Summary Basis of Decision for Erelzi

 

Clinical Pharmacology

Etanercept, the medicinal ingredient of Erelzi, is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human immunoglobulin G1 (IgG1). It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons.

Etanercept binds specifically to soluble and cell surface tumor necrosis factor (TNF) and blocks its interaction with cell surface TNF receptors. Etanercept inactivates TNF without causing in vitro lysis of cells involved in the immune response. The protein, TNF, is a naturally occurring cytokine, or immune system protein, that is implicated in the development and progression of inflammatory, infectious, and autoimmune diseases. This cytokine (TNF) plays an important role in the inflammatory processes of rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS) and the resulting joint pathology. Elevated levels of TNF are found in the synovial fluid of RA patients and in serum and synovial tissue of patients with AS.

As part of the clinical package, the sponsor provided clinical data to demonstrate the pharmacokinetic comparability of Erelzi with its reference product Enbrel in Study GP 15-104. This study was a randomized, double-blind, two-way cross-over comparative bioavailability study conducted in 54 healthy male volunteers which compared the pharmacokinetics, safety, and immunogenicity of etanercept (the medicinal ingredient in Erelzi and Enbrel). The analyses were conducted according to the recommendations set forth in the Canadian guidance document Conduct and Analysis of Comparative Bioavailability Studies.

The study design consisted of administering a single 50 mg dose by subcutaneous injection in 54 healthy male subjects and then following these subjects for 21 days to assess pharmacokinetic, safety, tolerability, and immunogenicity of etanercept. The treatment periods were separated by a 35-day washout period between administrations.

Results from the study showed pharmacokinetic comparability between Erelzi and Enbrel in the healthy male subjects, as demonstrated by the mean ratios (expressed as percentages for nominal dose 50 mg) for area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC_last) of 98.0 (90% Confidence Interval [CI]: 94.0, 102.0) and maximum observed plasma concentration (C_max) 111.0.

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

Clinical Efficacy

The comparative clinical efficacy of Erelzi and its reference product Enbrel was evaluated primarily in one pivotal Phase III, randomized, double-blind, multicenter study (GP15-302). The primary objective of the study was to compare the efficacy, safety, and immunogenicity, as well as the effect of repeated switching between Erelzi to Enbrel in 531 patients with chronic plaque psoriasis.

Study GP15-302 evaluated patients for a duration of 52 weeks and consisted of three treatment periods as follows:

• Treatment Period 1 (up to Week 12): patients were randomized in a 1:1 ratio to either Erelzi (Group 1) (Number of patients [N] = 264) or Enbrel (Group 2) (N = 267) and were administered a dose of 50 mg biweekly (recommended starting dose in psoriasis) for 12 weeks.
• Treatment Period 2 (Week 12 to Week 30): patients who achieved at least a 50% reduction in the Psoriasis Area and Severity Index (PASI) at Week 12 were re-randomized to progress to Treatment Period 2, which included a switching component to assess the potential impact of alternating treatment with Erelzi and Enbrel. A proportion of the patients in Groups 1 and 2 were to remain on their initial treatment, and the remaining patients received alternating treatment with Erelzi or Enbrel at a dose of 50 mg once weekly for periods of 6 consecutive weeks each (i.e., switching after Week 12 and switching back to the initial treatment after Week 18 followed by a third switching after Week 24).
• Extension Period (Week 30 to Week 52): follow-up period during which patients continued to receive the last treatment that they had received during Treatment Period 2, (i.e., Erelzi or Enbrel at a dose of 50 mg once weekly).

Enrolled patients consisted of adult male and female patients of at least 18 years of age with active, but clinically stable, chronic plaque-type psoriasis involving at least 10% of the body surface area, having a minimal PASI of 10 (indicating moderate to severe psoriasis). Patients had previously received at least one phototherapy or systemic therapy for psoriasis, or were candidates to receive such therapy in the opinion of the investigator. Randomization at baseline was stratified by body weight (<90 kg; ≥90 kg) and prior systemic psoriasis therapy.

The demographic characterization was balanced between the Erelzi and the Enbrel groups with a mean age of 42.1 (18-78) versus (vs.) 42.7 (19-75), male 59.5% vs. 64.4% male, Caucasian 99.6% vs. 98.9% and mean body weight of 86.3 kg vs. 85.9 kg (60.6% vs. 60.3% <90 kg). Baseline disease characteristics were also balanced between the Erelzi and the Enbrel groups in terms of PASI scores, body surface area (BSA), and Investigator Global Assessment (IGA).

