Randomized, Double-Blind, Multicenter Study on Efficacy, Safety, and Immunogenicity of Abatacept Biosimilar DRL_AB vs. Abatacept with Methotrexate in Rheumatoid Arthritis

The primary objective of this study is to compare the **efficacy** of the proposed Abatacept biosimilar (DRL_AB) with Orencia® in patients with moderate to severe **rheumatoid arthritis** who are also receiving methotrexate. This is measured by the change in DAS28-CRP from baseline to Week 25. This objective is clinically relevant as it aims to establish the therapeutic equivalence of the biosimilar to the reference product, potentially offering a more accessible treatment option for patients.

Secondary objectives include:

• **Efficacy**: Comparing the time course of efficacy using DAS28 (both ESR and CRP) and ACR20/50/70 at 4-week intervals until Week 25, and the time to first achievement of EULAR response criteria (moderate or good response).
• **Safety**: Evaluating safety and tolerability from baseline to Week 25, during the transition from Week 25 to Week 33, and from baseline to Week 53 in the long-term safety extension phase.
• **Immunogenicity**: Assessing immunogenicity during the same periods as safety.
• **Pharmacodynamics**: Comparing the effect on pharmacodynamic inflammatory markers.

The clinical trial involves a total of **231 participants** diagnosed with **Rheumatoid Arthritis**. The study population includes both male and female subjects, aged between 18 and 80 years. Participants are required to have moderately to severely active rheumatoid arthritis for at least six months, as defined by the American College of Rheumatology (ACR) criteria. All participants must be on a stable dose of methotrexate (MTX) and folic acid for at least three months prior to the study. The trial population was selected based on their ability to comply with study requirements and their current treatment regimen, which excludes the use of conventional disease-modifying antirheumatic drugs (cDMARDs) other than MTX and biological DMARDs (bDMARDs) within specified timeframes before the study. Lifestyle considerations include the use of glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs), which must be stable and within recommended doses. The study also includes vulnerable populations, ensuring comprehensive representation of the disease's impact across different demographics.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy, safety, and immunogenicity of a proposed **abatacept** biosimilar (DRL_AB) compared to Orencia®, both administered intravenously, as an add-on to methotrexate in patients with moderate to severe **rheumatoid arthritis**. The trial is expected to commence recruitment on July 1, 2024, and conclude by January 1, 2026, with a total duration of approximately 18 months. Participants will be involved in the study for a maximum of 52 weeks, during which they will receive the investigational product or comparator alongside methotrexate.

The study will include several key visits: an initial **screening visit** to assess eligibility based on inclusion criteria such as age, disease activity, and current treatment regimen, followed by a **baseline visit** where randomization occurs. Participants will then attend regular **follow-up visits** to monitor treatment response and safety, with assessments including changes in DAS28-CRP and DAS28-ESR scores, as well as the incidence of adverse events. The **end-of-study visit** will occur at the conclusion of the treatment period, where final evaluations will be conducted to assess the primary and secondary endpoints.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study protocols, or if the investigator deems it necessary for their safety. The trial will adhere to good clinical practice guidelines, ensuring that all procedures are conducted ethically and with participant safety as a priority. The study aims to provide robust data on the comparative effectiveness of the biosimilar and the reference product, contributing valuable insights into the management of rheumatoid arthritis.

The clinical trial involves the administration of **DRL_AB**, an experimental medication formulated as a **powder for concentrate for solution for infusion**. The active substance in DRL_AB is **abatacept**, a humanized monoclonal antibody. The pharmaceutical form is designed for **intravenous infusion**. The maximum daily dose is 1000 mg, with a total maximum dose of 52000 mg over a treatment period of 52 weeks. The administration schedule is determined by the study protocol, and participant compliance is monitored throughout the trial.

**ORENCIA 250 mg powder for concentrate for solution for infusion** serves as the comparator treatment in this study. It is also formulated for **intravenous infusion** and contains the active substance **abatacept**. The maximum daily dose and total dose are consistent with those of DRL_AB, at 1000 mg and 52000 mg, respectively, over a 52-week period. The product is provided by Bristol-Myers Squibb Pharma EEIG, and measures are taken to ensure blinding, including specific vial and carton labeling.

In addition to the experimental and comparator treatments, the study includes the administration of **METHOTREXATE/PFIZER** as a standard-of-care therapy. This medication is provided in **tablet** form and contains the active substance **methotrexate**, an antimetabolite cytotoxic agent. The maximum daily dose is 20 mg, with a total maximum dose of 1120 mg over a 56-week treatment period. The route of administration is **oral**, and dosing schedules are adhered to as per the study protocol, with compliance monitored throughout the trial duration.

The efficacy of the clinical trial will be assessed by evaluating the change in Disease Activity Score 28 - C-reactive protein (**DAS28-CRP**) from baseline to Week 25. This primary endpoint will be measured at Baseline and Week 13 to determine the efficacy of the proposed Abatacept biosimilar (DRL_AB) compared to Orencia® in patients with moderate to severe rheumatoid arthritis who are also receiving methotrexate. Secondary endpoints include changes from baseline in DAS28-ESR, DAS28-CRP, and the proportion of patients achieving ACR20/50/70 response. Additionally, the time to European League Against Rheumatism (EULAR) moderate or good response and the proportion of patients reaching moderate or good EULAR response based on DAS28-CRP will be evaluated.

Further assessments will include the incidence of adverse events (AEs) and serious adverse events (SAEs), as well as specific reactions such as anaphylactic and hypersensitivity reactions, infections requiring intravenous antibiotic therapy, infusion-related reactions, and new malignancies. The incidence of anti-drug antibodies (ADAs), including neutralizing antibodies (NAb) and ADA titres, will also be monitored, particularly during the transition phase. Changes in pharmacodynamic endpoints, specifically erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), will be tracked from baseline to selected time points up to Week 25. These efficacy parameters will be collected and analyzed using validated scales and laboratory tests at specified timepoints throughout the trial.