Summary Basis of Decision for Tyenne

Tyenne was developed as a biosimilar of the reference biologic drug, Actemra. The weight of evidence of similarity between a biosimilar and the reference biologic drug 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 with the reference biologic drug.

Comparative Structural and Functional Studies

The biosimilarity evaluation was conducted as a three-way pairwise analytical assessment using Tyenne, RoActemra authorized in the European Union (EU-RoActemra), and Actemra authorized in the United States (US-Actemra). The demonstration of similarity between EU-RoActemra and US-Actemra was included to provide support for the use of either one as the comparator to Tyenne in the comparative clinical studies. Health Canada considers EU-RoActemra a suitable proxy for Actemra authorized in Canada, as it meets all of the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

The approach to assessing biosimilarity included a statistical analysis of quantitative data to establish a quality range and a descriptive assessment of qualitative data for which statistical analysis is not feasible. Side-by-side analytical testing, as well as forced degradation, comparative variant characterization, and structure-function relationship studies were conducted.

Data from the similarity assessment studies demonstrated that Tyenne has the identical primary amino acid sequence to EU-RoActemra and US-Actemra, and is comparable to both reference products with respect to physicochemical properties, higher order structures, purity/impurity profiles, and biological activity. Comparative stability and forced degradation studies demonstrated similar stability and degradation profiles between Tyenne and the two reference drug products, with no new impurities or variants detected. Higher levels of oxidized variants and glycation were observed in batches of Tyenne compared to the reference products; however, these levels have been shown to have no impact on potency, fragment antigen-binding (Fab) region binding, or fragment crystallizable (Fc) region binding. Furthermore, data from forced degradation studies and structure-function relationship studies demonstrated that the levels of oxidized species and glycation found in Tyenne are sufficiently low and have no clinical impact. Overall, the comparative study results demonstrated that Tyenne is highly similar to both the EU-RoActemra and US-Actemra.

Characterization of the Drug Substance

Tocilizumab is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody composed of two covalently linked heterodimers, and has a molecular weight of approximately 148 kDa (including glycosylation). Tocilizumab binds specifically to both soluble interleukin 6 receptor (IL-6R) and membrane-bound IL-6R, and inhibits IL-6-mediated signaling through these receptors, thereby hindering the pro-inflammatory effects of IL-6.

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

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

The tocilizumab drug substance manufacturing process is initiated with the thawing and inoculation of the contents of one working cell bank vial (Chinese hamster ovary cell-based expression system), followed by cell expansion and growth in a production bioreactor. The clarified harvest is purified using a series of chromatographic, viral inactivation, and filtration steps. The resulting product is formulated in a histidine buffer solution, filtered, and filled into bags for long-term storage.

The manufacturing process for the Tyenne drug product for subcutaneous injection begins with the thawing and pooling of drug substance, dilution in an L-histidine buffer, and compounding of final drug product in a concentrated excipients solution followed by bioburden reduction, sterile filtration, and aseptic filling into 1 mL syringes. All pre-filled syringes are visually inspected prior to assembly into the Safe’n’Sound or auto-injector devices.

The manufacturing process for the Tyenne drug product for intravenous infusion begins with the thawing and pooling of drug substance, followed by dilution with formulation buffer, sterile filtration, and aseptic filling into glass vials.

Process performance qualification data demonstrate that the manufacturing process is capable of consistently manufacturing the drug substance and drug products at the proposed batch size ranges. All process parameters, in-process controls, release testing results, and stability results were consistent between batches and met pre-defined criteria, acceptance limits, and specifications. All ancillary validation studies were deemed successful and supportive of intermediate hold times, impurity clearance, resin/membrane lifetimes, filters, aseptic filling (media fills), extractables and leachables, shipping, and other supporting activities.

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 tocilizumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product manufacturing processes are controlled by process parameters and in-process controls with defined operating ranges, action limits, and acceptance criteria implemented at appropriate manufacturing unit operations to ensure process consistency and product quality. Criticality of each process control was appropriately defined and based on risk assessments, process characterization studies, and previous experience gained during development.