The physician assessment of psoriasis was evaluated using the IGA rating scale. The 5-point IGA scale is a modified tool for evaluating plaque psoriasis severity in clinical trials based on the standard Physician's Global Assessment, with a more stringent definition of a score of 1 (almost clear). Patients were required to have an IGA score of 3 or 4 to be eligible for enrollment.

The primary efficacy endpoint was the PASI 75 response rate (proportion of patients showing at least a 75% improvement in PASI) after the first 12 weeks of treatment (Treatment Period 1). The PASI 75 response rate at Week 12 was evaluated using the PASI scoring system which consists of a composite score which takes into consideration the severity of lesions and the area affected into a single score. The score may range from 0 (no disease) to 72 (maximal disease).

Comparability for the primary endpoint, PASI 75 response rate at Week 12, was considered as demonstrated if the 95% CI for the difference in response rates between the Erelzi and Enbrel treatment groups was completely contained within the interval (-18%; 18%) after the first 12 weeks of treatment (Treatment Period 1). The selection of this equivalence margin was based on PASI 75 response rates reported in earlier double-blind placebo controlled clinical trials conducted with the reference product.

Efficacy results from the GP15-302 study showed the PASI 75 response rate at Week 12 was 70.5% for the Erelzi treated-patients compared to 71.5% for Enbrel treated-patients. The difference in the proportion of patients achieving PASI 75 at Week 12 (Erelzi - Enbrel) was -1.1% (95% CI: -9.63%; 7.38%), and the 95% CI for this difference was contained within the specified interval (-18%; 18%), thereby demonstrating comparability between Erelzi and Enbrel.

Overall, the efficacy results from Study GP15-302 demonstrated comparability between Erelzi and Enbrel.

The clinical data presented, in combination with the results derived from comparative physiochemical and biological assays, provide sufficient evidence of similarity to support the authorization of Erelzi for use in adult patients with RA, AS and in patients (aged 4 to 17 years) with JIA who have had an inadequate response to one or more DMARDs.

Indication

In the New Drug Submission (NDS) for Erelzi, the sponsor sought market authorization for the following indications for which the Canadian reference product Enbrel is approved:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis (4 - 17 years of age)
• Ankylosing spondylitis

and an indication below which is not an approved indication for Enbrel:

 

• reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis. Erelzi can be used in combination with methotrexate in adult patients who do not respond adequately to methotrexate alone.

In accordance with Health Canada's Guidance for sponsors: Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document, "A biosimilar sponsor may request authorization for all indications held by the biologic drug authorized in Canada to which a reference is made". The last indication requested for Erelzi fell out of scope in reference to Enbrel's authorized indications, and therefore was not included as part of Health Canada's review. As a result, and upon Health Canada's request the sponsor withdrew this indication from the submission.

To ensure safe and effective use of the product, Health Canada approved the following indications:

Erelzi (etanercept) is indicated for:

• treatment of moderately to severely active rheumatoid arthritis (RA) in adults. Treatment is effective in reducing the signs and symptoms of RA, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function. Erelzi can be initiated in combination with methotrexate (MTX) in adult patients or used alone.
• reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients aged 4 to 17 years who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). Erelzi has not been studied in children less than 4 years of age.
• reducing signs and symptoms of active ankylosing spondylitis (AS).

Due to the dosage form and strength availability planned for Erelzi, the following additional statement was also deemed necessary for inclusion:

Only pediatric patients weighing 63 kg (138 pounds) or more, who do not require weight-based dosing, can be treated with the Erelzi 50 mg pre-filled syringe or the Erelzi 50 mg auto-injector pen. Patients weighing less than 63 kg should be accurately dosed on a mg/kg basis with other etanercept products.

