Summary Basis of Decision for Ziihera

Clinical Pharmacology

Zanidatamab, the medicinal ingredient in Ziihera, is a bispecific antibody directed against two non-overlapping epitopes of the extracellular domain of the human epidermal growth factor receptor 2 (HER2).

The clinical pharmacology of zanidatamab following intravenous administration in patients with HER2-expressing cancers was evaluated in a Phase I clinical study (Study ZWI-ZW25-101) and a Phase II clinical study (HERIZON-BTC-01, described in the Clinical Efficacy section).

Following multiple dosing over the dose range of 5 mg/kg to 30 mg/kg, zanidatamab exhibited non-linear pharmacokinetics, with more rapid clearance at low doses. Following the first dose, the geometric mean maximum concentration (C_max) of zanidatamab was dose proportional with increasing doses, while the total systemic exposure (as measured by the area under the curve from time zero to infinity, AUC_0-∞) was greater than dose proportional with increasing doses.

In a population pharmacokinetic analysis, the pharmacokinetics of zanidatamab was described by a two-compartment pharmacokinetic model with parallel linear and non-linear (Michaelis-Menten) elimination from the central compartment. Based on the estimated half-life of 21 days, it would take approximately 3.5 months (i.e., 5 half-lives) to reach steady state following multiple-dose administration of zanidatamab. The mean (standard deviation) accumulation ratio based on the trough concentration (C_trough) at steady state for zanidatamab 20 mg/kg once every 2 weeks was 3.35 (1.25) in patients with biliary tract cancers.

Based on the population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on age, sex, race, tumour size, HER2 expression, soluble HER2 extracellular domain concentration, body weight, mild hepatic impairment, and mild and moderate renal impairment. The pharmacokinetics of zanidatamab in patients with moderate or severe hepatic impairment and in those with severe renal impairment and end-stage renal disease is unknown.

Overall, the clinical pharmacology data support the use of Ziihera for the specified indication.

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

Clinical Efficacy

The efficacy of Ziihera was evaluated in an open-label, single-arm, Phase II study (HERIZON-BTC-01) in adult patients with locally advanced unresectable or metastatic HER2-positive biliary tract cancer (including gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma).

Enrolled patients had received at least one prior gemcitabine-based systemic chemotherapy regimen for advanced disease and were required to have adequate cardiac function (defined as left ventricular ejection fraction greater than or equal to 50%). Ziihera was administered as an intravenous infusion (20 mg/kg) once every 2 weeks until disease progression or unacceptable toxicity. The primary efficacy population included 80 patients whose tumours showed HER2 gene amplification by in situ hybridization and HER2 protein overexpression by immunohistochemistry (IHC) with a score of IHC 3+ or IHC 2+. The median age of patients was 64 years (range: 32 to 79 years) and 49% of patients were 65 years of age or older. Fifty-six percent of patients were female. The majority of patients (65%) were Asian; 29% were White. Most patients (73%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 1. Fifty-one percent of patients had gallbladder cancer, 29% had intrahepatic cholangiocarcinoma, and 20% had extrahepatic cholangiocarcinoma.

The primary efficacy endpoint was confirmed objective response rate assessed by an independent central review using the Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1).

In the primary efficacy population of 80 patients, the confirmed objective response rate was 41.3% (95% confidence interval [CI]: 30.4%, 52.8%) and the median duration of response was 14.9 months. The observed treatment benefit was primarily driven by patients whose tumours had higher HER2 overexpression. Among 62 patients with HER2 IHC 3+ biliary tract cancers, the confirmed objective response rate was 51.6% (95% CI: 38.6%, 64.5%), whereas among 18 patients with HER2 IHC 2+ biliary tract cancers, the confirmed objective response rate was 5.6% (95% CI: 0.1%, 27.3%).

The reported confirmed objective response rate of 51.6% achieved with Ziihera monotherapy in previously treated unresectable or metastatic HER2 IHC 3+ biliary tract cancer constitutes promising evidence of efficacy compared to available treatments. There was insufficient evidence to support efficacy of Ziihera in patients whose biliary tract cancers were HER2 IHC 2+. Therefore, the recommended target population was limited to patients with HER2 IHC 3+ disease.

In order to confirm the clinical benefit of Ziihera, the sponsor will provide the results from an ongoing, open-label, randomized Study JZP598-302 assessing the efficacy and safety of Ziihera with standard-of-care therapy against standard-of-care therapy alone for advanced HER2-positive biliary tract cancer.

Indication

The New Drug Submission for Ziihera was filed by the sponsor with the following proposed indication:

Ziihera (zanidatamab) is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic HER2-positive biliary tract cancer.

