Evaluation of Rapcabtagene Autoleucel Versus Standard Treatment in Severe Refractory Idiopathic Inflammatory Myopathies: A Phase 2 Randomized Controlled Trial

The primary objective of this study is to demonstrate the superiority of **rapcabtagene autoleucel** at a target dose of CAR-positive viable T cells, administered as a single infusion, over a comparator treatment chosen by the investigator. This will be assessed by achieving at least a moderate improvement in the Total Improvement Score (TIS) at Week 52 for participants who are MSA-positive. This objective is clinically relevant as it aims to provide a more effective treatment option for patients with severe refractory idiopathic inflammatory myopathies, potentially improving their quality of life and disease management.

Secondary objectives include demonstrating the superiority of rapcabtagene autoleucel over the comparator in several aspects:

• Achieving at least moderate improvement (TIS ≥ 40) at Week 52 for participants.
• Reducing cumulative use of glucocorticoids from baseline to Week 52 for MSA-positive participants.
• Improving pulmonary function at Week 52 in MSA-positive participants.
• Achieving major improvement (TIS ≥ 60) at Week 52 for MSA-positive participants.
• Reducing fatigue at Week 52 for MSA-positive participants.
• Reducing cumulative use of glucocorticoids from baseline to Week 52.
• Improving pulmonary function at Week 52 in participants.
• Achieving major improvement (TIS ≥ 60) at Week 52 for participants.
• Reducing fatigue at Week 52 for participants.
• Evaluating the overall safety and tolerability of rapcabtagene autoleucel.

The clinical trial involves a total of **45 participants** diagnosed with **severe refractory idiopathic inflammatory myopathies (IIM)**. The study population includes both male and female participants aged over 18 and up to 65 years. Participants were selected based on their diagnosis of probable or definite myositis according to the American College of Rheumatology/European League Against Rheumatism 2017 criteria, and they must be positive for myositis-specific autoantibodies (MSA). The trial includes individuals who have shown an inadequate response to high-dose glucocorticoids and at least two other therapeutic agents. The population is characterized by the presence of active disease, confirmed by an adjudication committee, and severe myositis at screening. The trial also considers vulnerable populations, ensuring comprehensive representation within the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, controlled study to evaluate the efficacy and safety of **rapcabtagene autoleucel** in participants with severe refractory idiopathic inflammatory myopathies. The trial aims to demonstrate the superiority of rapcabtagene autoleucel, administered as a single infusion, over a comparator treatment chosen by the investigator. The primary endpoint is achieving at least a moderate improvement in the Total Improvement Score (TIS) at Week 52 for MSA-positive participants. Secondary endpoints include changes in the adjusted annual cumulative glucocorticoid dose, percent predicted Forced Vital Capacity (FVC%), and Patient-Reported Outcome Measurement Information System (PROMIS)-Fatigue 7a, as well as safety parameters such as vital signs, adverse events, laboratory parameters, and ECG evaluation.

The trial is expected to commence recruitment on January 31, 2025, and conclude by March 4, 2030. Participants will be involved in the study for a maximum treatment period of 104 weeks. The study includes several key visits: an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and MSA positivity; regular follow-up visits to monitor treatment response and safety; and an end-of-study visit to assess the final outcomes. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent.

Eligible participants must be adults aged over 18 and under 65 years, with a diagnosis of probable or definite myositis according to the American College of Rheumatology/European League Against Rheumatism 2017 criteria. They must also have an inadequate response to high-dose glucocorticoids and two other therapeutic agents. The study will exclude individuals who do not meet these criteria or who have conditions that could interfere with the study's objectives. The trial's design and methodology ensure a rigorous evaluation of the investigational product's efficacy and safety, contributing valuable data to the understanding and treatment of severe refractory idiopathic inflammatory myopathies.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Rapcabtagene autoleucel** (YTB323) is the primary experimental treatment. It is a **dispersion for infusion** containing autologous T cells transduced with a lentiviral vector encoding a chimeric antigen receptor targeting CD19. This cell therapy is administered via **intravenous use** as a single infusion, with a maximum treatment period of 1 day. The dosing is based on a target number of CAR-positive viable T cells, and participant compliance is monitored through standard clinical trial procedures.

**Mycophenolic acid** is provided in the form of **gastro-resistant tablets** and is administered **orally**. The maximum treatment period for this medication is 104 weeks. **Mycophenolate mofetil**, another form of mycophenolic acid, is administered as **hard capsules** also via the **oral route** with the same maximum treatment period of 104 weeks. Both medications are chemically derived and serve as comparator treatments in the trial.

**Cyclophosphamide** is available as a **powder for solution for injection/infusion** and is administered via **intravenous use**. The maximum treatment period for cyclophosphamide is 6 weeks. It is a chemically derived substance used as a comparator in the study.

**Rituximab** is provided as a **concentrate for solution for infusion** and is administered through **IV infusion**. The maximum treatment period for rituximab is 104 weeks. It is a biological product with orphan drug designation, used as a comparator in the trial.

**Fludarabine phosphate** is also a **concentrate for solution for infusion** administered via **IV infusion**. The maximum treatment period is 3 days. It is a chemically derived substance used as an auxiliary treatment in the study.

**Tacrolimus** is administered in the form of **capsules** via **oral use**. The maximum treatment period for tacrolimus is 104 weeks. It is a chemically derived substance used as a comparator in the trial.

**Tocilizumab** is provided as a **concentrate for solution for infusion** and is administered through **IV infusion**. The maximum daily dose is 2400 mg, with a total maximum dose of 3200 mg over a treatment period of 2 days. It is used as an auxiliary treatment in the study.

All medications are subject to relabeling as part of the trial protocol, and participant compliance is monitored through standard clinical trial procedures. The trial aims to evaluate the efficacy and safety of rapcabtagene autoleucel compared to these comparator treatments in participants with severe refractory idiopathic inflammatory myopathies.

The efficacy of the investigational product, **rapcabtagene autoleucel**, will be assessed in a Phase 2 clinical trial involving participants with severe refractory idiopathic inflammatory myopathies. The primary endpoint for evaluating efficacy is achieving at least a moderate improvement in the Total Improvement Score (TIS) at Week 52, with a TIS of 40 or greater being considered a moderate improvement. This will be measured as a binary outcome (Yes/No) at the specified timepoint.

Secondary endpoints include several additional measures of efficacy: achieving a major improvement in TIS (≥ 60) at Week 52, changes from baseline in percent predicted Forced Vital Capacity (FVC%) at Week 52, and changes from baseline in the Patient-Reported Outcome Measurement Information System (PROMIS)-Fatigue 7a at Week 52. Additionally, the adjusted annual cumulative glucocorticoid (GC) dose up to Week 52 will be evaluated. These endpoints will provide a comprehensive assessment of the treatment's impact on disease symptoms and patient-reported outcomes.

Data collection will occur at baseline and at Week 52, with the use of validated scales and laboratory tests to ensure accuracy and reliability. The analysis will focus on comparing the efficacy of rapcabtagene autoleucel against the comparator, which is the investigator's choice of treatment, in achieving the defined improvements in TIS and other secondary endpoints. Safety parameters, including vital signs, adverse events, laboratory parameters, and ECG evaluations, will also be monitored throughout the trial to ensure participant safety.