study demonstrated statistically significant and clinically meaningful improvements in PFS and OS in patients who received Vyloy plus CAPOX compared with placebo plus CAPOX. In the intention-to-treat population, the median PFS was 8.2 months in the Vyloy treatment arm compared to 6.8 months in the placebo treatment arm, and the hazard ratio was 0.69 (95% CI: 0.54, 0.87). The median OS was 14.4 months in the Vyloy treatment arm compared to 12.2 months in the placebo treatment arm, and the hazard ratio was 0.77 (95% CI 0.62, 0.97).

In both studies, the exploratory sub-group PFS and OS results in Caucasian patients showed a reduced treatment benefit compared to the intention-to-treat population. Upon review of these results, along with additional exploratory analyses provided by the sponsor, the differences in efficacy appeared to be mainly due to reduced exposure to Vyloy and/or chemotherapy. The lower exposure in Caucasian patients was attributed to higher rates of treatment discontinuations and dose interruptions due mainly to nausea and vomiting events. Both nausea and vomiting are identified risks associated with Vyloy, and are considered manageable. In order to manage and mitigate the risk of early discontinuations and treatment interruptions of Vyloy, appropriate wording has been added to the Vyloy Product Monograph. This is aimed at emphasizing the importance of following close monitoring and pre-treatment measures to reduce treatment disruptions.

Indication

The New Drug Submission for Vyloy was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Vyloy (zolbetuximab for injection), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumours are Claudin (CLDN) 18.2 positive as determined by a validated test.

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

Clinical Safety

The clinical safety of Vyloy was evaluated based on data from the SPOTLIGHT and GLOW studies described in the Clinical Efficacy section above. The pooled safety population included the 533 patients who received Vyloy. Important identified risks include nausea, vomiting, hypersensitivity, and infusion-related reactions.

Serious treatment-emergent adverse events (TEAEs) (46.0% versus 46.5%) and fatal TEAEs (9.2% versus 10.6%) were balanced between the Vyloy and placebo treatment arms, respectively. The most common (≥2%) serious TEAEs in those treated with Vyloy were vomiting (7.1%), nausea (5.6%), malignant neoplasm progression (3.6%), diarrhea (2.8%), pyrexia (2.3%), pneumonia (2.3%), decreased appetite (2.1%), and hypokalemia (2.1%). Fatal TEAEs that occurred in more than one patient treated with Vyloy included malignant neoplasm progression (3.0%), respiratory failure (includes acute respiratory failure and acute respiratory distress syndrome) (0.8%), upper gastrointestinal hemorrhage (0.6%), death (0.6%), septic shock (0.6%), pneumonia (0.6%), sepsis (0.4%), disseminated intravascular coagulation (0.4%), and cerebral hemorrhage (0.4%).

A higher percentage of patients who received Vyloy compared to placebo had TEAEs resulting in permanent treatment discontinuation (19.9% versus 12.5%, respectively). The most common TEAEs leading to treatment discontinuation were vomiting (3.8%) and nausea (3.4%).

Additionally, a higher percentage of patients who received Vyloy compared to placebo had TEAEs resulting in treatment interruption (65.3% versus 34.5%, respectively). In the SPOTLIGHT study, 74.6% of patients treated with Vyloy experienced treatment interruption due to TEAEs. In the GLOW study, 55.1% of patients treated with Vyloy experienced treatment interruption due to TEAEs. In both studies, the most common TEAEs that resulted in treatment interruption were nausea (SPOTLIGHT 36.9% and GLOW 17.3%) and vomiting (SPOTLIGHT 31.5% and GLOW 24.4%).

Pre-medication with a combination of antiemetics prior to each infusion of Vyloy is important for the management of nausea and vomiting to prevent early treatment discontinuation and mitigate the potential risk of reduced exposure to Vyloy and/or chemotherapy.

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). There was insufficient information to characterize the ADA response to zolbetuximab and the effects of ADAs on the pharmacokinetics, pharmacodynamics, safety, or efficacy of zolbetuximab.

Overall, the safety profile of Vyloy is manageable and acceptable in the context of the prognosis of the target patient population.

Appropriate warnings and precautions are in place in the approved Vyloy Product Monograph to address the identified safety concerns.

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

Data from non-clinical studies characterized the mechanisms of action and anti-tumour activity of zolbetuximab as a monotherapy, as well as in combination with chemotherapeutic treatment. In vitro treatment of Claudin (CLDN) 18.2-positive gastric cancer cells with zolbetuximab induced both antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, where a concentration-dependent lysis of gastric cancer cells was observed. Chemotherapeutic treatment of gastric cancer cells increased the cell surface expression of CLDN 18.2, which resulted in an improved effect of zolbetuximab-induced antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. In a tumour model in mice, the combination of zolbetuximab and chemotherapy treatment also showed significantly improved inhibition of tumour growth when compared to each monotherapy treatment.