Based on the reviewed data, Health Canada revised the proposed indication to limit the intended patient population to patients whose biliary tract cancers show HER2 protein overexpression defined by an immunohistochemistry (IHC) score of 3+ and to specify that in this population, Ziihera is to be used as a single agent. In addition, caveat statements were included to clarify the nature of the evidence reviewed. Accordingly, Health Canada approved the following indication:

Ziihera (zanidatamab) is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic HER2-positive (IHC score of 3+) biliary tract cancer, as monotherapy.

The marketing authorization with conditions is based on objective response rate and durability of response. An improvement in survival has not yet been established.

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

Clinical Safety

The safety of Ziihera was evaluated based on data from a pooled population of 233 patients who received Ziihera 20 mg/kg intravenously as a single agent once every 2 weeks in the pivotal study HERIZON-BTC-01 (described in the Clinical Efficacy section) and the supportive study ZWI-ZW25-101. Of the 233 patients, 109 had biliary tract cancers and 124 had other cancers. Thirty-nine percent of the patients were exposed to Ziihera for 6 months or longer, and 18% were exposed for longer than 1 year.

In the pooled safety population, the most common treatment-emergent adverse events (occurring in at least 20% of Ziihera-treated patients) included diarrhea, infusion-related reactions, anemia, and fatigue. Serious treatment-emergent adverse events occurred in 35.2% of patients. The most frequently reported serious adverse events (occurring in at least 2% of patients) were pneumonia (4.7%), sepsis (3.0%), cholangitis (3.0%), and cholestatic jaundice (2.1%). Severe (Grade 3 or higher) treatment-emergent adverse events were experienced by 51.1% of patients. Permanent discontinuation of Ziihera due to adverse events occurred in 3.4% of patients. Fatal treatment-emergent adverse events included hepatic failure (1 patient), hematemesis (1 patient), coronavirus disease 2019 pneumonia (1 patient), cardiac arrest (2 patients), multiple organ dysfunction (1 patient), and sudden death (2 patients).

Overall, the observed safety profile of Ziihera was consistent with that of other HER2-targeted therapies. Left ventricular dysfunction, infusion-related reactions, and pneumonitis are important safety concerns associated with drugs that block HER2 activity and have been outlined in the Warnings and Precautions section of the Product Monograph for Ziihera. Importantly, based on the mechanism of action, Ziihera may cause fetal harm when administered to a pregnant woman. In the post-marketing setting, the use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Accordingly, a Serious Warnings and Precautions Box in the Product Monograph for Ziihera highlights the risk of embryo-fetal toxicity. Ziihera is not recommended for use during pregnancy and women of childbearing potential are recommended to use effective contraception while receiving Ziihera and for 4 months after the last dose of the drug.

Further safety evaluation will be conducted upon submission of the results from an ongoing, open-label, randomized Study JZP598-302 assessing the efficacy and safety of Ziihera with standard-of-care therapy against standard-of-care therapy alone for advanced HER2-positive biliary tract cancer.

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

The non-clinical data package for zanidatamab, the medicinal ingredient in Ziihera, consisted of in vitro and in vivo pharmacological characterization studies, pharmacokinetic studies, and toxicology studies.

The pharmacology studies demonstrated that zanidatamab bound with similar affinity to the extracellular domain of the human epidermal growth factor receptor 2 (HER2) in both humans and cynomolgus monkeys, supporting the use of cynomolgus monkeys for non-clinical toxicology testing. In addition, the potential mechanisms of action of zanidatamab were examined in cell lines expressing HER2 at different levels. The data demonstrated that, in vitro, zanidatamab employs the following immune mechanisms to target HER2-expressing tumour cells: antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, and antibody-dependent cellular cytotoxicity. These findings provided a strong proof of concept for the therapeutic potential of zanidatamab. The studies also demonstrated that in HER2-expressing cell lines, zanidatamab inhibited intracellular signalling of HER2, blocked ligand-independent dimerization of HER2/HER3, and interfered with the epidermal growth factor receptor (EGFR) signalling pathway. Furthermore, zanidatamab showed promising antitumour activity across multiple HER2-positive xenograft models, thereby indicating a potential to target HER2-expressing cancers originating from different tissues.

In a 13-week repeat-dose toxicity study in cynomolgus monkeys intravenously administered zanidatamab at doses of up to 150 mg once weekly, the primary treatment-related adverse finding was diarrhea, which is consistent with the known pharmacological effects of HER2-targeted therapies. No other adverse clinical events were noted in the study. In addition, no anti-zanidatamab antibodies were detected in the treated animals; however, due to the low number of animals, a definitive conclusion on the immunogenicity of zanidatamab could not be made.

