Lupin's Proposed Etanercept Biosimilar Shows Similarity to Enbrel, Has Lower Immunogenicity

In May of 2018, drug maker Lupin announced that the European Medicines Agency would review its application for YLB113, a proposed etanercept biosimilar referencing Enbrel. This week, results of a phase 3 study of the biosimilar in patients with rheumatoid arthritis (RA) revealed the similarity of the product with its reference, and also demonstrated that the product has lower immunogenicity than the reference drug.

The study, published in Rheumatology and Therapy, was conducted at 101 centers in Europe, Japan, and India. In total, 528 patients with RA were randomized to receive either the biosimilar (n = 266) or the reference (n = 262) at a dose of 50 mg once per week for 24 weeks with methotrexate. Patients who completed week 24 evaluations were then assigned to remain on their initial treatment (n = 471) or to switch to the other etanercept product (n = 18).

The primary end point of the first stage of the study was the percentage of patients who achieved American College of Rheumatology criteria for 20% improvement (ACR20) at week 24; the percentage was 87.1% in the reference arm and 81.3% in the biosimilar arm in the full analysis set population, for a difference of −5.8% (95% CI, −11.8% to 0.2%), which fell within the prespecified equivalence margin (±15%). The results were confirmed in the per protocol set population, with 90.6% of patients achieving ACR20 in the reference arm versus 86.0% of patients in the biosimilar arm, for a difference of −4.6% (95% CI, −10.1% to 0.8%).

In terms of safety, in the first period of the study, 60.3% of patients had at least 1 treatment-emergent adverse event (AE). The incidence of AEs considered related to the study drug was higher in the reference product arm (35.8%) than the biosimilar arm (22.0%), but the incidence of AEs leading to discontinuation was comparable. No new safety signals were reported.

In the patients who continued their same treatment in the second period, 26.4% of patients in the reference arm and 11.9% of patients in the biosimilar arm reported an AE considered related to etanercept. In the switch group, 25.0% and 10.0%, respectively, reported treatment-related AEs.

Immunogenicity was assessed by measuring the presence of antidrug antibodies (ADAs) before and after dosing with etanercept. The percentage of patients who tested positive for ADAs at any time during the 52 weeks of treatment, pooled from the first stage and the second stage in patients who continued on their same treatment, was lower (0.8%) in the biosimilar group than in the reference group (9.4%). Two patients in the reference group had neutralizing antibodies, versus no patients in the biosimilar group. In the switch group, 1 patient who switched from the biosimilar to the reference had an injection-site reaction (ISR) and ADA formation at week 36, but not at week 52.

“These results indicate that ISRs and ADAs may be dependent on product-specific variables (eg, product aggregation or impurities) or other factors,” write the authors.

According to the authors, the results of this study demonstrate the biosimilarity of YLB113 and its reference, and the lower immunogenicity of the proposed product does not impact its ability to be classified as a biosimilar, given its similar efficacy and safety.

Reference

Yamanaka H, Kamatani N, Tanaka Y, et al. A comparative study to assess the efficacy, safety, and immunogenicity of YLB113 and the etanercept reference product for the treatment of patients with rheumatoid arthritis [published online December 12, 2019]. Rheumatol Ther. doi: doi: 10.1007/s40744-019-00186-3.