Summary Basis of Decision for Jamteki

Jamteki was developed as a biosimilar of the reference biologic drug, Stelara. The weight of evidence of similarity between a biosimilar and the reference biologic drug is provided by structural and functional studies. Biosimilars are manufactured according 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 to the reference biologic drug.

Comparative Structural and Functional Studies

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

The results of the biosimilarity assessment demonstrated that Jamteki and Stelara have an identical primary amino acid sequence and similar physicochemical properties, higher-order structures, and impurity profiles. Observed differences in C-terminal lysine residues and fragment levels have no impact on biological activity and are unlikely to be clinically meaningful. The overall biological activity was very similar between Jamteki and Stelara, notwithstanding the differences in binding to fragment crystallizable (Fc) gamma receptor IIIa (FcγRIIIa) due to lower afucosylation and higher mannose levels in Jamteki. The difference in FcγRIIIa binding, however, has no impact on the efficacy of Jamteki, as ustekinumab lacks effector functions.

Comparative stability studies and forced degradation studies under stressed conditions showed similar stability and degradation profiles.

Overall, the results of the biosimilarity assessment demonstrate that Jamteki is highly similar to Stelara, with minor differences that are not considered clinically meaningful.

Characterization of the Drug Substance

Ustekinumab is a fully human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to the p40 subunit of interleukin (IL)-12 and IL-23, thereby preventing these interleukins from binding to the IL-12 receptor β1 subunit of the IL-12 and IL-23 receptor complexes expressed on the surface of immune cells. The antibody is composed of two identical heavy chains and two identical light chains and has an approximate molecular weight of 148,079 to 149,690 Da.

Detailed characterization studies were performed to provide assurance that ustekinumab 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

Jamteki drug substance is produced using the mammalian 17-Sp2/0-S cell line that is genetically engineered to express ustekinumab. Briefly, the commercial manufacturing process of the drug substance consists of cell expansion steps, purification of the harvested material through a series of chromatography steps, viral inactivation and removal, formulation, and final filtration prior to filling into storage containers.

The drug product is manufactured by thawing, pooling, and mixing of the formulated drug substance, followed by bioburden reduction filtration and transfer, sterile filtration and aseptic filling and stoppering, end-of-line step, manual visual inspection, and final labelling. There are no reprocessing steps during the manufacturing process. The two drug product strengths (45 mg/0.5 mL and 90 mg/1.0 mL) are identical in all aspects except for the fill volumes of the prefilled syringes. None of the non-medicinal ingredients (excipients) found in the drug product is prohibited by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

Controls of critical steps of the drug substance and drug product manufacturing processes were established during manufacturing development and were based on a risk assessment and process characterization. Process validation, conducted at commercial scale, demonstrated that the manufacturing processes are capable of consistently manufacturing drug substance and drug product of the desired quality.

Control of the Drug Substance and Drug Product

Release and stability specifications for the drug substance and drug product were appropriately established and justified. The analytical procedures used in the release and stability testing of the drug substance and drug product were adequately validated according to relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Compendial methods were satisfactorily verified under conditions of use.

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. No risk was identified of the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes. Therefore, no confirmatory testing is required.

Through Health Canada’s lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing results supported the authorization of Jamteki.

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 satisfactory.

The stability data support the proposed shelf life of 24 months at -80 °C to -60 °C for the drug substance and 24 months at 2 °C to 8 °C for the drug product, when protected from light. The drug product should not be frozen or shaken. If necessary, individual Jamteki prefilled syringes may be stored at room temperature of up to 30 °C and protected from light for a maximum single period of up to 30 days. The syringes must be discarded if not used within 30 days of being stored at room temperature.

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

Facilities and Equipment

Results from a recent inspection of the drug substance and drug product manufacturing site conducted by the United States Food and Drug Administration were leveraged by Health Canada in lieu of an on-site evaluation.

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured. The manufacturing site is compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. In-process testing is performed to monitor for bioburden, endotoxins, mycoplasma, and viruses. Purification process steps designed to inactivate and remove any potential viral contaminants from the cell culture process are adequately validated.

Except for the cell banks, the raw materials and excipients used in the manufacturing of Jamteki are not of animal or human origin.

The non-clinical data submitted for Jamteki were in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. For biosimilars, the degree of similarity 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. Where similarity is well established by structural and functional studies, and where extensive in vitro mechanistic studies are indicative of similarity, in vivo non-clinical studies may not be necessary.

Based on the extensive non-clinical data available for Stelara (the reference drug), the use of the same excipients in Stelara and Jamteki, and the comprehensive analytical similarity data from comparative testing of Jamteki and Stelara, comparative pharmacology and toxicology studies in animals were not deemed necessary to support demonstration of biosimilarity.

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

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.