Pivotal repeat dose studies of intravenously administered zolbetuximab in cynomolgus monkeys (4-weeks) and mice (13-weeks) resulted in no treatment-related general toxicities. Local tolerance assessment was incorporated into the repeated dose toxicology studies. No signs of toxicity were observed at the site of injection. The pivotal reproductive and developmental toxicology study in pregnant mice revealed no treatment-related toxicity in pregnant females or their fetuses.

In summary, the non-clinical toxicology assessment supports the use of Vyloy for the proposed clinical indication as no safety concerns were identified. The results of the non-clinical studies as well as the potential risks to humans have been included in the Vyloy Product Monograph. In view of the intended use of Vyloy, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

Characterization of the Drug Substance

Zolbetuximab is a recombinant mouse/human chimeric monoclonal antibody composed of variable regions derived from a mouse anti-human claudin-18 splice variant 2 (CLDN 18.2) monoclonal antibody and constant regions from human immunoglobulin G1. It binds to CLDN 18.2 on the surface of target tumour cells and triggers the host immune system via the ADCC and CDC pathways.

Detailed characterization studies were performed to provide assurance that the drug substance 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

The drug substance is produced from a Chinese hamster ovary (CHO) cell line using a fed-batch production bioreactor. The manufacturing process begins with the thawing of one vial of the working cell bank, followed by a series of expansions in shake flasks, roller bottles, bags, and seed bioreactors before inoculation of the production bioreactor. The cell culture fluid is harvested by depth filtration and subsequently purified through a series of chromatographic and filtration steps. Process validation was performed by the manufacture of consecutive process performance qualification (PPQ) batches. With minor exceptions that have been appropriately investigated, all process parameters were within their pre-defined ranges and all in-process control acceptance criteria were met. In addition to the execution of the PPQ campaign, the following supportive studies were performed: impurity clearance capability, in-process pool hold time, chromatography resin cleaning and reuse, reprocessing, and shipping. All results demonstrate that the drug substance manufacturing process is capable of consistently producing zolbetuximab of an acceptable quality in accordance with the control strategy.

The drug product is manufactured as a single-dose vial containing sterile, preservative-free, white to off-white lyophilized powder for reconstitution for intravenous infusion. The manufacturing process consists of thawing of the drug substance, compounding, filtering, filling, lyophilization, and capping. The validation approach consisted of manufacturing three consecutive PPQ batches at commercial scale according to the proposed manufacturing process. Batches were manufactured within the proposed target process parameters, and all in-process control acceptance criteria were met. In addition to the execution of the PPQ campaign, the following supportive studies were performed: filter validation studies, validation of aseptic processing, hold time validation, and shipping qualification. All results provided demonstrated that the drug product manufacturing process is capable of consistently producing Vyloy of an acceptable quality.

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 medicinal ingredient with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The control strategy for the drug substance includes control of materials, control of critical steps within the manufacturing process, and control of the product through release and stability testing. The generation of the expression construct and CHO cell substrates were well described and characterized as per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, where applicable. For both the drug substance and drug product processes, critical process parameters, in-process specifications, and critical in-process controls have been set to ensure the critical quality attributes of the product are met. Operational process parameters and non-critical in-process controls have also been established to ensure process consistency. The proposed parameters and in-process controls are appropriate to ensure that critical quality attributes are within their defined acceptance criteria and that the process remains consistent.

The drug substance and drug product specifications were set based on ICH guidelines, regulatory requirements, clinical experience, the manufacturing process, as well as release and stability data from clinical and commercial lots. Non-compendial analytical methods were appropriately validated and transferred, and support the proposed specifications. A two-tiered reference program has been established. The reference standards have been well characterized and an appropriate program is in place to qualify new reference standard materials in the future.

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).

Vyloy is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale 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 40-month shelf life at 5°C for Vyloy is considered acceptable. In addition, the in-use shelf lives of not more than 24 hours at 2 °C to 8 °C (including infusion time) and not more than 6 hours at room temperature (including infusion time) are also considered acceptable.

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

Apart from the CHO cell line of hamster origin, no materials of biological origin were used in the cell line generation or banking, or the drug substance and drug product manufacturing processes. Raw materials used in the cell line generation are properly sourced and adequately tested to ensure absence of adventitious agents.

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Unprocessed bulk harvest 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.