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

Clinical Safety

The clinical safety of Erelzi was evaluated in comparison to its reference product, Enbrel, primarily in a Phase III clinical trial (GP15-302) conducted in patients with moderate to severe plaque-type psoriasis previously described in the Clinical Efficacy section. Although treatment of moderate to severe plaque psoriasis is an indication not being claimed in this submission (it is an indication held by Enbrel), the rationale for selecting this patient population was that these patients represent an adequately sensitive patient population to detect potential clinically meaningful differences in efficacy and safety when comparing Erelzi to Enbrel. As a result, authorisation of the three claimed indications (RA, JIA, and AS) was requested by way of similarity between Erelzi and the reference biologic drug.

Overall, safety profiles in patients with moderate to severe plaque-type psoriasis receiving multiple doses of Erelzi or Enbrel for 52 weeks were consistent with the known safety profile of Enbrel. The differences observed between the patients treated with Erelzi or Enbrel were not considered clinically meaningful in terms of nature, frequency and severity of treatment-emerged adverse events (AE), AEs leading to treatment discontinuation, and the AEs of special interest. The most commonly reported AEs were infections and infestations, and skin and subcutaneous tissue disorders, in both treatment groups.

In the GP15-302 study, immunogenicity of Erelzi and Enbrel was also assessed in 531 psoriasis patients. Up to Week 12, 5 patients (1.9%) were confirmed positive for binding anti-drug antibodies (ADAs) in the Enbrel group, while all patients in the Erelzi group were negative for binding ADAs. By the end of the study at week 52, one additional patient had tested positive for ADA binding while on Erelzi treatment. All positive ADA results had low titers, were transient and negative for neutralizing capacity.

Based on observed results as noted above, Erelzi was shown to be consistent with the known safety profile of Enbrel. Etanercept (the medicinal ingredient of Enbrel and Erelzi) has over four million patient-years of post-market exposure. The Adverse Reactions section of the Erelzi Product Monograph is based on the clinical experience with the reference product Enbrel, and some of this information is noted below.

Among patients with RA treated in placebo-controlled studies, serious adverse events occurred at a frequency of 4% in 349 patients treated with etanercept compared to 5% of 152 placebo-treated patients. In a subsequent study (Study III), serious adverse events occurred at a frequency of 6% in 415 patients treated with etanercept compared to 8% of 217 methotrexate-treated patients. In long-term open-label studies in adults with RA, there were no new or unexpected serious adverse events reported.

Among RA patients in placebo-controlled, active-controlled, and open-label trials of etanercept, infections and malignancies were the most common serious adverse events observed. As such, infections and malignancies are specially referred to in a Serious Warnings and Precaution box and the Warnings and Precautions section of the Erelzi Product Monograph. These sections highlight that serious infections leading to hospitalization or death, including sepsis, tuberculosis, invasive fungal and other opportunistic infections have been observed with the use of TNF blocking agents, including etanercept. Treatment with Erelzi should not be initiated in patients with active infection, including tuberculosis, chronic or localized infections. Caution should be exercised when considering the use of Erelzi in patients with a history of recurring or latent infections, including tuberculosis, or with underlying conditions, which may predispose patients to infections, such as advanced or poorly controlled diabetes. Before starting treatment with Erelzi, all patients should be evaluated for both active and inactive ('latent') tuberculosis. Patients should be monitored for the development of signs and symptoms of infection during and after treatment with Erelzi, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

In post-marketing studies of patients with JIA, serious infections have been reported in approximately 3% of patients. Sepsis has also been reported in the post-market setting (0.8%). Erelzi is contraindicated in patients with, or at risk of, sepsis syndrome, such as immunocompromised and human immunodeficiency virus (HIV)-positive patients.

Furthermore, the Serious Warnings and Precautions box points out that, lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including etanercept.

In controlled trials, the proportion of patients who discontinued treatment due to AEs was approximately 4% in both the etanercept and placebo treatment groups. Among patients with RA in placebo-controlled studies, deaths occurred in 10 of 2,696 (0.37%) etanercept-treated patients compared to 3 of 1,167 (0.26%) placebo-treated patients. In controlled and uncontrolled RA studies there were 58 deaths in 6,973 patients treated with at least one dose of etanercept over an exposure period of 11,765 patient-years (exposure-adjusted rate of 0.49). In the long-term open-label RA studies, the rate of death did not increase over time with increasing exposure to etanercept. No deaths were reported in AS or JIA studies.

Overall, the safety profile of Erelzi is considered comparable to that which has been established for its reference product Enbrel. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions box and the Warnings and Precautions section of the Erelzi Product Monograph.

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