All starting materials used in the manufacture of the Tyenne drug substance and drug product comply with compendial or in-house specifications. All excipients used in the formulation of the Tyenne drug products comply with compendial requirements and are commonly used for parenteral antibody formulations.

The proposed release and stability specifications, which include assays to control for identity, protein content, purity/impurities, biological activity, and safety, have been established based on available batch data and in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. All in-house analytical methods were appropriately validated and compendial methods have been qualified for use.

A two-tiered reference standard program has been established. The reference standards have been extensively characterized and an appropriate program is in place to qualify future primary and working reference materials.

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).

Tyenne 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 proposed 36-month shelf life at 5 ± 3 °C for Tyenne (vials and pre-filled syringes) is considered acceptable when stored in the commercial container closure system and protected from light.

The compatibility of the drug product with the container closure systems was demonstrated through compendial testing and stability studies. The container closure systems met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

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

Adventitious Agents Safety Evaluation

All raw materials and excipients used in the drug product formulation are not of animal or human origin. All raw materials and excipients are controlled routinely for bioburden/sterility, endotoxins and, where required, for mycoplasma. All cell banks are 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.

For biosimilars, the degree of similarity to the reference biologic drug 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. According to the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs, where similarity is well established by structural and functional studies, and where extensive in vitro mechanistic studies are indicative of similarity, non-clinical in vivo studies may not be necessary.

The results from the analytical similarity assessment (see Comparative Structural and Functional Studies) demonstrated a high degree of similarity between Tyenne and Actemra. There were no residual uncertainties identified that needed to be resolved by additional comparative non-clinical in vivo pharmacodynamic, pharmacokinetic, and toxicology studies.

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. Within this submission, Tyenne was developed as a biosimilar of the reference biologic drug, Actemra. The demonstration of similarity between US-licensed Actemra (US-Actemra) and RoActemra authorized in the European Union (EU-RoActemra) was included in the quality assessment to provide support for the use of either one as the comparator to Tyenne in the comparative clinical studies. Health Canada considers EU-RoActemra a suitable proxy for Actemra authorized in Canada, as it meets all of the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Comparative Pharmacokinetics and Pharmacodynamics

Three comparative pharmacology studies (Study MS200740-0001, Study FKS456-002, and Study FKS456-003) were conducted to establish therapeutic equivalence and pharmacokinetic and pharmacodynamic similarity between Tyenne and Actemra, and the pre-filled and auto-injector presentations of Tyenne.

Study MS200740-0001 was a Phase I, randomized, double-blind, parallel-group, single-dose study comparing the pharmacokinetics, pharmacodynamics, safety, tolerability, and immunogenicity of Tyenne, US-Actemra and EU-RoActemra in healthy adult subjects. Results showed that the comparative pharmacokinetic bioavailability standards were met for a single 162 mg subcutaneous dose of Tyenne versus US-Actemra and for a single 162 mg subcutaneous dose of Tyenne versus EU-RoActemra given in healthy subjects. The safety profiles and immunogenicity incidences were similar between the Tyenne, US-Actemra, and EU-RoActemra treatment groups.

Study FKS456-002 was a Phase I, randomized, double-blind, parallel-group, single-dose study comparing the pharmacokinetics, safety, tolerability, and immunogenicity of intravenous administration of Tyenne versus US-Actemra in healthy adult subjects. The comparative pharmacokinetic bioavailability standards were met for a single intravenous infusion of 8 mg/kg Tyenne compared to a single intravenous infusion of 8 mg/kg US-Actemra in healthy subjects. The safety profiles and immunogenicity were similar between the Tyenne and US-Actemra groups.

Study FKS456-003 was a Phase I, randomized, open-label, fixed-dose, cross-over study comparing the pharmacokinetics, safety, and tolerability of the pre-filled syringe and auto-injector presentations of Tyenne in healthy subjects. Results showed that the comparative pharmacokinetic bioavailability standards were met for a single subcutaneous dose of 162 mg Tyenne given by pre-filled syringe and auto-injector in healthy subjects. In addition, the safety profiles between the groups were comparable.

Comparative Clinical Efficacy and Safety

Study FKS456-001, a comparative clinical efficacy and safety study, was designed to rule out any clinically meaningful difference between Tyenne and Actemra. This was a Phase III, randomized, double-blind, multi-dose, parallel-group, two-arm clinical study comparing Tyenne with EU-RoActemra, the non-Canadian reference biologic drug. The study enrolled patients with moderately to severely active rheumatoid arthritis who have experienced an inadequate clinical response to at least one disease-modifying antirheumatic drug (either synthetic or biologic) and were concomitantly receiving a stable dose of methotrexate.

The study comprised four periods: a Screening Period of a maximum 28 days prior to first study drug administration, a double-blind 24-week Core Treatment Period, a subsequent 28-week double-blind Extended Treatment Period with last study drug administration at Week 51, and a 12-week Safety Follow-Up Period starting at Week 51 with a final end of study visit at Week 63. The Overall Period covered Day 1 to Week 55. At the Week 24 visit, after the evaluation of the primary endpoint, patients in the EU-RoActemra treatment group were re-randomized in a 1:1 ratio to either continue EU-RoActemra treatment or switch to Tyenne treatment. Demographic characteristics as well as baseline disease characteristics were balanced across the Tyenne and EU-RoActemra treatment groups in the efficacy analysis. All patients had been diagnosed with rheumatoid arthritis 6 months or more prior to the screening visit and were assessed as American College of Rheumatology (ACR) functional Class I to III.

The primary efficacy endpoint, mean absolute change from baseline in Disease Activity Score-28 with Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24, was evaluated at the end of the Core Treatment Period, before re-randomization. Clinically relevant least squares mean decreases in DAS28-ESR from baseline were evident at Week 24 in both treatment groups, with a point estimate difference between Tyenne and EU-RoActemra of 0.01 and a two-sided 95% confidence interval (CI) of -0.19 to 0.22. This was within the prespecified similarity margin of -0.6 to 0.6, thus supporting a demonstration of no clinically meaningful differences between Tyenne and Actemra. The therapeutic equivalence of Tyenne and EU-RoActemra administered weekly at a subcutaneous dose of 162 mg to patients with moderately to severely active rheumatoid arthritis was also supported by the results of the key secondary endpoint, which was based on the treatment difference in ACR20 response rate at Week 24.

In Study FKS456-001, of the 908 patients screened, 604 were randomized and received study drug. All 604 patients were included in the safety analysis set (302 patients in each treatment arm).

In the Core Treatment Period, the proportions of patients who experienced at least 1 treatment-emergent adverse event (TEAE) were similar in the Tyenne (65.9%) and EU-RoActemra (62.9%) groups. The TEAE most commonly observed in the Tyenne and EU-RoActemra groups was increased alanine aminotransferase, reported in 28 (9.3%) and 35 (11.6%) patients, respectively, followed by coronavirus disease 2019 (COVID-19), neutropenia, leukopenia, and increased aspartate aminotransferase. The distribution of the most frequently reported TEAEs was similar between the Tyenne and EU-RoActemra groups. During the Extended Treatment Period, TEAEs were reported in 45.1%, 41.0%, and 40.4% of patients in the Tyenne, EU-RoActemra-to-Tyenne, and EU-RoActemra groups, respectively, and in 77.5%, 71.9%, and 75.5% of patients, respectively, during the Overall Period. The distribution of TEAEs by system organ class was similar between the Tyenne and EU-RoActemra groups and consistent with the Core Treatment Period.

