Summary Basis of Decision for Rymti

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.

The submission included a Phase I comparative pharmacokinetic study in healthy volunteers and a Phase III comparative efficacy study in patients with active rheumatoid arthritis. The sponsor’s approach to supporting a lack of clinically meaningful difference involved demonstrating comparative biopharmaceutics as well as the safety, efficacy, and immunogenicity of Rymti compared to the reference biologic drug.

Comparative Pharmacokinetic and Pharmacodynamic Studies

Etanercept, the medicinal ingredient in Rymti, binds specifically to soluble and cell surface tumour 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. Tumour necrosis factor is a naturally occurring cytokine, or immune system protein, that is implicated in the development and progression of inflammatory, infectious, and autoimmune diseases. It plays an important role in the inflammatory processes of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, and the resulting joint pathology. In addition, TNF plays an important role in the inflammatory process of plaque psoriasis and resulting skin pathology. Elevated levels of TNF are found in the synovial fluid of patients with rheumatoid arthritis, in both the synovium and psoriatic plaques of patients with psoriatic arthritis and plaque psoriasis, and in serum and synovial tissue of patients with ankylosing spondylitis. In plaque psoriasis, infiltration by inflammatory cells including T cells leads to increased TNF levels in psoriatic lesions, compared with levels in uninvolved skin.

Two distinct receptors for TNF, a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNF receptor. Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules. This dimeric binding provides substantially greater competitive inhibition of TNF than monomeric soluble receptors. Much of the joint pathology in rheumatoid arthritis is mediated by proinflammatory molecules that are linked in a network controlled by TNF. Etanercept competitively inhibits binding of both TNF alpha (TNF‑α) and lymphotoxin α to cell surface TNF receptors, rendering TNF biologically inactive. Etanercept does not cause lysis of TNF-producing cells in vitro, in the presence or absence of complement.

Study ETA.50/334 was a Phase I, randomized, open-label, active-controlled, single dose crossover study evaluating the pharmacokinetics of Rymti or Enbrel sourced from the European Union (EU‑Enbrel) in healthy male volunteers. The primary objective of this study was to compare the relative bioavailability of Rymti and EU‑Enbrel. Each subject received two 50 mg subcutaneous injections of either Rymti or EU‑Enbrel 28 days apart.

Serum samples were collected up to Day 20 and a non-compartmental analysis method was used to estimate pharmacokinetic parameters. The study demonstrated pharmacokinetic comparability between Rymti and EU‑Enbrel; the point estimate for the Rymti and EU‑Enbrel geometric least square mean ratio for the maximum concentration and the 90% confidence intervals (CI) for the area under the concentration versus time curve to the time of the last quantifiable concentration were within the prespecified comparability margins of 80.0% to 125.0%.

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

Comparable Clinical Efficacy, Safety, and Immunogenicity

Study YLB113-002 was a Phase III, randomized, double-blind, active controlled study that was conducted to compare the efficacy, safety, and immunogenicity of 50 mg/mL of Rymti or Enbrel, administered once a week as a subcutaneous injection in patients with active moderate to severe rheumatoid arthritis despite methotrexate therapy. The primary comparison was performed at Week 24 of treatment with additional safety and immunogenicity data presented up to Week 52. The study randomized 524 patients to Rymti or Enbrel in a 1:1 ratio, with 497 patients included in the primary analysis population.

The study included male and female patients aged 18 to 75 years with diagnosed rheumatoid arthritis according to the American College of Rheumatology (ACR) classification criteria. For the primary analysis time point at Week 24, the median age of patients was 53.0 years. Overall, the majority of the patients were female (409 [78.1%]). The mean weight was 66.1 (±16.30) kg with the mean body mass index of 24.9 (±5.18) kg/m². Approximately half of the patients were randomized in Japan (49.8%) and the rest were randomized in Europe (44.1%) and India (6.1%). Baseline characteristics were comparable across treatment groups.

The primary endpoint was the proportion of patients that achieved a 20% reduction in the ACR score (ACR20) at Week 24. The response rate of Rymti and Enbrel from baseline was compared at Week 24 with a predefined equivalence margin of (‑15%, 15%). The objective of the study would be met if the two-sided 95% CI of the difference between the ACR20 responses at Week 24 fell entirely within the equivalence margin.

The study met its primary objective. At Week 24, the proportion of patients achieving an ACR20 response in the Rymti and Enbrel groups was 81.3% and 87.1%, respectively. The results of the study demonstrated a difference of ‑5.8% (95% CI [‑11.8, 0.2]), which was found to fall within the predefined equivalence margin of (‑15%, 15%). Secondary endpoints, ACR50 and ACR70 response rates at additional time points, supported the comparability of Rymti and Enbrel. Sensitivity analyses supported the primary analysis. These responses were comparable up to Week 52.

For the primary assessment period (Week 24), there was at least one treatment emergent adverse event (TEAE), experienced by 316 (60.3%) patients in the Rymti (146 [55.3%]) and Enbrel (170 [65.4%]) groups. The most frequently reported TEAEs overall were nasopharyngitis (56 [10.7%]), injection site reaction (45 [8.6%]), injection site erythema (30 [5.7%]), abnormal hepatic function (17 [3.3%]), rheumatoid arthritis (12 [2.3%]), and headache (12 [2.3%]). There were no deaths reported in the study and no new safety signals were identified. The reported incidence and impact of immunogenicity was comparable, with a numerically lower incidence of anti-drug antibodies in the Rymti group that was not clinically meaningful. Overall, the safety and immunogenicity profile of Rymti was comparable with that of Enbrel and was consistent with clinical studies carried out for the reference biologic drug.

Overall, Rymti demonstrated a comparable benefit/risk profile for the treatment of rheumatoid arthritis to the Canadian reference biologic drug, Enbrel. Based on the sponsor’s rationale and scientific justification, this favourable profile is extended to other indications that are authorized for the Canadian reference product, in line with relevant guidelines. Overall, the benefit/risk profile of Rymti is considered to be favourable for the authorized indications.

Appropriate warnings and precautions are in place in the approved Rymti Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Enbrel, including a Serious Warnings and Precautions box describing the risk of serious infections and malignancies.

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

Indications

Rymti is considered to be biosimilar to Enbrel, the reference biologic drug. Enbrel is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Enbrel is authorized are rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and plaque psoriasis in adult and pediatric patients.

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

Similarity between Rymti and Enbrel 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 Rymti and the reference biologic drug, in structural, functional, non-clinical, clinical pharmacokinetic, and clinical efficacy and safety comparisons.