Comparative Pharmacokinetics

The pharmacokinetic similarity of Jamteki, Stelara authorized in the European Union (EU-Stelara), and Stelara authorized in the United States (US-Stelara) was demonstrated in a Phase I, randomized, double-blind, three-arm, parallel-group study (AVT04-GL-101). For the purpose of this drug submission, Health Canada considered EU-Stelara a suitable proxy for Stelara authorized in Canada, as it met all of the requirements for a non-Canadian reference biologic drug stipulated in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Study AVT04-GL-101 was conducted in 298 healthy adult male and female subjects aged 18 to 55 years. The subjects received a single dose of 45 mg/0.5 mL of the assigned drug as a subcutaneous injection on Day 1. Serum samples were collected up to Day 92. A non-compartmental analysis method was used to estimate pharmacokinetic parameters. For each of the three pairwise comparisons (Jamteki versus EU-Stelara, Jamteki versus US-Stelara, and US-Stelara versus EU-Stelara), the pharmacokinetic similarity standards were met both for the uncorrected and the protein content-normalized pharmacokinetic parameters. The point estimates of the geometric mean ratios of the maximum concentration observed (C_max) and the 90% confidence intervals of the geometric mean ratios of the area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC_0-t) were within the comparative pharmacokinetic bioavailability margins of 80.0% to 125.0%, as specified in Health Canada’s Guidance Document: Comparative Bioavailability Standards: Formulations Used for Systemic Effects (2018).

In Study AVT04-GL-101, the systemic exposure to ustekinumab was shown to be dependent on body weight, as previously reported for Stelara. The geometric mean values for C_max, AUC_0-t, and AUC from time 0 to infinity (AUC_0-inf) were higher in the non-Japanese subjects with lower body weight (less than or equal to 80 kg) than in the non-Japanese subjects with higher body weight (greater than 80 kg). These values were similar across the three treatment groups, indicating that differences in systemic exposure among subgroups were not specific to a treatment.

The steady-state pharmacokinetics of Jamteki and EU-Stelara was assessed in male and female patients with chronic moderate-to-severe plaque psoriasis in Study AVT04-GL-301 (described in the Comparative Efficacy, Safety, and Immunogenicity section). Mean serum trough concentrations (C_trough) of Jamteki and EU-Stelara up to Week 28 were comparable across the treatment groups. There were no clinically meaningful differences in the pharmacokinetics of Jamteki and EU-Stelara.

Comparative Efficacy, Safety, and Immunogenicity

The efficacy, safety, and immunogenicity of Jamteki in comparison to the reference drug, EU-Stelara, were assessed in study AVT04-GL-301 in patients with chronic moderate-to-severe psoriasis.

Study AVT04-GL-301 was a Phase III, multicentre, randomized, double-blind, parallel-group, active-controlled, 52-week study. It comprised two stages: Stage 1, from baseline (Day 1) to Week 15, including a double-blind, primary efficacy assessment at Week 12; and Stage 2, from Week 16 to Week 52, including a double-blind, long-term efficacy and safety assessment. In total, 581 patients were randomized in a 1:2 ratio to receive Jamteki (194 patients) or EU-Stelara (387 patients). Randomization was stratified by exposure to previous biologic treatment for psoriasis (yes/no) and by body weight category (less than or equal to 80 kg, greater than 80 kg to less than or equal to 100 kg, and greater than 100 kg). Patients received an initial dose of 45 mg (those with body weight of less than or equal to 100 kg) or 90 mg (those with body weight of greater than 100 kg) of Jamteki or EU-Stelara, administered subcutaneously on Day 1, followed by the same dose 4 weeks later and every 12 weeks thereafter (at Week 16, Week 28, and Week 40), in accordance with the recommended dosage regimen for Stelara in patients with plaque psoriasis. In Stage 2 of the study, patients who were initially randomized to the Jamteki group continued to receive the drug at the assigned dose at Week 16, Week 28, and Week 40 (referred to as Jamteki/Jamteki group). Patients who were initially randomized to the EU-Stelara group were rerandomized in a 1:1 ratio to receive Jamteki or to continue receiving EU-Stelara at Week 16, Week 28, and Week 40 (referred to as EU-Stelara/Jamteki group and EU-Stelara/EU-Stelara group, respectively).

The primary efficacy endpoint of the study was percent improvement in Psoriasis Area and Severity Index (PASI) from baseline to Week 12.

Interim comparative data collected up to Week 28 (from 96.3% of patients who completed Week 28 of the study) and results of the primary efficacy analysis were provided in the clinical data package of the submission.

Clinical similarity between Jamteki and EU-Stelara was established in accordance with acceptance criteria prespecified by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan. The analyses of the primary efficacy endpoint were performed for the per-protocol set including all patients in the per-protocol set (as required by the FDA) or including the subset of patients in the per-protocol set with body weight of less than or equal to 100 kg (as required by the EMA and PMDA). The per-protocol set is defined as all patients who have completed the study up to Week 12 without protocol deviations that may impact the efficacy assessment.

For all patients in the per-protocol set, the primary efficacy analysis demonstrated that the 90% confidence interval (CI) (-2.14%, 3.01%) for the least squares mean difference in the percent improvement in PASI from baseline to Week 12 between the Jamteki group and the EU-Stelara group was within the acceptance range of -10% to 10%, as per the FDA requirements. The results were similar in patients with body weight of less than or equal to 100 kg (90% CI: -2.71%, 2.89%). In addition, for the patients with body weight of less than or equal to 100 kg, the 95% CI (-3.25%, 3.43%) for the least squares mean difference in the percent improvement in PASI from baseline to Week 12 between the Jamteki group and the EU-Stelara group was within the acceptance range of -15% to 15%, consistent with the EMA/PMDA requirements. Similar results were obtained for the overall population (95% CI: -2.63%, 3.50%).

The robustness of the primary efficacy results was confirmed by the sensitivity analyses that used data from the intention-to-treat set up to Week 16, including observed data and data imputed by last observation carried forward method. The intention-to-treat set was defined as all randomized subjects who received at least one dose of the randomly allocated treatment.

Jamteki demonstrated a comparable safety profile with that established for its reference biologic drug. In Study AVT04-GL-301, Jamteki was received by 386 patients, including 194 patients who were treated with Jamteki in Stage 1 and continued receiving the same drug in Stage 2, and 192 patients who started treatment with Jamteki in Stage 2 after switching from EU-Stelara. The most frequently reported treatment-emergent adverse events through Week 28 were infections and infestations. There were no notable differences between treatment groups in the reported serious treatment-emergent adverse events, treatment-emergent adverse events that led to discontinuation of study treatment, and treatment-emergent adverse events of special interest. None of the serious treatment-emergent adverse events and treatment-emergent adverse events leading to discontinuation of study treatment were deemed related to study treatment. No deaths were reported in the study and no new safety signals have been identified.

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). In Study AVT04-GL-301, the incidence of treatment-emergent ADAs through Week 28 was 4.8%, 4.5%, and 6.5% in Jamteki/Jamteki, EU-Stelara/Jamteki, and EU-Stelara/EU-Stelara groups, respectively. Among the patients who had treatment-emergent ADAs, none was positive for neutralizing antibodies through Week 28. Results were similar for patients with body weight of less than or equal to 100 kg.

Overall, the submitted results of Study AVT04-GL-301 indicate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The sponsor is expected to provide the final clinical study report including all data up to Week 52.

Appropriate warnings and precautions are in place in the approved Jamteki Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Stelara. The Adverse Reactions section of the Jamteki Product Monograph is based on the clinical experience with Stelara.

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

Indications

Within this drug submission, the sponsor requested the authorization of Jamteki for all of the indications granted for the reference biologic drug, Stelara. In Canada, Stelara is authorized for the treatment of plaque psoriasis in adults, plaque psoriasis in pediatric patients 6 to 17 years of age, psoriatic arthritis in adults, Crohn disease in adults, and ulcerative colitis in adults.

Similarity between Jamteki and Stelara was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. The demonstration of similarity between a proposed biosimilar and its reference biologic drug enables the sponsor’s submission for the proposed biosimilar to rely on the safety and efficacy information already generated for the reference biologic drug, and therefore clinical trials are not required to support each of the sought indications. The sponsor provided data from a comparative clinical trial conducted in adult patients with moderate-to-severe plaque psoriasis. In addition, the sponsor provided an acceptable scientific rationale for requesting the authorization of indications that were not directly studied in the clinical development program for Jamteki. The rationale addressed each of the critical points for extrapolation of data including the mechanism of action of ustekinumab across all indications, the pharmacokinetics and biodistribution of the product in different patient populations, and the safety and immunogenicity profiles of ustekinumab across indications. The primary focus of the scientific justification was on the similarity demonstrated through comparative physicochemical and functional assessments, and clinical pharmacokinetic, efficacy, safety, and immunogenicity comparisons.

Importantly, as per the Stelara Product Monograph, in adult patients with Crohn disease and adult patients with ulcerative colitis, the recommended induction treatment regimen is a single dose based on body weight and administered intravenously from a vial presentation. Furthermore, in pediatric patients (aged 6 to 17 years) with plaque psoriasis, the vial presentation is recommended for obtaining a relevant volume for subcutaneous dosing of those weighing less than 60 kg. However, the drug submission for Jamteki only sought authorization for the prefilled syringe presentation, which is intended for subcutaneous administration. Therefore, Health Canada raised concerns over the sponsor’s request for granting all of the proposed indications for Jamteki, given the absence of a vial presentation to allow for intravenous induction dosing in adult patients with Crohn disease and adult patients with ulcerative colitis, and subcutaneous dosing based on body weight in pediatric patients (aged 6 to 17 years) with plaque psoriasis. Under such circumstances, notwithstanding the similarity demonstrated between Jamteki and Stelara, the sponsor was advised to file a Supplement to a New Drug Submission to seek authorization of the vial presentations and the said indications at a later date.

Upon review of the evidence submitted, Jamteki was authorized for the following indications:

Plaque psoriasis

Jamteki (ustekinumab) is indicated in adult patients for the treatment of chronic moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Psoriatic arthritis

Jamteki (ustekinumab) is indicated for the treatment of adult patients with active psoriatic arthritis. Jamteki can be used alone or in combination with methotrexate.