Since embryo-fetal toxicity is known to be associated with HER2-targeting agents, an embryo-fetal toxicology study and a prenatal and postnatal development study of zanidatamab were not conducted. The risk of embryo-fetal toxicity has been highlighted in a Serious Warnings and Precaution Box and the Warnings and Precautions section in the Product Monograph for Ziihera.

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

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

Characterization of the Drug Substance

Zanidatamab, the medicinal ingredient in Ziihera, is a recombinant, humanized, bispecific, immunoglobulin G1 (IgG1)-like monoclonal antibody directed against two non-overlapping epitopes of the extracellular domain of the human epidermal growth factor receptor 2 (HER2).

Detailed characterization studies were performed to provide assurance that zanidatamab 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 limits. A risk assessment for the presence of nitrosamine impurities was conducted according to the requirements outlined in the 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

Zanidatamab is produced using a mammalian expression system (a Chinese hamster ovary [CHO] cell line that is genetically engineered to express the protein) and standard processes for the manufacture of monoclonal antibodies A single vial of the working cell bank is thawed to initiate the cell culture process. Cells are expanded in progressively larger vessels before inoculating production bioreactors that are operated concurrently in a fed-batch mode. After the production bioreactor culture is harvested, zanidatamab is purified using a combination of chromatography, virus inactivation, and virus filtration steps. Purified zanidatamab is further concentrated and formulated by ultrafiltration/diafiltration. Formulated zanidatamab is then filtered, filled into single-use bags, and stored frozen at -80 °C to -60 °C.

The drug product manufacturing process consists of thawing the drug substance, pooling and compounding, bioburden-reduction filtration, sterile filtration, aseptic vial filling and partial vial stoppering, and lyophilization. After lyophilization, the vials are fully stoppered, crimped, and visually inspected before long-term storage at 2 °C to 8 °C. None of the non-medicinal ingredients (excipients) in Ziihera are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of zanidatamab with the excipients is supported by the stability data provided.

The drug substance and drug product manufacturing processes are controlled by multiple process parameters, in-process controls, and in-process tests with defined operating ranges, action limits, and acceptance criteria. The criticality of each parameter is appropriately defined.

Process validation studies were conducted using at least three consecutive batches of the drug substance and the drug product produced at the proposed commercial scales and manufacturing site. All critical process parameters, in-process controls, and release testing results met pre-established acceptance criteria and specification limits across all validation batches. No critical deviations were reported that could impact product quality and process validation. Ancillary validation studies with respect to in-process hold times, impurity clearance, resin and membrane reuse, reprocessing, extractables and leachables testing, media fills, and shipping, were successfully completed. The process validation data collectively confirm that the commercial manufacturing processes implemented consistently yield Ziihera drug substance and drug product batches that comply with established specifications and quality standards.

Control of the Drug Substance and Drug Product

The release and stability specifications for the drug substance and drug product were established based on relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, compendial guidelines, product and process knowledge, and statistical analyses of release and stability data. The corresponding analytical procedures have been adequately validated in accordance with the ICH guidelines. Compendial methods were satisfactorily verified under conditions of use. The sponsor has accepted post-marketing commitments to update the release and stability specifications with two additional validated methods.

A two-tiered reference standard system is in place, including well-characterized reference standards. The program in place is deemed appropriate to qualify future working reference standards.

Ziihera 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 stability data support the proposed shelf life of 36 months for Ziihera, when the drug product is stored at 2 °C to 8 °C. The reconstituted solution and the diluted solution should be used immediately. If not used immediately, in-use storage time for the reconstituted solution should not exceed 4 hours at room temperature or in the refrigerator (at 2 °C to 8 °C), whereas in-use storage time for the diluted solution should not exceed 12 hours at room temperature or 24 hours in the refrigerator (at 2 °C to 8 °C). These storage times start from the time of reconstitution.

The compatibility of the drug product with the primary container closure system was demonstrated through stability studies and extractables and leachables studies.

Facilities and Equipment

Based on the information reviewed by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary. The design, operations, and controls of all facilities and equipment involved in the production are considered suitable. The manufacturing sites are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The zanidatamab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control.

No raw materials of human or animal origin are directly used in the zanidatamab manufacturing process other than the CHO-derived cell line and the L-fucose (derived from bovine milk lactose) used in the cell culture process. Relevant information was provided to demonstrate that the animal-derived raw materials are compliant with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3).

Extensive testing of the master cell bank, working cell bank, end-of-production 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, mycoplasma, and viruses. Small-scale 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.