Summary Basis of Decision for Idacio

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 in support of the indications being sought, and therefore clinical trials are not required to support each indication.

For biosimilars, the purpose of the clinical program 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.

Idacio (adalimumab) is a biosimilar to Humira (adalimumab), which has been authorized in Canada since 2004. Adalimumab is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody produced in Chinese hamster ovarian (CHO) cells that specifically targets tumour necrosis factor alpha (TNF-α). It is a biologic disease modifying anti‑rheumatic agent used in the management of a variety of immune-mediated conditions with shared inflammatory pathways involving TNF-α. In Canada, adalimumab is authorized for the treatment of adult rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, ulcerative colitis; adult and pediatric Crohn's disease and hidradenitis suppurativa; and pediatric polyarticular juvenile idiopathic arthritis and uveitis.

Two clinical studies were conducted to demonstrate similarity with respect to pharmacokinetics, efficacy, safety, and immunogenicity: a Phase I pharmacokinetic study in healthy adult subjects (Study EMR200588-001) and a comparative Phase III efficacy and safety study in subjects with moderate to severe plaque psoriasis (Study EMR200588-002).

Comparative Pharmacokinetics

Adalimumab binds specifically to TNF-α and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF‑β). Tumour necrosis factor is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis, including polyarticular juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis and play an important role in both pathologic inflammation and joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques, which contribute to the inflammatory response, to the proliferation and decreased maturation of keratinocytes and to the associated vascular damages that are characteristic of the disease. Increased levels of TNF are also found in hidradenitis suppurativa lesions.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (endothelial leukocyte adhesion molecule‑1 [ELAM‑1], vascular cell adhesion molecule‑1 (VCAM‑1), and intercellular adhesion molecule‑1 (ICAM‑1) with a half-maximal inhibitory concentration [IC₅₀] of 1 to 2 x 10^-10M].

As part of the clinical development program, a Phase I study (Study EMR200588-01) was conducted to compare the pharmacokinetic profiles of Idacio, Humira sourced from the United States (US Humira), and Humira sourced from the European Union (EU Humira). The randomized, double-blind, parallel-group, single-dose study included 237 healthy adult subjects, each of whom received a single subcutaneous dose of 40 mg of Idacio, US Humira, or EU Humira on Day 1. The pharmacokinetic parameters were assessed by a non-compartmental analysis.

Overall, demographic characteristics were similar between treatment arms. The mean age of the randomized subjects was 32.7 years (range: 18 to 56 years). The mean weight was 77.6 kg (range: 60.2 to 94.8 kg) and the mean body mass index was 24.9 kg/m² (range: 20.06 to 29.79 kg/m²), in accordance with the inclusion criteria. The majority of subjects were male (99.2%) and Caucasian (68.8%). As EU Humira was designated as the reference biologic product in the Idacio development program, the following results focus on the pharmacokinetic comparison between Idacio and EU Humira.

The results of the study demonstrated pharmacokinetic comparability between Idacio and EU Humira. The point estimate for the Idacio and EU Humira geometric least square mean ratios for the maximum serum concentration (C_max) and the 90% confidence interval (CI) for the area under the concentration-time curve measured from the time dosing to the last measurable concentration (AUC_T) were within the acceptance margins of 80.0% to 125.0%.

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

Comparative Clinical Efficacy and Safety

In the absence of a pharmacodynamic endpoint to rule out differences in clinical efficacy, the comparative clinical efficacy of Idacio and its reference biologic drug Humira was evaluated in a pivotal Phase III efficacy and safety study (Study EMR200588-002). Study EMR200588-002 was a double-blind, randomized controlled study in patients with moderate to severe plaque psoriasis to demonstrate equivalence between the investigatory product Idacio and the reference product EU Humira. Patients with plaque psoriasis were selected due to the relatively high treatment effect and immunogenicity rates observed in the Humira clinical studies in this indication. Plaque psoriasis is a disease where sensitive, clinically meaningful, and measurable clinical efficacy endpoints exist. There were 69 study sites that recruited subjects in North America, South America, and Europe, including 9 sites in Canada that enrolled 51 patients. The total study duration was 54 weeks, with a 15‑week core treatment period (Weeks 1-16) followed by a 37‑week extended treatment period (Weeks 16-52, with treatment to Week 50) and a safety follow-up period.

A total of 443 subjects were randomized 1:1 to receive Idacio (number of patients [n] = 222) or EU Humira (n = 221). Doses were administered as a subcutaneous injection using a pre-filled syringe at an initial dose of 80 mg on Day 1 of Week 1 (baseline), followed by 40 mg every other week starting at Week 2 (1 week after the initial dose) up to and including Week 14.

After completion of the core treatment period, patients who achieved a Psoriasis Area and Severity Index (PASI) score reduction of ≥50% from Baseline (PASI 50) entered a 37‑week extended treatment period, including a treatment transition. Patients on EU Humira were re-randomized 1:1 to receive either Idacio or EU Humira at Week 16 (Idacio patients remained on that treatment). All patients received doses of 40 mg every other week up to Week 50, with a final assessment at Week 52 (end of the extended treatment period).A total of 93.7% of patients completed the core treatment period and 90% the patients who continued into the extended treatment period completed it.

Demographic variables were well balanced between the two randomized treatment arms at baseline. Of the enrolled patients, 67% were male and 91% were Caucasian. The mean patient age was 43.6 years (range 19-74 years) and the mean patient weight was approximately 80 kg. At baseline, 86.7% of patients had previously used a biologic therapy for plaque psoriasis. The mean PASI score was 21 (range 12-61.8), the mean percent body surface area affected was 29%, 70% had a Physician's Global Assessment (PGA) score of 3 (moderate), and the remaining 30% had a PGA score of 4 (severe).