Similar proportions of patients in the Tyenne and EU-RoActemra groups experienced a serious adverse event (SAE) during the Core Treatment Period (Tyenne [9.3%] and EU-RoActemra [9.9%]). During the Extended Treatment Period, SAEs were reported in 7.5%, 7.2%, and 8.8% of patients in the Tyenne, EU-RoActemra-to-Tyenne, and EU-RoActemra groups, respectively, and in 15.9%, 12.2%, and 20.2% of patients, respectively, during the Overall Period. The most commonly reported SAE was COVID-19; none of the other SAEs were reported in more than 1 patient in the Core or Extended Treatment Periods, except for myocardial infarction and spinal stenosis (2 patients each). There were no discernable patterns in terms of the nature, frequency, or other characteristics of the SAEs that would suggest a difference between the Tyenne and EU-RoActemra groups.

The incidences of TEAEs and TEAEs of special interest (AESIs) during the Overall Period were similar between the Tyenne and EU-RoActemra groups for each of the anti-drug antibodies (ADA)-positive and ADA-negative subsets. There were 4 TEAEs with an outcome of death up to Week 55. Three deaths occurred in the EU-RoActemra group; two during the Core Treatment Period (COVID-19 and an acute myocardial infarction) and one during the Extended Treatment Period (COVID-19 pneumonia). Another death occurred in the EU-RoActemra-to-Tyenne group during the Extended Treatment Period (myocardial infarction). The TEAEs with an outcome of death were not considered related to investigational medicinal product by the investigator.

Overall, the safety profile of Tyenne is considered to be comparable to that which has been established for the reference biologic drug Actemra. Appropriate warnings and precautions are in place in the approved Tyenne Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Actemra.

Indications

Tyenne is considered to be biosimilar to Actemra, the reference biologic drug. Actemra is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Actemra is authorized are rheumatoid arthritis; systemic juvenile idiopathic arthritis in patients 1 year (subcutaneous route)/2 years of age and older (intravenous route); juvenile idiopathic polyarthritis in patients 2 years of age and older; giant cell arteritis; chimeric antigen receptor-T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older; and coronavirus disease 2019 in hospitalized adults who are receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation.

Within this drug submission, the sponsor requested the authorization of Tyenne for all of the indications that are currently authorized for Actemra.

Similarity between Tyenne and Actemra was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. 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. The indications have been authorized on the basis of demonstrated similarity between Tyenne and the reference biologic drug, in structural and functional studies, mechanisms of action, pharmacological effect, clinical studies, safety profile, and clinical experience with the reference biologic drug.

Indications

Rheumatoid Arthritis (RA) (Intravenous or subcutaneous formulations)

Tyenne (tocilizumab) is indicated for:

• reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis.

Tyenne (intravenous only) in combination with methotrexate (MTX) has been shown to reduce the rate of progression of radiographic joint damage at Week 52.

Tyenne is to be given in combination with MTX or other disease-modifying antirheumatic drugs (DMARDs); however, in cases of intolerance to MTX or where treatment with MTX is not appropriate Tyenne may also be given as monotherapy.

Giant Cell Arteritis (GCA) (Subcutaneous formulation only)

Tyenne is indicated for the treatment of giant cell arteritis (GCA) in adult patients.

Polyarticular Juvenile Idiopathic Arthritis (pJIA) (Intravenous or subcutaneous formulations)

Tyenne is indicated for the treatment of signs and symptoms of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older who have responded inadequately to previous therapy with DMARDs.

Systemic Juvenile Idiopathic Arthritis (sJIA) (Intravenous or subcutaneous formulations)

Tyenne is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients 2 years of age and older, who have responded inadequately to previous therapy with one or more non-steroidal anti-inflammatory drugs and systemic corticosteroids.

Cytokine release syndrome (CRS) (Intravenous formulation only)

Tyenne is indicated for the treatment of patients with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS), in accordance with patient populations specified for authorized CAR T cell products.

Coronavirus disease 2019 (COVID-19) (Intravenous formulation only)

Tyenne is indicated for the treatment of hospitalized adult patients with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids, and require supplemental oxygen, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation.