Summary Basis of Decision for Zynyz

Clinical Pharmacology

Retifanlimab, the medicinal ingredient in Zynyz, is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to programmed cell death protein 1 (PD-1) and blocks its interaction with its ligands programmed death-ligand 1 and 2 (PD-L1 and PD-L2). Engagement of PD-1 with its ligands PD-L1 and PD-L2, which are expressed by antigen presenting cells and may be expressed by tumour cells and/or other cells in the tumour microenvironment, results in inhibition of T-cell functions such as proliferation, cytokine secretion, and cytotoxic activity. Retifanlimab binds to the PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2, and potentiates T-cell activity.

Of the five studies that contributed to the pharmacokinetic (PK) dataset, only one was adequately sampled to support a noncompartmental analysis. The PK analysis showed slight accumulation (1.3 times) based on maximum concentration (C_max), with steady-state reached around 16 weeks (sixth cycle). The PK parameter area under the concentration-time curve from time 0 to infinity (AUC_inf) was approximately linear, while the C_max parameter showed linear kinetics.

The pharmacokinetics of retifanlimab was described by a two-compartment linear disposition model, with time-dependent elimination on the logarithmic scale. When the parameters were adjusted with the covariates, estimates of retifanlimab concentrations could be predicted with an acceptable level of accuracy.

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). A validated bridging enzyme-linked immunosorbent assay (ELISA) was used to detect ADAs for retifanlimab. A total of 441 patients treated with 500 mg retifanlimab every 4 weeks across studies of retifanlimab monotherapy were included in the analysis pool. Treatment-emergent ADA positivity was reported in 1.8% of patients; 0.9% were positive for neutralizing antibodies. The effect of the ADA on the pharmacokinetics, safety and/or efficacy of retifanlimab monotherapy is inconclusive given the low ADA incidence.

The clinical pharmacology data support the use of Zynyz for the recommended indication. For further details, please refer to the Product Monograph for Zynyz, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Zynyz was evaluated in the pivotal, open-label, single-arm, multiregional POD1UM-201 study. A total of 101 adult patients with treatment-naïve metastatic or recurrent locally advanced Merkel cell carcinoma (MCC) were treated with Zynyz monotherapy 500 mg every 4 weeks, until disease progression or unacceptable toxicity occurred, or for a maximum of 24 months.

Among the 101 patients, the median age was 71.1 years (range: 38 to 90 years), with 38.6% aged 75 years or older. In addition, 67.3% of patients were male and 32.7% were female. The majority of patients were Caucasian (77.2%), while 1.0% were Asian, and 21.8% either did not know or did not report their race. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able to carry on all pre-disease performance without restriction; 73.3%) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 26.7%). The majority of patients (90.1%) had metastatic disease at baseline. Patients with active autoimmune disease or a medical condition that required immunosuppression, severe hepatic or renal impairment, evidence of interstitial lung disease, clinically significant cardiac disease, history of organ transplant, known central nervous system metastases or an ECOG performance score of 2 or higher were ineligible. Patients who were human immunodeficiency virus (HIV)-positive, with an undetectable viral load, a CD4+ count of 300 cells/microliter or higher, and who were receiving antiretroviral therapy were eligible.

The primary efficacy outcome measure of the study was the confirmed overall response rate (ORR) in treatment-naïve patients as assessed by an independent central review (ICR) committee according to the Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v 1.1). The key secondary outcome was duration of response (DoR). As of the data cutoff of the analysis, the median duration of follow-up was 17.6 months (range: 1.1 to 38.7 months), with all ongoing responses having been followed for a minimum of 6 months.

At the data cutoff, the ORR was 53.5% (95% confidence interval [CI]: 43.3%, 63.5%) for the 101 treatment-naïve patients, with 17 (16.8%) complete responses and 37 (36.6%) partial responses. Among the 54 responders, the median DoR was estimated to be 25.3 months (95% CI: 14.2, not reached).

The magnitude of benefit in terms of ORR and DoR observed in the pivotal study is considered clinically meaningful for the treatment of MCC. At the time of authorization of Zynyz, no survival evidence from a randomized clinical trial was available to support the use of any systemic therapy regimen in the treatment of advanced MCC.

Indication

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

Zynyz (retifanlimab for injection) is indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC).

Health Canada revised the proposed indication to clearly define the target population for whom the benefit-risk profile with the treatment of Zynyz is considered favourable based on the submitted data. Accordingly, Health Canada approved the following indication:

Zynyz (retifanlimab for injection), as monotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC) not amenable to curative surgery or radiation therapy.

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

Clinical Safety

The clinical safety of Zynyz was evaluated in the pivotal POD1UM-201 study described in the Clinical Efficacy section. As of the data cutoff of the analysis, the median duration of exposure was 10.3 months (range: 1 day to 24.8 months), 62.4% of patients received Zynyz for more than 6 months, and 47.5% for more than 1 year. The median number of infusions was 12 doses (range: 1 to 28 doses).

In the 101 treatment-naïve patients with metastatic or recurrent locally advanced MCC treated with Zynyz, the safety profile was generally consistent with the known safety profile of the class of PD-1/PD-L1 inhibitors, which is characterized by immune-mediated adverse events and infusion-related reactions.

The most common adverse reactions, occurring in 10% or more of patients treated with Zynyz were: fatigue (30.7%), pruritus (21.8%), diarrhea (18.8%), rash (17.8%), arthralgia (16.8%), musculoskeletal pain (16.8%), coronavirus disease 2019 (COVID-19; 13.9%), constipation (11.9%), cough (10.9%), and pyrexia (10.9%).

In 20.8% of patients, treatment-emergent adverse events (TEAEs) led to treatment discontinuation. These included an infusion-related reaction (2%), and colitis, diarrhea, demyelinating polyneuropathy, fatigue, hepatitis, increased transaminases, eosinophilic fasciitis, polyarthritis, hypophysitis, pancreatitis, toxic epidermal necrolysis, and tubulointerstitial nephritis (1% each). Fatal TEAEs were reported in 4.0% of patients, which were acute respiratory failure, asthenia, COVID-19, and concomitant disease progression of chronic lymphocytic leukemia.

The most common immune-mediated adverse events occurring in 5% or more of patients were: hypothyroidism, skin reactions, hyperthyroidism, and pneumonitis. The incidence of infusion-related reactions was 6.2%.

There is insufficient data in patients with severe renal impairment and no data for patients with end-stage renal disease. Similarly, there are insufficient data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. Therefore, at the time of authorization, no dosing recommendation could be made for these populations.

There are no available data on the use of Zynyz in pregnant women. Based on its mechanism of action, Zynyz can cause fetal harm if administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to an increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Additionally, human IgG4 are known to cross the placenta; therefore, retifanlimab has the potential to be transmitted from the mother to the developing fetus. Zynyz is not recommended during pregnancy and in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk. Women of childbearing potential should use effective contraception during treatment with Zynyz and for at least 4 months after the last dose of Zynyz.

It is unknown whether Zynyz is excreted in human milk. As human IgGs are known to be excreted in breast milk, a risk to breastfeeding newborns/infants cannot be excluded. Women should be advised not to breastfeed during treatment and for at least 4 months after the last dose of Zynyz.

Overall, the safety profile of Zynyz is considered manageable. Appropriate warnings and precautions are in place in the approved Product Monograph for Zynyz to address the identified safety concerns. For more information, refer to the Product Monograph for Zynyz, approved by Health Canada and available through the Drug Product Database.

Retifanlimab, the medicinal ingredient in Zynyz, is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to programmed cell death protein 1 (PD-1). Standard in vitro assays using human and primate cell lines established proof-of-concept and mechanism of action of retifanlimab, namely, its binding to PD-1, thereby blocking the binding of the inhibitory ligands programmed death-ligand 1 and 2 (PD-L1 and PD-L2) to PD-1 receptors.

A 4-week good laboratory practice (GLP)-compliant toxicology study performed in cynomolgus monkeys provided no evidence of retifanlimab-related adverse effects on the central nervous, cardiovascular or respiratory systems.

In 4-week and 13-week repeat-dose GLP-compliant toxicity studies in cynomolgus monkeys, no unexpected deaths or significant treatment-related toxicities were observed. The no-observed-adverse-effect levels (NOAELs) were the highest doses tested in each study (150 mg/kg and 100 mg/kg, respectively).

It has previously been shown that blockade of PD-1 signalling in mice can negatively impact maternal immune tolerance to the fetus resulting in an increased severity of infection and an increased risk of fetal loss. This information has been captured in the Product Monograph for Zynyz.

A moderate anti-drug antibody (ADA) response against retifanlimab was detected after repeat dosing. The overall positive ADA incidence rate in monkeys treated with retifanlimab was 47% (14/30) and 33% (10/30) for the 4-week and 13-week GLP studies, respectively.

Overall, the non-clinical data are considered supportive of the use of retifanlimab in adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma. The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Zynyz. In view of the intended use of Zynyz, 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 Zynyz, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

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

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

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.

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

The drug substance is manufactured using a recombinant Chinese hamster ovary (CHO) cell line and standard monoclonal antibody production methods. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

To manufacture the drug substance, cells from a working cell bank are thawed and progressively expanded through a series of cell growth steps, followed by a harvesting step, and a sequence of purification steps that include chromatography, viral inactivation, and filtration steps. The resulting formulated drug substance is concentrated, filtered, filled into bags, and stored frozen. The drug substance is shipped frozen to the manufacturing sites of the Zynyz drug product.

To manufacture the drug product, drug substance batches are thawed, pooled, and mixed to obtain a homogeneous solution. The protein concentration is determined, and the solution is filtered for bioburden reduction. The drug product solution is then sterile filtered and filled into vials, which are closed, capped, 100% visually inspected, and stored at 2 °C to 8 °C.

Zynyz is supplied as a sterile, clear to slightly opalescent, colourless to pale yellow solution, in a single-use vial for intravenous (IV) infusion after dilution. Each 500 mg/20 mL vial of Zynyz contains 25 mg/mL retifanlimab in 10 mM sodium acetate, 9.0% sucrose and 0.01% polysorbate 80, pH 5.1. An overfill is included to ensure the labeled amount of the active ingredient is delivered. Zynyz solution is diluted in either a 0.9% sodium chloride IV bag or 5% dextrose (glucose) IV bag prior to administration.

The materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered suitable and/or meet standards appropriate for their intended use. 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 retifanlimab with the excipients is supported by the stability data provided.

The manufacturing process and the controls used during the manufacturing of both the drug substance and drug product are validated and the overall process is considered to be adequately controlled within justified limits. Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review. In-process controls and lot release tests for the drug substance and drug product were established and validated.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with ICH guidelines.

Each lot of Zynyz drug product is tested for appearance, color, clarity, sub-visible particles, polysorbate 80 concentration, potency, purity, protein concentration, volume in container, pH, osmolality, bacterial endotoxins, and sterility. Established test specifications and validated analytical test methods are considered acceptable.

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.)

Zynyz 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 24‑month shelf life is acceptable when Zynyz is stored between 2 °C to 8 ºC, protected from light. Once prepared, if the diluted solution is not administered immediately, it may be stored temporarily either at room temperature up to 25 °C for no more than 8 hours from the time of preparation to the end of the infusion or under refrigeration at 2 °C to 8 °C for no more than 24 hours from the time of preparation to the end of the infusion. If refrigerated, the diluted solution must come to room temperature prior to administration and be administered within 4 hours (including infusion time) of its removal from the refrigerator.

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

The design, operations, and controls of all facilities and equipment that are involved in the production are considered suitable.

An on-site evaluation (OSE) of the facility involved in the manufacture and testing of Zynyz drug substance was not conducted, however, information obtained from a recent United States Food and Drug Administration (FDA) inspection was reviewed and taken into consideration during the assessment.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The retifanlimab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot 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.

Raw materials of animal and recombinant deoxyribonucleic acid (DNA) origin used in the manufacturing process are adequately tested to ensure absence of adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.