The primary endpoint was PASI 75 achievement, the percentage of patients with a 75% reduction in their PASI score from baseline, at Week 16. This is a validated and commonly-used method of assessing improvement in plaque psoriasis signs and symptoms. The primary analysis used a pre-specified equivalency margin of the 95% CI of the mean difference between groups being within the range of ±18%.

At Week 16, 86.0% of Idacio patients and 83.3% of EU Humira patients achieved PASI 75, for a mean difference of 2.7% and a 95% CI of -4.00% to +9.57%, therefore achieving equivalency. Sensitivity and subgroup analyses were consistent with the primary analysis. Supportive endpoints, including PASI 90, PASI 100, and PGA response, showed similar responses in the Idacio and EU Humira arms. At Week 52, of the patients who had achieved at least a partial response (≥PASI 50) at Week 16, ~86% retained a PASI 75 response, ~78% retained a PASI 90 response, and ~67% retained a PASI 100 response.

The clinical efficacy study indicated there are no clinically meaningful differences between the biosimilar and the reference biologic drug.

With respect to clinical safety profile, a few differences were observed between the Idacio and EU Humira arms. A higher number of patients experienced serious adverse events (SAEs) in the Idacio group as compared to the EU Humira group. Other safety endpoints were generally similar between the two treatment groups. Overall, ~76% of patients experienced treatment-emergent adverse events (TEAEs), ~33% experienced adverse drug reactions (ADRs), and ~7% experienced SAEs. The types of AEs that occurred in the study were consistent with the known profile for Humira, with infections being the most common in both treatment groups (19.5%). Treatment-emergent adverse events that occurred in ≥5% of patients in the core treatment period included nasopharyngitis (6.4%), injection site erythema (5.5%), and injection site pain (5.0%), and these occurred in similar proportions of patients in each arm.

The safety and tolerability of Idacio, as compared to US Humira and EU Humira was also evaluated as a secondary objective in the Phase I Study EMR200588-01 (described in the Comparative Pharmacokinetics section) conducted in healthy subjects. No deaths or SAEs related to the study drug were reported. At least one TEAE was reported for 49 subjects (62.8%; 95 TEAEs) in the Idacio arm, for 45 subjects (56.3%, 82 TEAEs) in the US Humira arm, and for 49 subjects (62.0%; 86 TEAEs) in the EU-approved Humira arm.

The most frequently reported TEAE was headache. No serious infections were reported. Hypersensitivity reactions were reported for 2 subjects (2.6%) in the Idacio arm, for 2 subjects (2.5%) in the US Humira arm, and for 6 subjects (7.6%) in the EU Humira arm.

No safety concerns based on laboratory measurements, vital signs, or 12-lead electrocardiogram (ECG) were reported.

Based on results from the studies above, the safety profiles between the Idacio and the reference product, EU Humira, are clinically comparable and are consistent with the known safety profile of Humira as currently labelled in Canada. Discrepancies between groups were not of substantial magnitude or consistency to conclude clinically meaningful differences in safety profile between the two drugs.

As with Humira, appropriate warnings and precautions are in place in the approved Idacio Product Monograph to address the identified safety concerns. In addition, similar to Humira, a Serious Warnings and Precautions box describing reports of hepatosplenic T-cell lymphoma, infections, and pediatric malignancies in patients treated with TNF‑blockers has been included in the Product Monograph for Idacio.

Overall, the safety profile of Idacio is considered to be comparable to that which has been established for the reference biologic drug Humira. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warning and Precautions section of the Idacio Product Monograph, as they are in the Product Monograph for Humira.

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

Comparative Immunogenicity

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). The immuogenicity of Idacio relative to that of its reference biologic drug, Humira, was evaluated the pivotal Phase III Study EMR200588‑002. In addition, immunogenicity was evaluated as a secondary objective in the Phase I Study EMR200588‑01 (described in the Comparative Pharmacokinetics section).

In the Phase III study, approximately 90% of patients in each treatment arm developed ADAs and about half of those developed neutralizing antibodies. Consistent with the known impact of ADAs and neutralizing antibodies on Humira, serum adalimumab levels and associated clinical efficacy were lowered in patients that developed antibodies. However, given the high rate of ADA development, the magnitude of the difference cannot be definitively quantified based on actual patient data. In terms of safety, there were no strong or consistent trends indicating increased risks over time as more patients developed ADAs or after rates had reached a plateau during longer-term maintenance treatment. There were no differences between Idacio and EU Humira terms of rates of ADAs or their impacts on pharmacokinetics or efficacy.

Results from the Phase I study demonstrated that the ADA incidence was comparable across the three treatment arms. The overall incidence rate of ADA was 82.1% (64 of 78), 81.3% (65 of 80), and 83.5% (66 of 79) for Idacio, US Humira, and EU Humira, respectively. The overall serum concentrations appeared to be lower in the ADA-positive subjects compared to those observed in the ADA-negative subjects for all three treatment arms. The pharmacokinetics were similar among the three treatment groups for ADA-positive versus ADA-negative subgroup analysis.

Indications

Idacio is considered to be biosimilar to Humira, the reference biologic drug. Humira is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Humira is authorized are rheumatoid arthritis, axial spondyloarthritis (including ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis), psoriatic arthritis, chronic plaque psoriasis, Crohn's disease, ulcerative colitis, hidradenitis suppurativa, and uveitis.

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

Similarity between Idacio and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. 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 Idacio and the reference biologic drug in structural and functional studies, mechanism of action, pharmacological effect, pathophysiological mechanism of the diseases or conditions involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug.