Comparative Study of Efficacy, Safety, Pharmacokinetics, and Immunogenicity of MB04 and EU-Sourced Etanercept in Moderate to Severe Rheumatoid Arthritis

The primary objective of this study is to compare the **efficacy** of MB04 with European Union (EU)-sourced Enbrel® at Week 24 in terms of the American College of Rheumatology 20% response criteria (ACR20) in patients with moderate to severe **rheumatoid arthritis** (RA) on methotrexate (MTX) therapy. This comparison is clinically relevant as it aims to establish the therapeutic equivalence of MB04, a proposed etanercept biosimilar, to the established treatment, Enbrel®, thereby potentially expanding treatment options for RA patients.

Secondary objectives include:

• Evaluating the efficacy of MB04 compared to EU-sourced Enbrel® using a time response model for ACR20 and other relevant efficacy endpoints at Week 24, and assessing effect maintenance at Week 36.
• Assessing and comparing the trough concentrations (Ctrough) of MB04 with EU-sourced Enbrel®.
• Evaluating and comparing the safety, tolerability, and immunogenicity of MB04 and EU-sourced Enbrel®.
• Assessing and comparing pharmacokinetics (Ctrough), safety, tolerability, and immunogenicity of MB04 after a single transition from EU-sourced Enbrel® to the biosimilar candidate.

The clinical trial involves a total of **148 participants** diagnosed with **Rheumatoid Arthritis**. The study population comprises both male and female adults aged between 18 to 75 years. Participants were selected based on their diagnosis of moderate to severe rheumatoid arthritis, with a disease duration of at least six months but less than 15 years. All participants are on a stable dose of methotrexate therapy, ranging from 10 to 25 mg weekly, for at least 12 weeks prior to randomization. Additionally, they may be on a stable dose of NSAIDs, other analgesics, or prednisone, provided these have been consistent for a minimum of four weeks before randomization. The trial includes individuals who are otherwise medically stable, as determined by the investigator. Participants are required to use highly effective contraceptive methods up to six months after the last dose. The trial population includes a vulnerable group, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics.

The clinical trial is designed as a **randomized**, **double-blind**, parallel-group study to evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of MB04 compared to EU-sourced Enbrel® in patients with moderate to severe **rheumatoid arthritis**. The trial will involve adult participants aged 18 to 75 years who have been diagnosed with rheumatoid arthritis for at least six months and are on stable methotrexate therapy. The study will span approximately 36 weeks, with the primary endpoint being the American College of Rheumatology 20% response criteria (ACR20) at Week 24. Secondary endpoints include ACR20 response rates at Weeks 4, 8, 12, and 36, as well as ACR50 and ACR70 response rates, changes in the disease activity score at 28 joints (DAS28), and other related measures.

Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to assess eligibility based on the inclusion criteria. Following randomization, participants will attend follow-up visits at Weeks 4, 8, 12, 24, and 36 to monitor treatment effects and safety. The end-of-study visit will occur at Week 36, marking the conclusion of the participant's involvement in the trial. The expected length of participant involvement is approximately 36 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The investigational product, MB04, and the comparator, Enbrel®, will be administered subcutaneously in a solution for injection in pre-filled syringes, with a maximum daily dose of 50 mg and a total dose not exceeding 1800 mg over the treatment period.

The clinical trial involves the administration of two **etanercept**-based treatments to evaluate their efficacy, safety, pharmacokinetics, and immunogenicity in patients with moderate to severe rheumatoid arthritis. The experimental medication, identified by the sponsor product code MB04, is a **solution for injection in a pre-filled syringe**. This formulation is produced by MABXIENCE RESEARCH SL and is classified under the ATC code L04AB01, which pertains to tumor necrosis factor alpha (TNF-α) inhibitors. The active substance, etanercept, is a protein of non-human origin. The medication is administered subcutaneously at a maximum daily dose of 50 mg, with a total maximum dose of 1800 mg over a treatment period of 36 weeks. The pre-filled syringe used for administration is equipped with a BD's syringe Hypak with a 29 ½ G needle and West's plunger stopper WESTAR, although it does not possess a CE mark.

The comparator treatment in the study is the commercially available Enbrel 50 mg solution for injection in a pre-filled syringe, manufactured by PFIZER EUROPE MA EEIG. This product is also a **solution for injection** and contains the same active substance, etanercept, which is similarly classified as a protein of non-human origin. The administration route is subcutaneous, with the same dosing regimen as the experimental medication: a maximum daily dose of 50 mg and a total maximum dose of 1800 mg over 36 weeks. The pre-filled syringe used for Enbrel does not have a specified trade name for the device, and it also lacks a CE mark. Both treatments are administered in conjunction with methotrexate (MTX) therapy, which is a standard-of-care therapy for rheumatoid arthritis.

The efficacy of the investigational product MB04 will be assessed in a clinical trial comparing it to EU-sourced Enbrel® in patients with moderate to severe **Rheumatoid Arthritis** (RA) who are on methotrexate (MTX) therapy. The primary endpoint for evaluating efficacy is the American College of Rheumatology 20% response criteria (ACR20) at Week 24, which measures the proportion of patients achieving a 20% improvement in RA symptoms. Secondary endpoints include ACR20 response rates at Weeks 4, 8, 12, and 36, as well as ACR50 and ACR70 response rates at the same timepoints. Additional secondary endpoints involve changes in the disease activity score at 28 joints (DAS28), the numeric index of the ACR response (ACR-N) at Week 24, and the area under the curve (AUC) for both ACR-N and DAS28 changes from the first administration up to Week 24. The European League Against Rheumatism (EULAR) response classification will also be evaluated from the first administration up to Week 24.